Esoprotect lyophilisate for injection 40 mg No. 1

Instructions for Ezoprotect lyophilisate for injection 40 mg No. 1

Composition

active ingredient: esomeprazole;

1 vial contains 42.5 mg of esomeprazole sodium, equivalent to 40 mg of esomeprazole;

excipients: disodium edetate, sodium hydroxide.

Dosage form

Lyophilisate for solution for injection and infusion.

Main physicochemical properties: White or almost white, homogeneous, porous mass.

Pharmacotherapeutic group

Drugs used in acidity disorders. Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs). ATC code A02B C05.

Pharmacological properties

Pharmacodynamics.

Esomeprazole is the S-isomer of omeprazole, which inhibits gastric acid secretion by a specific, targeted mechanism of action. It is a specific inhibitor of the parietal cell acid pump. Both the R- and S-isomers of omeprazole have similar pharmacological activities.

Site and mechanism of action

Esomeprazole is a weak base that concentrates and converts to the active form in the highly acidic environment of the secretory tubules of parietal cells, where it inhibits the enzyme H+K+-ATPase – the acid pump – and suppresses both basal and stimulated acid secretion.

Effect on gastric juice secretion

After 5 days of oral administration of 20 mg and 40 mg esomeprazole, gastric pH above 4 was maintained for an average of 13 hours and 17 hours over a 24-hour period, respectively, in patients with symptomatic gastroesophageal reflux disease (GERD). The effect was similar whether esomeprazole was administered orally or intravenously. The area under the pharmacokinetic concentration-time curve (AUC) as a proxy for plasma drug concentration was used to demonstrate a relationship between acid suppression and exposure following oral administration of esomeprazole. When esomeprazole was administered intravenously to healthy volunteers at a dose of 80 mg as a bolus infusion over 30 minutes followed by a continuous intravenous infusion at a rate of 8 mg/hour for 23.5 hours, gastric pH levels above 4 and above 6 were maintained for an average of 21 hours and 11-13 hours, respectively, over a 24-hour period.

Therapeutic effect of inhibiting acid secretion.

With oral administration of esomeprazole at a dose of 40 mg, approximately 78% of patients with reflux esophagitis recovered after 4 weeks and 93% after 8 weeks of treatment. In a randomised, double-blind, placebo-controlled clinical trial, patients with endoscopically proven peptic ulcer class Ia, Ib, IIa or IIb (9%, 43%, 38% and 10% respectively) according to Forrest were randomised to esomeprazole, solution for infusion (n=375) or placebo (n=389). After endoscopic haemostasis, patients received either esomeprazole 80 mg as an intravenous infusion over 30 minutes followed by a continuous infusion at a rate of 8 mg/hour or placebo for 72 hours. After an initial 72-hour period, all patients were switched to open-label oral esomeprazole 40 mg for 27 days to suppress acid secretion. The 3-day rebleeding rate was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after treatment, the rebleeding rate was 7.7% and 13.6% in the esomeprazole and placebo groups, respectively.

Other effects related to inhibition of acid secretion.

During treatment with antisecretory agents, serum gastrin levels increase in response to decreased acid secretion. Chromogranin A (CgA) levels also increase due to decreased gastric acidity. Laboratory tests for neuroendocrine tumors may be affected by elevated CgA levels. Published evidence suggests that PPI treatment should be discontinued for 5 days to 2 weeks before CgA measurements to allow CgA to normalize, as CgA levels may be elevated after treatment with proton pump inhibitors (PPIs).

An increase in the number of enterochromaffin-like cells, possibly related to increased gastrin levels, has been observed in some patients during long-term treatment with oral esomeprazole. These findings are considered to be of no clinical significance.

A slight increase in the frequency of gastric glandular cyst formation has been observed during long-term treatment with oral antisecretory drugs. These changes are a physiological consequence of pronounced inhibition of gastric juice secretion, are benign and reversible in nature.

Decreased gastric acidity from any cause, including PPI use, leads to an increase in the number of bacteria normally present in the gastrointestinal tract in the stomach. PPI treatment may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and in hospitalized patients, possibly also Clostridium difficile.

A placebo-controlled study (98 patients aged 1 to 11 months) evaluated the efficacy and safety of the drug in patients with signs and symptoms of GERD. Esomeprazole 1 mg/kg once daily was administered orally for 2 weeks (open-label phase), and 80 patients were enrolled for an additional 4 weeks (double-blind, treatment withdrawal phase). There was no significant difference between esomeprazole and placebo in terms of reaching the primary endpoint and discontinuation due to worsening symptoms.

