Omez lyophilized for preparation of solution for injection 40 mg vial No. 1

Instructions Omez lyophilized for preparation of solution for injection 40 mg vial No. 1

Composition

active ingredient: omeprazole;

1 bottle contains omeprazole sodium equivalent to omeprazole 40 mg;

excipient: sodium carbonate anhydrous.

Dosage form

Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized powder from white to light yellow, without visible inclusions.

Pharmacotherapeutic group

Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Omeprazole. ATC code A02B C01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion through a highly targeted mechanism of action. Omeprazole 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 in a similar manner to that achieved by repeated oral doses of 20 mg, an intravenous dose of 40 mg is recommended as the first dose. 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 Helicobacter pylori (H. pylori)

H. pylori is associated with the development of peptic ulcer disease, 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 gastric cancer.

Eradication of H. pylori with omeprazole and antimicrobials 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 the evaluation for neuroendocrine tumors. It has been reported that proton pump inhibitor (PPI) 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 PPIs, increases the number of bacteria normally found in the gastrointestinal tract. 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 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 of the substance in the 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 the 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 AUC in “poor metabolizers” is 5-10 times higher than in individuals with a functional CYP2C19 enzyme (in “extensive metabolizers”). The mean maximum plasma concentrations are 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 half-life of omeprazole is usually less than 1 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 excretion.

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-dependence 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., sulfone). No effect of any metabolites on gastric acid secretion was observed.

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. When omeprazole is administered once daily, there is no tendency for accumulation of the drug.

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 cases.

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 of the drug.

Omeprazole, like other PPIs, should not be used concomitantly with nelfinavir and atazanavir.

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 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 by omeprazole. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (in two out of ten subjects – up to 30%).

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 not recommended.

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 in healthy volunteers 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 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 drug monitoring of digoxin should be increased. In case of concomitant use with digoxin, patients should be closely monitored.

Clopidogrel

In the study, clopidogrel (300 mg loading dose followed by 75 mg daily) 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 interfere with their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Conflicting data on the clinical manifestations of this pharmacokinetic/pharmacodynamic interaction in terms of major cardiovascular diseases have been reported in observational and clinical studies. Therefore, concomitant use of omeprazole and clopidogrel should be avoided.

Other medicines

The absorption of posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced, therefore clinical efficacy may be reduced. Concomitant use of the drug 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.

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. 4 times the standard daily dose), 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. 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.

Cilostazol

In healthy volunteers, administration of omeprazole at a dose of 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and of 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 treatment with omeprazole; if phenytoin dose adjustment has been made, monitoring and further dose adjustment of the drug should be carried out after the end of treatment with omeprazole.

Unknown mechanism of interaction

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 dosage 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

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 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 not usually necessary. 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 cause 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 unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and in the presence or suspicion of gastric ulcer, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Concomitant use of atazanavir with PPIs is not recommended. If the combination of atazanavir with a PPI 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 gastric acid secretion, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account when treating 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 PPIs slightly increases the risk of developing gastrointestinal infections such as Salmonella and Campylobacter.

Use of PPIs, especially at high doses and over a long period (> 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% overall. 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 intake 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. Some patients had a severe course of hypocalcemia and hypomagnesemia, with the development of convulsive syndrome, cardiac arrhythmia, tetany, mental disorders and severe vomiting, which led to electrolyte imbalance.

During treatment with antisecretory drugs, the concentration of gastrin in the blood plasma increases as a result of a decrease in hydrochloric acid secretion. As a result of a decrease in hydrochloric acid secretion, the level of CgA increases. An increase in the concentration of CgA may affect the results of studies for the detection of neuroendocrine tumors. To avoid such an effect, PPIs should be discontinued 5 days before the determination of CgA levels. 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.

The use of PPIs may be associated with very rare cases of PsA. 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 PsA following previous treatment with a PPI increases the risk of PsA with other PPIs.

Kidney dysfunction

Acute tubulointerstitial nephritis (TIN) has been reported in patients taking omeprazole. It can occur at any time during omeprazole therapy (see section 4.8) and can progress to renal failure. If TIN is suspected, omeprazole should be discontinued and appropriate treatment should be initiated immediately.

This medicinal product contains 1.93 mmol (or 44.52 mg) sodium/dose. Caution should be exercised when administering this medicinal product to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Epidemiological studies on more than 1000 pregnant women with successful delivery indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole should be used during pregnancy only if, in the opinion of the physician, the expected benefit to the mother outweighs the potential risk to the foetus.

Omeprazole is excreted in small amounts in breast milk, but its effect on the child is unknown. Therefore, breastfeeding should be discontinued during the period of use of the drug.

Ability to influence reaction speed when driving vehicles or other mechanisms

It is unlikely that the drug affects the ability to drive a car or operate other mechanisms.

Considering that sensitive patients may experience adverse reactions (dizziness, drowsiness, hallucinations, reversible confusion, etc.) when using the drug, such patients should refrain from driving or working with other mechanisms that require concentration of attention while taking the drug.

Method of administration and doses

Dosage

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 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 not later than 3 hours. The diluted omeprazole solution should not be stored in the refrigerator. Any unused solution should be discarded.

Instructions for reconstitution of the drug before administration

For intravenous injection, the contents of each vial containing 40 mg of omeprazole are 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 containing 40 mg of omeprazole are 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 is administered as an intravenous infusion over 20–30 minutes.

The solution should be used immediately after preparation, but no later than 3 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

A daily dose of 10–20 mg may be sufficient for patients with impaired liver function.

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 up to 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.

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.

Treatment. There is no specific antidote. It is poorly removed by dialysis. Gastric lavage, symptomatic and supportive therapy are indicated.

Side effects

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.

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.

The adverse event profile observed in children is consistent with that seen in adults, both during short-term and long-term therapy.

Expiration date

2 years.

Powder vials (without cardboard box) can be stored in normal ambient light for up to 24 hours.

Reconstituted solution:

Chemical and physical stability after opening the package has been demonstrated for 12 hours at 25°C after reconstitution with 0.9% sodium chloride solution and for 6 hours at 25°C after reconstitution with 5% glucose solution.

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.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 ºС.

Keep out of reach of children.

Incompatibility

This medicinal product should not be mixed with other solvents except those mentioned in the section “Method of administration and dosage”.

Packaging

The medicine is placed in dark glass vials, sealed with a rubber stopper and an aluminum crimp cap equipped with a flip-off lid, which ensures control of the first opening.

1 bottle in a cardboard pack.

Vacation category

According to the recipe.

Producer

Naprod Life Sciences Pvt. Ltd.

NAPROD lIFE SCIENCES Pvt. Ltd.

Location of the manufacturer and address of its place of business.

G-17/1, M.I.D.C., Tarapur, Boisar, Distt. Thane 401 506, Maharashtra, India

G-17/1, MIDC, Tarapur, Boisar, Dist-Thane 401 506, Maharashtra State, India

Applicant

M.Biotech Ltd.

M.Biotech Ltd

Location of the applicant.

Gladstone House, 77-79 High Street, Egham TV20 9GY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom