Instructions Omeprotect powder for solution for injection 40 mg bottle complete with 1 ampoule with solvent No. 1
Composition
active ingredient: omeprazole;
1 vial contains omeprazole sodium equivalent to omeprazole 40 mg;
excipient: sodium hydroxide.
1 ampoule with solvent contains macrogol 400; citric acid monohydrate; water for injections.
Dosage form
Powder for solution for injection.
Main physicochemical properties: white or almost white mass in a colorless bottle.
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 highly targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically affecting 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 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 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 hydrochloric acid in gastric juice, 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 stomach cancer.
Eradication of H. Pylori with omeprazole and antimicrobial drugs is associated with high rates 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 screening for neuroendocrine tumors. It has been reported that proton pump inhibitor treatment 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 gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased 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 metabolized by the cytochrome P450 (CYP) system. The main part of its metabolism depends on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in blood plasma. The rest 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 have an inhibitory effect on the main 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 usually 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 of the drug. This increase is dose-dependent and provides a non-linear relationship between AUC and dose after repeated administration of the drug. 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 liver dysfunction
The metabolism of omeprazole is slowed in patients with impaired liver function, leading to an increase in AUC. No tendency for drug accumulation was observed with once-daily administration of omeprazole.
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
Intravenous omeprazole is indicated as an alternative to oral therapy in the following indications.
Adults
- Treatment of duodenal ulcers.
- Prevention of duodenal ulcer recurrence.
- Treatment of stomach ulcers.
- Prevention of recurrence of stomach ulcers.
- In combination with appropriate antibiotics for the eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease.
- Treatment of gastric and duodenal ulcers associated with the use of nonsteroidal 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.
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
Inhibition of gastric secretion by omeprazole and other PPIs may either reduce or increase the absorption of drugs whose absorption is dependent 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 by omeprazole. Concomitant administration of omeprazole (20 mg daily) and digoxin has been reported to increase the bioavailability of digoxin by 10%.
Nelfinavir, atazanavir
Plasma levels of nelfinavir and atazanavir are decreased when co-administered with omeprazole.
Co-administration of omeprazole (40 mg once daily) reduces the mean exposure of nelfinavir by approximately 40%, and the mean exposure of the pharmacologically active metabolite M8 is reduced 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 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 coadministered, 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 coadministered. 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 have been reported regarding the clinical manifestations of this PK/PD interaction in terms of major cardiovascular diseases.
Other medicines
The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced, 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. a dose 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 maximal inhibitory effect on (ADP-induced) platelet aggregation. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.
However, it remains unclear to what extent this interaction may be of clinical significance. There is no evidence of an increased risk of pathological cardiovascular disease with the concomitant use of clopidogrel and PPIs.
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.
It has been reported that when clopidogrel was used in combination with acetylsalicylic acid and esomeprazole, compared with clopidogrel alone, there was a decrease in exposure to the active metabolite of clopidogrel by almost 40%. 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 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 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) 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 metabolised by CYP2C19 and CYP3A4, medicinal products known to inhibit CYP2C19 or CYP3A4, or both (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 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 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) and in the presence or suspicion of gastric ulcer, malignancy should be ruled out, as treatment may alleviate 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 may lead to a slightly increased 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 disappear and the condition normalizes after the use of magnesium drugs and the withdrawal of 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), may slightly increase the risk of fractures of the spine, wrist, and hip, especially in the elderly and in the presence of predisposing factors. Observational studies have suggested that PPIs may increase the overall risk of fractures by 10–40%. This increased risk 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 development of PsA. 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 PsA that developed after the use of the drug may increase the risk of PsA with the use of other PPIs.
Impact on laboratory test results
Patients who use the drug for a long period (especially when the treatment period lasts more than 1 year) should be under regular medical supervision.
Omeprazole can cause serious skin reactions. Symptoms may include: skin redness; blisters; rash.
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding.
Studies have been reported that indicate no adverse effects of omeprazole on pregnancy or on the health of the fetus/newborn child. Omeprazole 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.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Omeprazole 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 Omeprotect 40 mg 1 time per day intravenously. For patients with Zollinger-Ellison syndrome, the recommended initial dose of the drug is 60 mg per day, which should be administered intravenously. 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 taken 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 Omeprotect solution should not be stored in the refrigerator. Any unused solution should be discarded.
Instructions for reconstitution of the medicinal product before administration
For intravenous injections, the contents of each vial of Omeprotect containing 40 mg of omeprazole should be dissolved in 10 ml of sterile water for injection. The product in the form of an intravenous injection should be administered slowly (over 5 minutes).
For intravenous infusions, the contents of each vial of Omeprotect 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.
Administer the drug as an intravenous infusion over 20–30 minutes.
The solution should be used immediately after preparation, but no later than 4 hours. The diluted Omeprotect 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 the drug for intravenous administration in pediatric practice is limited, therefore the drug should not be prescribed to this category of patients.
Overdose
There is limited information on the effects of omeprazole overdose in humans. 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 rate of drug elimination did not change (first-order kinetics) with increasing drug doses.
If necessary, symptomatic treatment should be carried out.
In clinical studies, the drug was administered intravenously in doses of up to 270 mg for one day and up to 650 mg for 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.
From the blood and lymphatic system: rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia.
Immune system disorders: Rare: hypersensitivity reactions, such as fever, angioedema and anaphylactic reactions/shock.
Metabolism and nutrition disorders: rarely - hyponatremia; very rarely - hypomagnesemia, severe hypomagnesemia, which can lead to hypocalcemia; hypomagnesemia can also cause hypokalemia.
On the part of the psyche: infrequently - insomnia; rarely - agitation, confusion, depression; very rarely - aggression, hallucinations.
From the nervous system: often - headache; infrequently - dizziness, paresthesia, drowsiness; rarely - taste disturbance.
On the part of the organs of vision: rarely - blurred vision.
From the organs of hearing and balance: infrequently - vertigo.
Respiratory, thoracic and mediastinal disorders: rarely - 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: infrequently - increased liver enzymes; rarely - hepatitis with or without jaundice; very rarely - hepatic failure, encephalopathy in patients with 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, connective tissue and bone disorders: uncommon - fractures of the hip, wrist or spine; rare - arthralgia, myalgia; very rare - muscular weakness.
Renal and urinary disorders: not known - tubulointerstitial nephritis (with possible progression to renal failure).
From the reproductive system and mammary glands: very rarely - gynecomastia.
Disorders and reactions at the site of administration of the drug: infrequently - malaise, peripheral edema; rarely - 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.
Kidney dysfunction
Acute tubulointerstitial nephritis (TIN) has been reported in patients taking omeprazole and may occur at any time during omeprazole therapy. Acute tubulointerstitial nephritis may progress to renal failure. If TIN is suspected, omeprazole should be discontinued and appropriate treatment should be initiated immediately.
Reporting of suspected adverse reactions.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Store the reconstituted solution in the refrigerator for no more than 12 hours.
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 vial of powder complete with 1 ampoule of solvent in a pack.
Vacation category
According to the recipe.
Producer
ANPHARM HELLAS S.A.
Location of the manufacturer and address of its place of business.
61st km of the Athens-Lamia National Road, Schematari Viotia 32009, Greece.
