Instructions for use Omenax powder for solution for injection 40 mg vial No. 1
Composition
active ingredient: omeprazole;
1 bottle contains omeprazole sodium equivalent to omeprazole 40 mg;
excipient: sodium hydroxide.
Dosage form
Powder for injection.
Main physicochemical properties: lyophilized powder from white to almost white.
Pharmacotherapeutic group
Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Omeprazole. ATC code A02B C01.
Pharmacological properties
Pharmacodynamics
Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion by a targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically affecting the proton pump in parietal cells. The drug, when administered once daily, acts rapidly and provides control of reversible inhibition of gastric acid secretion.
Omeprazole is a weak base that accumulates and is converted to the active form in the highly acidic environment of the intracellular tubules of parietal cells, where it inhibits the enzyme H+, K+-ATPase (proton pump). This effect on the final stage of the process of hydrochloric acid formation of gastric juice is dose-dependent and provides highly effective inhibition of both basal and stimulated secretion of hydrochloric acid, regardless of the type of stimulation.
All pharmacodynamic effects can be explained by the effect of omeprazole on hydrochloric acid secretion.
Effect on the secretion of hydrochloric acid in the stomach.
Intravenous administration of omeprazole causes a dose-dependent inhibition of gastric acid secretion in humans. In order to immediately reduce intragastric acidity to the same extent as that achieved by repeated oral doses of 20 mg, a first intravenous dose of 40 mg is recommended. This results in an immediate reduction in intragastric acidity and a subsequent maintenance of this reduction by an average of 90% for 24 hours after both intravenous injection and intravenous infusion.
The inhibition of hydrochloric acid secretion is associated with the area under the concentration-time curve (AUC) of omeprazole and is independent of the actual plasma concentration of omeprazole at a given time.
No signs of tachyphylaxis were observed during treatment with omeprazole.
Effect on H. pylori
H. pylori is associated with the development of peptic ulcers, including duodenal and gastric ulcers. H. pylori is a major factor in the development of gastritis.
H. pylori, together with gastric acid, is a major factor in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis, which is associated with an increased risk of developing gastric cancer.
Eradication of H. pylori with omeprazole and antimicrobials is associated with high healing rates and long-term remission of peptic ulcer disease.
The remaining effects are associated with inhibition of hydrochloric acid secretion in the stomach.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. Chromogranin A (CgA) levels also increase in response to decreased gastric acidity. Elevated CgA levels may interfere with the investigation of neuroendocrine tumors. It has been reported that proton pump inhibitor treatment should be discontinued 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not yet normalized.
An increase in the number of ECL cells, possibly related to an increase in serum gastrin levels, has been observed in both children and adults during long-term treatment with omeprazole. These findings are not considered to be of clinical significance.
An increased incidence of iron cysts in the stomach has been reported during long-term treatment. These changes are a physiological consequence of the marked inhibition of hydrochloric acid secretion; this process is benign and probably reversible.
Reducing stomach acid by any means, including proton pump inhibitors, increases the number of bacteria in the stomach that are normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased risk of developing gastrointestinal infections caused by Salmonella and Campylobacter.
Pharmacokinetics
The estimated volume of distribution in healthy volunteers is about 0.3 l/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.
Approximately 3% of Caucasians and 15-20% of Mongoloids lack a functional CYP2C19 enzyme; they are referred to as poor metabolizers. In these individuals, the metabolism of omeprazole is likely to be catalyzed primarily by the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 20 mg once daily, the mean AUC in poor metabolizers was 5-10 times higher than in subjects with a functional CYP2C19 enzyme (extensive metabolizers). The mean maximum plasma concentrations were also 3-5 times higher. However, these findings do not affect the dosage of omeprazole.
Total plasma clearance is about 30-40 l/h after a single dose. The plasma half-life of omeprazole is usually less than 1 h after both single and repeated once-daily administration. Omeprazole is completely eliminated from plasma between doses without a tendency to accumulate with once-daily administration. Almost 80% of the omeprazole dose is excreted as metabolites in the urine, the remainder in the faeces, mainly via biliary excretion.
The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and provides a non-linear relationship between AUC and dose after repeated administration. This time- and dose-dependent relationship is due to a decrease in first-pass metabolism and systemic clearance, which may be due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., the sulfone). None of the metabolites have been shown to affect gastric acid secretion.
Patients with impaired liver function
The metabolism of omeprazole is slowed in patients with impaired liver function, leading to an increase in AUC. When omeprazole is administered once daily, no tendency for accumulation of the drug was observed.
Patients with renal impairment
The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with reduced renal function.
Elderly patients
The metabolic rate of omeprazole in elderly patients (75-79 years) is slightly reduced.
Indication
Omenax for intravenous use is indicated as an alternative to oral therapy in the following indications.
