Instructions Omeprazole Astra powder for solution for injection 40 mg vial No. 1
Composition
active ingredient: omeprazole;
1 vial contains omeprazole sodium equivalent to omeprazole 40 mg;
excipients: mannitol, disodium edetate, meglumine, sodium bisulfite, sodium hydroxide.
Dosage form
Powder for solution for injection.
Main physicochemical properties: white or almost white free-flowing mass or powder.
Pharmacotherapeutic group
Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02B C01.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion by a specifically targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically acting on the proton pump in the parietal cells. The drug, when administered once daily, acts rapidly and provides control by reversible inhibition of gastric acid secretion.
Omeprazole is a weak base that accumulates and is converted to its 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.
Pharmacodynamic effects
All pharmacodynamic effects can be explained by the effect of omeprazole on hydrochloric acid secretion.
Effect on gastric acid secretion
Intravenous administration of omeprazole causes a dose-dependent inhibition of gastric acid secretion in humans. In order to immediately reduce intragastric acidity similar to that achieved with repeated oral doses of 20 mg, a first intravenous dose of 40 mg is recommended. This causes an immediate reduction in intragastric acidity, with an average reduction of 90% maintained for 24 hours after both intravenous injection and intravenous infusion.
Inhibition of hydrochloric acid secretion is associated with the area under the plasma 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 also 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 results in a high rate of healing and long-term remission of peptic ulcer disease.
Other effects associated with inhibition of gastric acid secretion
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 evaluation for neuroendocrine tumors. It has been reported that proton pump inhibitor therapy should be discontinued 5–14 days before CgA measurement. Measurements should be repeated if levels have not returned to normal by this time.
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.
A slightly increased incidence of gastric glandular cysts 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 normally present in the stomach. Treatment with acid-reducing drugs slightly increases the risk of developing gastrointestinal infections caused by Salmonella and Campylobacter.
Pharmacokinetics.
Distribution
The estimated volume of distribution is approximately 0.3 l/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.
Omeprazole is completely metabolised by the cytochrome P450 (CYP) system. Its metabolism is mainly dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remainder depends on another specific isoform (CYP3A4), responsible for the formation of omeprazole sulfone. Due to the high affinity of omeprazole for CYP2C19, there is a possibility of competitive inhibition and metabolic drug-drug interactions with other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole has no ability to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole does not inhibit the major CYP enzymes.
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 probably catalyzed mainly by the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 20 mg once daily, the mean area under the AUC in “poor metabolizers” was 5-10 times higher than in individuals with a functional CYP2C19 enzyme (in “extensive metabolizers”). The mean maximum plasma concentration was also 3-5 times higher. However, these findings do not affect the dosage of omeprazole.
Breeding
Total plasma clearance is approximately 30–40 l/h after a single dose. The plasma elimination half-life of omeprazole is generally less than one hour after both single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma between doses without a tendency for accumulation with once-daily dosing. Almost 80% of the omeprazole dose is excreted as metabolites in the urine, the remainder in the faeces, mainly via biliary secretion.
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 is probably due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulfone). None of the metabolites were found to affect gastric acid secretion.
Special patient groups
Patients with hepatic impairment: The metabolism of omeprazole is reduced in patients with hepatic impairment, resulting in an increase in AUC. No tendency for accumulation of the drug was observed when omeprazole was administered once daily.
Patients with renal impairment: The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with reduced renal function.
Elderly patients: The metabolic rate of omeprazole is slightly reduced in elderly patients (75-79 years).
Indication
Omeprazole Astra for intravenous use is indicated in adults as an alternative to oral therapy:
for the treatment of duodenal ulcers;
for the prevention of recurrence of duodenal ulcers;
for the treatment of stomach ulcers;
for the prevention of recurrence of stomach ulcers;
in combination with appropriate antibiotics for the eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease;
for the treatment of gastric and duodenal ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs);
for the prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk;
for the treatment of reflux esophagitis;
for long-term treatment of patients with inactive reflux esophagitis;
for the treatment of symptomatic gastroesophageal reflux disease;
for the treatment of Zollinger-Ellison syndrome.
Contraindication
Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients.
Omeprazole, like other proton pump inhibitors (PPIs), should not be used concomitantly with nelfinavir and atazanavir (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Effect of omeprazole on the pharmacokinetics of other drugs
Drugs whose absorption depends on gastric pH
The inhibition of gastric secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption depends on gastric pH. The absorption of drugs such as ketoconazole, itraconazole, erlotinib may be reduced, and the absorption of drugs such as digoxin may be increased during treatment with omeprazole. It has been reported that concomitant use of omeprazole (20 mg daily) and digoxin increased the bioavailability of digoxin by 10%.
Nelfinavir, atazanavir
Plasma levels of nelfinavir and atazanavir are decreased when co-administered with omeprazole.
The simultaneous use of omeprazole and nelfinavir is contraindicated.
Concomitant use of omeprazole with atazanavir is contraindicated.
Co-administration of omeprazole (40 mg once daily) and atazanavir 300 mg or ritonavir 100 mg 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 or ritonavir 100 mg resulted in an approximately 30% decrease in atazanavir exposure compared to atazanavir 300 mg or ritonavir 100 mg once daily.
