Instructions for use Omeprazole-Darnitsa powder for solution for infusion 40 mg bottle No. 1
Composition
active ingredient: omeprazole;
1 bottle contains omeprazole sodium 42.6 mg, equivalent to omeprazole 40 mg;
excipients: disodium edetate, sodium hydroxide.
Dosage form
Powder for solution for infusion.
Main physicochemical properties: white or almost white, porous homogeneous lyophilized 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 is a racemic mixture of two enantiomers that reduces gastric acid secretion through a targeted mechanism of action. It is a specific inhibitor of the gastric proton pump (PPI) in parietal cells. It is rapidly acting and causes controlled reversible inhibition of gastric acid secretion when administered once daily.
Omeprazole is a weak base that is concentrated and converted to the active form in the acidic environment of the intracellular tubules in parietal cells, where it inhibits the enzyme H+/K+-ATPase - the acid pump. This effect on the final stage of the process of gastric acid formation is dose-dependent and provides highly effective inhibition of both basal and stimulated acid secretion, regardless of the nature of the stimulus.
Pharmacodynamic effects
All observed pharmacodynamic effects can be explained by the effect of omeprazole on acid secretion.
Effect on gastric acid secretion
Intravenous administration of omeprazole causes a dose-dependent inhibition of gastric acid secretion in humans. In order to immediately achieve a similar reduction in intragastric acidity as after repeated oral administration of 20 mg, a first dose of 40 mg intravenously is recommended. This results in an immediate reduction in intragastric acidity and an average reduction within 24 hours of approximately 90% after both intravenous injection and intravenous infusion.
The inhibition of acid secretion correlates with the area under the plasma concentration-time curve (AUC) of omeprazole, not with the actual plasma concentration at that time.
No tachyphylaxis was observed during treatment with omeprazole.
Effect on Helicobacter pylori (H. pylori)
Peptic ulcer disease, including duodenal ulcer and gastric ulcer, is associated with H. pylori and is considered a major factor in the development of gastritis and, together with gastric acid, is a crucial factor in the development of peptic ulcer disease. H. pylori is also a major factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.
Eradication of H. Pylori with omeprazole and antimicrobial drugs is associated with high cure rates and long-term remission of peptic ulcers.
Other effects related to acid suppression
A slightly increased incidence of gastric glandular cysts has been reported during long-term treatment. These changes are a physiological consequence of acid suppression, and the cysts are benign and reversible.
Reduced stomach acidity, caused by any agent, including PPIs, increases the number of bacteria normally found in the gastrointestinal tract in the stomach. Treatment with acid-reducing agents slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter.
During treatment with antisecretory drugs, plasma gastrin concentration increases as a result of decreased hydrochloric acid secretion. Decreased hydrochloric acid secretion results in increased chromogranin A (CgA) levels. Increased CgA levels may interfere with the results of neuroendocrine tumor screening tests. Available published data suggest that PPIs should be discontinued 5 to 14 days before scheduled CgA measurements. This allows CgA levels, which may be falsely elevated after PPI administration, to normalize to reference values.
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.
Pharmacokinetics.
Distribution
The apparent volume of distribution in healthy volunteers is approximately 0.3 l/kg body weight. Omeprazole is 97% bound to plasma proteins.
Metabolism
Approximately 3% of Caucasians and 15–20% of Asians lack a functional CYP2C19 enzyme and are therefore referred to as “poor metabolizers”. In these individuals, omeprazole metabolism is likely to be catalyzed primarily by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the AUC in “poor metabolizers” was 5–10 times higher than in patients with a functional CYP2C19 enzyme (“extensive metabolizers”). The mean peak plasma concentrations were also 3–5 times higher. However, these findings have no impact on the dosage of omeprazole.
Breeding
Total plasma clearance is approximately 30-40 l/h after a single dose. The plasma half-life of omeprazole is usually less than 1 hour after both single and repeated once-daily dosing. Omeprazole is completely eliminated from plasma in the dose interval without any tendency for accumulation with once-daily dosing. Almost 80% of the omeprazole dose is excreted as metabolites in the urine, the remainder in the feces via biliary secretion.
Linearity/nonlinearity
The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear relationship between AUC and dose after repeated administration. This time- and dose-dependence is due to reduced first-pass metabolism and systemic clearance, probably due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulfone).
No effect of omeprazole metabolites on gastric acid secretion was found.