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 ulcers. treatment of gastric and duodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk. treatment of reflux esophagitis. long-term treatment of patients with inactive reflux esophagitis. treatment of symptomatic gastroesophageal reflux disease. treatment of Zollinger-Ellison syndrome.
Contraindication
Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Concomitant use of omeprazole, as with other proton pump inhibitors (PPIs), with nelfinavir and atazanavir is contraindicated.
Interaction with other medicinal products and other types of interactions
Effect of omeprazole on the pharmacokinetics of other drugs.
Drugs whose absorption depends on the pH of the stomach.
Inhibition of gastric secretion by omeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption depends on gastric pH. As with other drugs that reduce gastric acidity, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced, while the absorption of drugs such as digoxin may be increased during treatment with omeprazole. Concomitant administration of omeprazole (20 mg/day) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (in two out of ten subjects - up to 30%).
elfinavir, atazanavir
Plasma levels of nelfinavir and atazanavir are decreased when co-administered with omeprazole. Concomitant use of omeprazole and nelfinavir is contraindicated.
Co-administration of omeprazole (40 mg once daily) decreased the mean exposure of nelfinavir by approximately 40% and the mean exposure of the 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 contraindicated.
Co-administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a 75% decrease in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers resulted in an approximately 30% decrease in atazanavir exposure compared to atazanavir 300 mg/ritonavir 100 mg daily.
Concomitant treatment with omeprazole (20 mg/day) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10%. Rare cases of toxicity caused by digoxin have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic monitoring of digoxin should be intensified. Patients should be under medical supervision when used concomitantly with digoxin.
Clopidogrel
In studies, clopidogrel (300 mg loading dose followed by 75 mg/day) was administered as monotherapy and with omeprazole (80 mg co-administered with clopidogrel) for 5 days. When clopidogrel and omeprazole were co-administered, the exposure to the active metabolite of clopidogrel was reduced by 46% (day 1) and 42% (day 5). The mean inhibition of platelet aggregation was reduced by 47% (after 24 hours) and 30% (day 5) when clopidogrel and omeprazole were co-administered. In another study, it was shown that taking clopidogrel and omeprazole at different times did not prevent their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Conflicting data on the clinical manifestations of this pharmacokinetic/pharmacodynamic (PK/PD) interaction in terms of major cardiovascular diseases have been reported in studies. Therefore, concomitant use of omeprazole and clopidogrel should be avoided.
Other medicines
The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and therefore clinical efficacy may be reduced. Concomitant use with posaconazole and erlotinib should be avoided.
Medicinal products metabolized by CYP2C19
Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme that metabolizes omeprazole. Therefore, the metabolism of concomitant drugs that are also metabolized by CYP2C19 may be reduced and the systemic exposure of these drugs may be increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
Studies in healthy volunteers have shown a PK/PD interaction between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and omeprazole (80 mg orally daily, i.e. a dose that is 4 times the standard daily dose), resulting in an average 46% decrease in exposure to the active metabolite of clopidogrel and an average 16% decrease in the maximum inhibitory effect on (ADP-induced) platelet aggregation. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided. However, the extent to which this interaction may be clinically relevant remains unclear.
Based on the results of one randomized (but incomplete) study (comparing placebo treatment with omeprazole at a dose of 20 mg in patients treated with clopidogrel and acetylsalicylic acid) and non-randomized post-hoc analyses of data from large randomized clinical outcome trials, an increased risk of pathological cardiovascular outcomes with the simultaneous use of clopidogrel and PPIs, including esomeprazole.
A number of studies have shown conflicting results on whether the risk of cardiovascular thromboembolic events is increased if a patient receives clopidogrel together with a PPI.
In a study in healthy volunteers, in which clopidogrel was co-administered with a combination of acetylsalicylic acid and esomeprazole compared with clopidogrel alone, exposure to the active metabolite of clopidogrel was reduced by almost 40%. However, the maximum inhibitory activity against (ATP-induced) platelet aggregation in these subjects was the same in the groups receiving clopidogrel alone and clopidogrel in combination with acetylsalicylic acid and esomeprazole, which is probably due to the co-administration.
Cilostazol
In a crossover study, administration of omeprazole 40 mg to healthy volunteers increased the maximum concentration and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.
Phenytoin
Monitoring of phenytoin plasma concentrations is recommended during the first 2 weeks after starting omeprazole treatment; and if phenytoin dose adjustment has been made, monitoring and further dose adjustment of the drug should be carried out after the end of omeprazole treatment.
Unknown mechanism
Saquinavir
Concomitant use of omeprazole with saquinavir/ritonavir resulted in an increase in plasma levels of saquinavir of approximately 70%, which was associated with good tolerability in HIV-infected patients.
Tacrolimus
Increased serum tacrolimus levels have been reported with concomitant use of omeprazole. Increased monitoring of tacrolimus concentrations and renal function (creatinine clearance) should be performed and the tacrolimus dosage adjusted if necessary.