Digoxin
Concomitant treatment with omeprazole (20 mg daily) and digoxin increases the bioavailability of digoxin by 10%. Rare cases of digoxin-induced toxicity have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.
Clopidogrel
When clopidogrel and omeprazole were co-administered, the exposure of the active metabolite of clopidogrel was reduced from 46% to 42% from day 1 to day 5. The mean inhibition of platelet aggregation was reduced from 47% to 30% from day 1 to day 5 when clopidogrel and omeprazole were co-administered. Taking clopidogrel and omeprazole at different times did not prevent their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. The data on the clinical manifestations of this pharmacokinetic/pharmacodynamic interaction in major cardiovascular diseases are conflicting.
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 include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.
Studies in healthy volunteers have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and omeprazole (80 mg orally daily, i.e. 4 times the standard daily dose), resulting in a mean 46% reduction in exposure to the active metabolite of clopidogrel and a mean 16% reduction in the maximum inhibitory effect of [adenosine diphosphate (ADP)-induced] platelet aggregation. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.
However, the clinical significance of this interaction remains unclear. There is no evidence of an increased risk of cardiovascular events with the concomitant use of clopidogrel and PPIs, including esomeprazole.
A number of observational studies have shown conflicting results regarding whether the risk of cardiovascular thromboembolic events is increased if a patient receives clopidogrel together with a PPI.
When clopidogrel was used in combination with acetylsalicylic acid and esomeprazole, compared with clopidogrel monotherapy, a decrease in exposure to the active metabolite of clopidogrel by almost 40% was noted. However, the maximum inhibitory activity against (ATP-induced) platelet aggregation in these subjects was the same in the groups taking clopidogrel alone and in combination with acetylsalicylic acid and esomeprazole, which is probably explained by the simultaneous administration of a low dose of acetylsalicylic acid.
Cilostazol
When omeprazole is administered at a dose of 40 mg, the Cmax and AUC of cilostazol increase by 18% and 26%, respectively, and that 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 starting omeprazole treatment; and if the phenytoin dose has been adjusted, monitoring and further dose adjustment should be performed after omeprazole treatment has been discontinued.
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) is required, and if necessary, tacrolimus dosage adjustment.
Methotrexate
Increased methotrexate levels have been reported in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are necessary, temporary withdrawal of omeprazole should be considered.
Effect of other drugs on the pharmacokinetics of omeprazole
Since omeprazole is metabolized by CYP2C19 and CYP3A4, drugs that inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may increase omeprazole serum levels by decreasing its metabolic rate. 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 necessary. However, dose adjustment should be considered in patients with severe hepatic impairment and in the case of long-term treatment.
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 that induce CYP2C19 or CYP3A4 activity (such as rifampicin and St. John's wort) may cause a decrease in serum levels of omeprazole as a result of increased metabolism.
Application features
In the presence of any alarming symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena), as well as in the presence of gastric ulcer or suspicion of gastric ulcer, malignancy should be excluded, as treatment may reduce the severity of symptoms and delay diagnosis.
Concomitant use of omeprazole with atazanavir is contraindicated.
Concomitant use of atazanavir with proton pump inhibitors is not recommended. 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 discontinuing 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 slightly increases the risk of developing gastrointestinal infections such as Salmonella and Campylobacter.
Severe hypomagnesemia has been reported in patients taking PPIs, including omeprazole, for at least 3 months (in most cases of hypomagnesemia, patients had been taking the drug for about 1 year). Hypomagnesemia can manifest as serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia can also be asymptomatic and may not be diagnosed in time. In most patients, the symptoms of hypomagnesemia resolve and the condition normalizes after taking magnesium supplements and discontinuing the PPI.
In patients who are planning to use PPIs for a long time or who are taking digoxin or other drugs that can cause magnesium depletion (e.g. diuretics), serum magnesium levels should be measured before starting PPI therapy and periodically during treatment.
PPIs, especially when used at high doses and over long periods (>1 year), slightly increase the risk of fractures of the spine, wrist, and hip, especially in the elderly and in the presence of risk factors. Observational studies have suggested that PPIs may increase the overall risk of fractures by 10–40%. This may be partly due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and take vitamin D and calcium at the recommended doses.
Subacute cutaneous lupus erythematosus (SCL)
The use of PPIs can sometimes cause the appearance of PSCV. If skin manifestations occur, especially in areas exposed to sunlight and accompanied by arthralgia, you should immediately consult a doctor and consider stopping omeprazole. The presence of a history of PSCV that developed after the use of the drug increases the risk of PSCV with the use of other PPIs.
Impact on laboratory test results
Elevated CgA levels may interfere with the results of neuroendocrine tumor tests. To prevent this interference, omeprazole should be temporarily discontinued 5 days prior to CgA testing. If CgA and gastrin levels have not returned to the normal range after initial measurements, these measurements should be repeated 14 days after discontinuation of the drug.
Patients taking omeprazole for a long period (especially when the treatment period lasts more than 1 year) should be under regular medical supervision.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Studies indicate no adverse effects of omeprazole on pregnancy or the health of the fetus/newborn child. Omeprazole Astra can be used during pregnancy.