Special patient groups
Liver dysfunction
The metabolism of omeprazole is impaired in patients with hepatic impairment, leading to an increase in AUC. Omeprazole did not show a tendency for accumulation when administered once daily.
Kidney dysfunction
The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with renal impairment.
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 cases.
Adults:
- 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 H. Pylori in peptic ulcer disease;
- for the treatment of gastric and duodenal ulcers associated with the use of non-steroidal 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 the active substance, substituted benzimidazoles or to any of the excipients of the medicinal product.
Omeprazole, like other PPIs, should not be used concomitantly with nelfinavir.
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
Suppression of gastric secretion during treatment with omeprazole may reduce or increase the absorption of drugs whose absorption depends on gastric pH.
Nelfinavir, atazanavir
Plasma levels of nelfinavir and atazanavir are decreased when co-administered with omeprazole.
Concomitant use of omeprazole and nelfinavir is contraindicated, as omeprazole (40 mg once daily) reduced the mean exposure of nelfinavir by approximately 40% and the mean exposure of the pharmacologically active metabolite M8 by 75–90%. The interaction may also be due to inhibition of CYP2C19 activity.
Concomitant use of omeprazole with atazanavir is not recommended. Co-administration of omeprazole (40 mg once daily) 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. Concomitant use 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 once daily.
Digoxin
Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased 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 monitoring of digoxin should be intensified.
In healthy volunteers, a pharmacokinetic (PK)/pharmacodynamic (PD) interaction was observed between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg daily orally), resulting in a mean 46% decrease in exposure to the active metabolite of clopidogrel and a mean 16% decrease in maximal inhibitory effect on (ADP-induced) platelet aggregation.
The results of observational and clinical studies on the clinical manifestations of this PK/PD interaction in relation to major cardiovascular diseases have been inconsistent. The 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 has a moderate inhibitory effect on CYP2C19 (the main enzyme responsible for the metabolism of 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.
Cilostazol
In healthy volunteers, the use of omeprazole at a dose of 40 mg increased the maximum plasma concentration (Cmax) 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 two weeks after initiation of omeprazole treatment. If phenytoin dose adjustment has been made, monitoring and further dose adjustment should be carried out after discontinuation 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 the tacrolimus dose should be adjusted if necessary.
Methotrexate
Increased methotrexate levels have been reported in some patients when co-administered with PPIs. If high doses of methotrexate are required, temporary withdrawal of omeprazole should be considered.
Effect of other drugs on the pharmacokinetics of omeprazole
CYP2C19 and/or CYP3A4 inhibitors
Since omeprazole is metabolised by CYP2C19 and CYP3A4, medicinal products that inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may increase omeprazole serum levels by slowing its metabolism. 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 not usually necessary. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases of long-term treatment.
CYP2C19 and/or CYP3A4 inducers
Medicinal products that induce CYP2C19 and/or CYP3A4 activity (such as rifampicin and St. John's wort) may lead to a decrease in serum levels of omeprazole as a result of an increase in its metabolic rate.
Application features
In the presence of any alarming symptom (e.g. significant weight loss not due to diet; frequent vomiting; dysphagia; vomiting with blood or melena) and in the presence of diagnosed or suspected gastric ulcer, malignant disease should be excluded, since taking the drug may mask its symptoms and delay the establishment of the correct diagnosis.
Concomitant use of atazanavir with PPIs is not recommended. If the combination of atazanavir with omeprazole 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 during long-term therapy in patients with low body weight 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.
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 be manifested by serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, ventricular arrhythmia. Hypomagnesemia can also be asymptomatic and may not be diagnosed in time. In most patients, the manifestations of hypomagnesemia disappear and the condition normalizes after the use of magnesium drugs and discontinuation 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 for 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 suggest that PPIs 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 take vitamin D and calcium.
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. A history of PsA that developed after the use of the drug increases the risk of PsA with the use of other PPIs.
Impact on laboratory test results
Elevated CgA levels may interfere with the results of tests for neuroendocrine tumors. To avoid this interference, omeprazole should be temporarily discontinued 5 days prior to the CgA test.
Patients who use the drug for a long period (especially when treatment lasts more than 1 year) should be under regular medical supervision.
Important information about excipients.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy
Results from prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn. Omeprazole can be used during pregnancy.
Breast-feeding
Omeprazole passes into breast milk, but the likelihood of affecting the child is low when used in therapeutic doses.