Methotrexate
Increased methotrexate levels have been reported in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are required, temporary withdrawal of omeprazole should be considered.
Effect of other drugs on the pharmacokinetics of omeprazole.
Since omeprazole is metabolised by CYP2C19 and CYP3A4, drugs known to inhibit CYP2C19 or CYP3A4, or both (such as clarithromycin and voriconazole) may increase omeprazole levels within 10 minutes. Concomitant use of voriconazole resulted in a more than two-fold increase in omeprazole exposure. Since high doses of omeprazole were well tolerated, dose adjustment of omeprazole is generally not required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Omeprazole is also partially metabolized by CYP3A4, but does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.
CYP2C19 and/or CYP3A4 inducers
Drugs known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased serum levels of omeprazole due to an increase in its metabolic rate.
Application features
In the presence of any alarming symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and in the presence or suspicion of gastric ulcer, malignancy should be ruled out, as treatment may alleviate symptoms and delay diagnosis.
In healthy volunteers, a pharmacokinetic/pharmacodynamic interaction was observed between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and omeprazole (80 mg orally daily, i.e. a dose 4 times the standard daily dose). A decrease in exposure to the active metabolite of clopidogrel by an average of 46% and a decrease in the maximum inhibitory effect on (ADP-induced) platelet aggregation by an average of 16%.
Concomitant use of atazanavir with proton pump inhibitors is contraindicated. If the combination of atazanavir with a proton pump inhibitor cannot be avoided, close clinical monitoring (e.g. viral load) is recommended in conjunction 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, like all drugs that inhibit the secretion of hydrochloric acid in the stomach, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with cachexia or risk factors for reduced absorption of vitamin B12 during long-term therapy.
Omeprazole is an inhibitor of CYP2C19. When initiating or ending treatment with omeprazole, the possibility of interactions with medicinal products metabolised 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.
Treatment with proton pump inhibitors may lead to a slightly increased risk of developing gastrointestinal infections such as Salmonella and Campylobacter.
Use of PPIs, especially at high doses and for long periods (> 1 year), slightly increases the risk of fractures of the hip, wrist and spine, mainly in elderly patients or in the presence of other risk factors. According to studies, PPIs increase the risk of fractures by 10-40%. In some cases, this is associated with the presence of other risk factors in the patient. Patients at risk of osteoporosis should be provided with appropriate treatment and adequate use of vitamin D and calcium.
As with any long-term treatment, especially when the period of treatment with omeprazole exceeds 1 year, patients need medical supervision and regular laboratory determination of serum magnesium and calcium.
Patients taking PPIs, including omeprazole, for at least 3 months may develop significant hypomagnesemia (in most cases of hypomagnesemia, patients had been taking the drug for approximately 1 year).
After drug withdrawal, serum magnesium levels returned to normal. The clinical picture of hypomagnesemia is characterized by: increased neuromuscular excitability, manifested by spasm of the muscles of the hands and feet, motor excitement; tachycardia, cardiac arrhythmia, increased blood pressure; dystrophic disorders in the form of trophic erosions and skin ulcers. The criterion for establishing the diagnosis of hypomagnesemia is a decrease in the concentration of magnesium in the blood serum of less than 1 mEq/l. In addition, cases have been identified when hypomagnesemia led to the development of hypocalcemia, caused by inhibition of parathyroid hormone secretion in conditions of low magnesium content in the body.
During treatment with antisecretory drugs, plasma gastrin concentration increases due to decreased secretion of hydrochloric acid. As a result of decreased secretion of hydrochloric acid, CgA levels increase. Increased CgA levels may interfere with the results of studies for the detection of neuroendocrine tumors. To avoid such interference, PPIs should be discontinued 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference values after initial measurements, measurements should be repeated 14 days after discontinuation of PPI treatment.
Subacute cutaneous lupus erythematosus (SCL)
The use of PPIs may be associated with very rare cases of Psoriatic arthritis. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical advice immediately and the healthcare professional should consider discontinuing omeprazole. A history of Psoriatic arthritis following previous treatment with a PPI increases the risk of Psoriatic arthritis with other PPIs.
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.
Ability to influence reaction speed when driving vehicles or other mechanisms
Omeprazole is unlikely to affect the ability to drive or use machines. Adverse reactions such as dizziness and visual disturbances may occur. If such disturbances occur, patients should not drive or use machines.
Use during pregnancy or breastfeeding
The efficacy and safety of omeprazole have not been established, therefore the drug is not recommended for use during pregnancy.
Omeprazole passes into breast milk, but its effects on the baby are unknown, so it is not recommended to use the drug during breastfeeding.