Omeprazole passes into breast milk, but the risk of exposure to the child is unlikely if the mother uses the drug in therapeutic doses.
Ability to influence reaction speed when driving vehicles or other mechanisms
Omeprazole Astra is unlikely to affect the ability to drive or use machines. Undesirable effects such as dizziness and visual disturbances may occur. If such disorders occur, patients should not drive or use machines.
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 Omeprazole Astra 40 mg 1 time per day intravenously. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose of the drug is 60 mg per day. Higher daily doses may be required, so the dose should be selected individually. If the dose exceeds 60 mg per day, it should be divided equally into 2 parts and administered 2 times a day.
The drug should only be used intravenously and should not be administered by any other route.
The solution should be used immediately after preparation, but no later than 4 hours later. The diluted solution of Omeprazole Astra should not be stored in the refrigerator. Any unused solution should be discarded.
Reconstitution of the drug before administration
For intravenous injections, the contents of each vial of Omeprazole Astra containing 40 mg of omeprazole should be dissolved in 10 ml of sterile water for injection. The intravenous injection should be administered slowly (over 5 minutes).
For intravenous infusions, the contents of each vial of Omeprazole Astra containing 40 mg of omeprazole should be reconstituted in 10 ml and made up to 100 ml with 0.9% sodium chloride solution or 5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution, therefore other solvents or their amounts should not be used for dilution.
The drug should be administered as an intravenous infusion over 20–30 minutes.
The solution should be used immediately after preparation, but no later than 4 hours. The diluted omeprazole solution should not be stored in the refrigerator.
Any unused product or waste material should be disposed of in accordance with local requirements.
Special categories of patients
Kidney dysfunction
Dose adjustment is not required in 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 intravenous administration in pediatric practice is limited, therefore the drug should not be prescribed to this category of patients.
Overdose
Information on the effects of omeprazole overdose in humans is limited. Cases of use of the drug in doses up to 560 mg have been described; there have also been isolated reports of single oral doses of omeprazole reaching 2400 mg (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhea and headache have been reported. Apathy, depression and confusion have also been reported in isolated cases.
The symptoms described were transient, no serious effects were reported. The elimination rate did not change (first-order kinetics) with increasing doses of the drug.
If necessary, symptomatic treatment should be carried out.
In clinical studies, the drug was administered intravenously in doses of up to 270 mg in one day and up to 650 mg in three days, which did not lead to any dose-related adverse reactions.
Side effects
The most common adverse reactions (1–10% of patients) are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.
The following adverse drug reactions have been identified during clinical trials with omeprazole and in the post-marketing period. None of the events were considered dose-related. The adverse reactions listed below are classified by frequency and system organ class. The frequency is defined according to the following categories: 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), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Rare: leukopenia, thrombocytopenia; very rare: agranulocytosis, pancytopenia.
Immune system disorders: Rare: hypersensitivity reactions, such as fever, angioedema and anaphylactic reactions/shock.
On the part of the psyche: infrequently: insomnia; rarely: agitation, confusion, depression; very rarely: aggression, hallucinations.
Nervous system disorders: common: headache; uncommon: dizziness, paresthesia, drowsiness; rare: taste disturbance.
On the part of the organs of vision: rarely: blurred vision.
Hearing and balance disorders: uncommon: vertigo.
Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm.
On the part of the digestive tract: often: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign); rarely: dry mouth, stomatitis, gastrointestinal candidiasis, 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.
Skin and subcutaneous tissue disorders: uncommon: dermatitis, pruritus, rash, urticaria; rare: alopecia, photosensitivity; very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN); frequency unknown: subacute cutaneous lupus erythematosus.
Musculoskeletal system: uncommon: fractures of the hip, wrist or spine; rare: arthralgia, myalgia; very rare: muscular weakness.
Renal and urinary disorders: Rare: interstitial nephritis.
Reproductive system and breast disorders: very rare: gynecomastia.
Administration site conditions and reactions: uncommon: malaise, peripheral edema; rare: increased sweating.
In isolated cases, irreversible visual impairment has been reported in critically ill patients who received omeprazole as an intravenous injection, especially in high doses, but a causal relationship has not been established.
Expiration date
2 years (from the date of manufacture of the bulk form).
Storage conditions
Store in the original packaging out of the reach of children at a temperature not exceeding 25 ºС.
Shelf life of the reconstituted solution: up to 4 hours at a temperature not exceeding 25 °C.
Shelf life of the powder after opening: up to 24 hours.
From a microbiological point of view, the product should be used immediately, unless reconstitution has taken place in controlled and aseptic conditions, confirmed by validated methods.
Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in the section “Method of administration and dosage”.
Packaging
1 or 10 vials in a cardboard box.
Vacation category
According to the recipe.
Producer
ASTRAPHARM LLC (packaging from the form in bulk: Shandong Yuxin Pharmaceutical Co., Ltd., People's Republic of China).
Location of the manufacturer and its business address.
Ukraine, 08132, Kyiv region, Kyiv-Svyatoshynskyi district, Vyshneve, Kyivska st., 6.