Fertility
Animal studies of the racemic mixture of omeprazole indicate no effect of omeprazole on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
It is unlikely that Omeprazole-Darnitsa will affect the ability to drive or use machines. Undesirable effects such as dizziness and visual disturbances may occur. If such disorders are observed, patients should not drive or use machines.
Method of administration and doses
Adults
Alternative to oral therapy
For patients for whom oral administration is unacceptable, omeprazole 40 mg once daily intravenously is recommended. For patients with Zollinger-Ellison syndrome, the recommended initial dose of the drug administered intravenously 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 into two equal doses and administered 2 times a day.
The drug should only be administered by intravenous infusion over 20–30 minutes—it should not be administered by any other route.
Reconstitution of the drug before administration
For intravenous infusions, the contents of each vial of omeprazole containing 40 mg of omeprazole should be dissolved in approximately 5 ml and then immediately diluted to 100 ml. Sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%) solution for infusion should be used. The stability of omeprazole depends on the pH of the infusion solution, therefore other solvents or other volumes should not be used for dilution.
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.
Experience with the use of the drug for intravenous administration in pediatric practice is limited, therefore Omeprazole-Darnitsa should not be prescribed to this category of patients.
Overdose
Data on the effects of omeprazole overdose in humans are limited. Cases of omeprazole overdose up to 560 mg have been described in the scientific literature, and there have been isolated reports of single oral doses of omeprazole up to 2400 mg (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Apathy, depression and confusion have also been reported in isolated cases. However, all of these symptoms were transient and no serious consequences have been reported. The rate of drug elimination did not change (first-order kinetics) with increasing dose. Symptomatic treatment should be given if necessary.
In clinical studies, intravenous administration of the drug was used 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-dependent adverse reactions.
Adverse reactions
The most common side effects (in 1–10% of patients) are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.
The following adverse drug reactions have been identified (or suspected) during clinical trials with omeprazole or during post-marketing use. They were not found to be dose-related. All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 - uncommon (≥ 1/1,000 - cannot be estimated from the available data).
On the part of the organs of vision: rarely - blurred vision.
From the side of the organs of hearing and vestibular apparatus: infrequently - vertigo.
Respiratory, thoracic and mediastinal disorders: rarely - bronchospasm.
Gastrointestinal: often - abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting; rarely - dry mouth, stomatitis, gastrointestinal candidiasis; frequency unknown - microscopic colitis.
Hepatobiliary disorders: infrequently - increased liver enzymes; rarely - hepatitis with or without jaundice; rare - hepatic failure, encephalopathy in patients with pre-existing liver disease.
Renal and urinary disorders: rarely - interstitial nephritis.
Metabolism and metabolism: rarely - hyponatremia; frequency unknown - hypomagnesemia, severe hypomagnesemia can lead to hypocalcemia. Hypomagnesemia, which can cause hypokalemia.
From the nervous system: often - headache; infrequently - dizziness, paresthesia, drowsiness; rarely - taste disturbance.
On the part of the psyche: infrequently - insomnia; rarely - agitation, confusion, depression; rare - aggression, hallucinations.
From the blood and lymphatic system: rarely - leukopenia, thrombocytopenia; rare - agranulocytosis, pancytopenia.
Immune system disorders: Rare: hypersensitivity reactions, including fever, angioedema and anaphylactic reactions/shock.
Skin and subcutaneous tissue disorders: infrequently - dermatitis, itching, rash, urticaria; rarely - alopecia, photosensitivity; rare - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown - subacute cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders: uncommon - fractures of the hip, wrist or spine; rare - arthralgia, myalgia; rare - muscular weakness.
From the reproductive system and mammary gland function: rare - gynecomastia.
General disorders and administration site conditions: uncommon - malaise, peripheral edema; rare - 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 the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua/.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Incompatibility
(if available).
Do not mix with other solvents except those specified in the "Method of administration and dosage" section.
Packaging
1 bottle per pack.
Vacation category
According to the recipe.
Producer
LABORATORIOS NORMON S. AND. / LABORATORIOS NORMON, SA
Location of the manufacturer and address of its place of business.
Ronda de Valdecarizo, 6, Tres Cantos, Madrid, 28760, Spain /
Ronda de Valdecarrizo, 6, Tres Cantos, Madrid, 28760, Spain.
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the applicant.
Ukraine, 02093, Kyiv, Boryspilska St., 13.