Method of administration and doses
Dosage
Alternative to oral therapy
For patients for whom the oral form of the drug is unacceptable, it is recommended to use Omenax 40 mg 1 time per day intravenously. For patients with Zollinger-Ellison syndrome, the recommended initial dose of Omenax, which should be administered intravenously, is 60 mg/day. Higher daily doses may be required, so the dose should be selected individually. If the dose exceeds 60 mg/day, it should be divided equally into two parts and taken 2 times a day.
Omenax should be administered intravenously as an infusion over 20-30 minutes.
For intravenous injections, the contents of each vial of Omenax 40 mg are dissolved in 10 ml of sterile water (or 0.9% sodium chloride solution) for injection. The product in the form of an intravenous injection should be administered slowly (over 5 minutes).
Instructions for reconstitution of the drug before administration
The entire contents of each vial should be dissolved in approximately 5 ml and then immediately diluted to 100 ml. 0.9% sodium chloride solution or
5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution, therefore no other solvent or other amount should be used for dilution.
Preparation
Using a syringe, withdraw 5 ml of the infusion solution from the 100 ml bottle or infusion bag. Add this volume to the vial of lyophilized omeprazole, mix thoroughly to ensure that all the drug has dissolved. Withdraw the omeprazole solution back into the syringe. Transfer the solution to the infusion bag or bottle. Repeat steps 1-4 to ensure that the entire volume of omeprazole has been transferred from the vial to the infusion bag or bottle.
An alternative method of preparing an infusion solution in an elastic container.
Attach the double-ended needle adapter to the injection membrane of the infusion bag. Connect the other end of the needle to the vial with lyophilized omeprazole.
Dissolve the omeprazole substance by pumping the infusion solution back and forth between the infusion bag and the vial.
Make sure that all the drug has dissolved.
The resulting solution should be used for intravenous infusion over 20-30 minutes.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Kidney dysfunction
No dose adjustment is required for patients with renal impairment.
Liver dysfunction
For patients with impaired liver function, a daily dose of 10-20 mg may be sufficient.
Elderly patients (>65 years)
Dose adjustment is not required for elderly patients.
Children
Experience with the use of omeprazole for administration in pediatric practice is limited, therefore the drug should not be prescribed to this age group of patients.
Overdose
The symptoms described were transient and no serious consequences were reported. The rate of drug elimination did not change (first-order kinetics) with increasing doses of the drug. Symptomatic treatment should be carried out if necessary.
In clinical studies, doses of up to 270 mg for one day and up to 650 mg for 3 days were administered, which did not result in any dose-related adverse reactions.
Adverse reactions
The most common adverse reactions are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.
The following adverse drug reactions were observed during the studies. None of the events were considered dose-related.
From the blood and lymphatic system: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.
Immune system disorders: Hypersensitivity reactions, including fever, angioedema and anaphylactic reactions/shock.
Metabolism and nutrition: hyponatremia, hypomagnesemia, severe hypomagnesemia may lead to hypocalcemia; hypomagnesemia may also cause hypokalemia;
Psychiatric: insomnia, anxiety, slight disorientation, agitation, confusion, depression, aggression, hallucinations. Nervous system: headache, dizziness, paresthesia, sleep disturbances, feeling of weakness, drowsiness, taste disturbances.
On the part of the organs of vision: blurred vision, visual impairment. On the part of the organs of hearing and balance: vertigo.
Respiratory, thoracic and mediastinal disorders: sudden wheezing or shortness of breath (bronchospasm).
Gastrointestinal: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis, fundic gland polyps (benign). Hepatobiliary: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders: dermatitis, hyperemia, itching, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
Musculoskeletal, connective tissue and bone disorders: arthralgia, myalgia, fracture of the hip, wrist or spine, muscle weakness. Renal and urinary disorders: interstitial nephritis, dark urine. Reproductive system and breast disorders: impotence, gynecomastia. General disorders and administration site conditions: malaise, peripheral oedema, increased sweating.
In isolated cases, irreversible visual impairment has been reported in critically ill patients receiving omeprazole as an intravenous injection, especially at high doses, but a causal relationship has not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after a medicinal product has been authorised is very important. This allows the benefit/risk balance of the product to be continuously monitored. Healthcare professionals are asked to report suspected adverse reactions via the national reporting system.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 ° C in the original packaging. Keep out of the reach of children.
Shelf life of the powder after opening: up to 24 hours at a temperature not exceeding 25 ºС.
Shelf life of the reconstitution solution: up to 4 hours at a temperature not exceeding 25 ºС.
Incompatibility
The drug should not be mixed with other medicinal products, except those mentioned in the "Method of administration and dosage" section.
Packaging
1 bottle of powder in a cardboard box.
Vacation category
According to the recipe.
Producer
DEMO S.A. Pharmaceutical Industry.
Location of the manufacturer and its business address
21st kilometer of the Athens - Lamia national highway, Krioneri Attica, 14568, Greece.