A placebo-controlled study (52 patients <1 month of age) evaluated the efficacy and safety of the drug in patients with GERD. Esomeprazole 0.5 mg/kg once daily was administered orally for a minimum of 10 days. There was no significant difference between esomeprazole and placebo on the primary endpoint of change from baseline in the number of GERD symptoms.

Results from studies in paediatric patients show that doses of esomeprazole 0.5 mg/kg and 1.0 mg/kg in infants <1 month and 1-11 months of age, respectively, reduce the mean percentage of time that intraesophageal pH is <4.0. The safety profile of the drug was similar to that in adults.

In a study of pediatric patients with GERD (aged <1 to 17 years) receiving long-term PPI treatment, 61% of children had mild ECL cell hyperplasia of unknown clinical significance; no atrophic gastritis or carcinoid tumors were observed.

Pharmacokinetics.

Distribution.

The apparent volume of distribution at steady state in healthy volunteers is approximately 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Metabolism and excretion.

Esomeprazole is completely metabolised by the cytochrome P450 (CYP) system. The main part of the metabolism of esomeprazole depends on the polymorphic CYP2C19, which is responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining metabolism is carried out by another specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in plasma.

The following parameters mainly reflect the pharmacokinetics in subjects with a functional CYP2C19 enzyme, i.e. extensive metabolisers. Total plasma clearance is approximately 17 l/h after a single dose and approximately 9 l/h after repeated administration. The elimination half-life (t1/2) of the drug from plasma is approximately 1.3 hours after repeated administration once daily. Esomeprazole is completely eliminated from plasma between doses, and there is no tendency for its accumulation in the body with once daily administration. The main metabolites of esomeprazole do not affect gastric secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent compound is excreted in the urine. AUC increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear relationship between dose and AUC after repeated administration. This time and dose dependence is due to a decrease in first-pass metabolism and systemic clearance, likely due to inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

After repeated intravenous administration of 40 mg, the mean maximum plasma concentration is approximately 13.6 μmol/l. The mean maximum plasma concentration after corresponding oral doses is approximately 4.6 μmol/l. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared with oral administration. A linear dose-dependent increase in exposure was observed when esomeprazole was administered as an intravenous infusion over 30 minutes (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) for 23.5 hours.

Patients of special groups.

Slow metabolizers.

Approximately 2.9 ± 1.5% of the population lack a functional CYP2C19 enzyme and are referred to as poor metabolisers. In these individuals, the metabolism of esomeprazole is likely to be catalysed predominantly by CYP3A4. After multiple oral doses of 40 mg esomeprazole once daily, the mean total exposure was approximately 100% higher in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). The mean maximum plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These findings do not require any changes in the dosage of esomeprazole.

Sex.

After a single oral dose of 40 mg esomeprazole, the mean total exposure in women is approximately 30% higher than in men. No gender differences were observed with repeated once daily dosing. Similar differences were observed with intravenous administration of esomeprazole. These findings do not impact the posology of esomeprazole.

The metabolism of esomeprazole in patients with mild to moderate hepatic impairment may be impaired. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of the total exposure to esomeprazole. Therefore, in patients with GERD and severe hepatic impairment, the maximum dose of 20 mg should not be exceeded. In the case of bleeding ulcers and severe hepatic impairment, after an initial bolus dose of 80 mg, a continuous intravenous infusion of up to 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show a tendency to accumulate when administered once daily.

Kidney dysfunction.

No studies have been conducted in patients with reduced renal function. Since the kidneys are responsible for the excretion of esomeprazole metabolites, but not the parent compound, no changes in metabolism are expected in patients with impaired renal function.

Elderly patients.

The metabolism of esomeprazole is slightly altered in the elderly (71–80 years). Children.

In a randomised, open-label, international, multiple-dose study, esomeprazole was administered as a 3-minute injection once daily for 4 days. A total of 59 children aged 0 to 18 years were enrolled, 50 of whom (7 children aged 1 to 5 years) completed the study and the pharmacokinetics of esomeprazole were assessed.

Table 1 presents the results of the systemic exposure of esomeprazole after intravenous administration by injection over 3 minutes in pediatric patients and healthy adult volunteers. The values in Table 1 are presented as geometric means (range). A dose of 20 mg for adults was administered by infusion over 30 minutes. The maximum steady-state plasma concentration (Css, max) was estimated 5 minutes after dosing in pediatric patients in all age groups and 7 minutes after dosing with a 40 mg dose and at the end of the 20 mg infusion in adult patients.

Table 1

*The age group 0 to 1 month included patients with adjusted ages (sum of intrauterine age and postnatal age in completed weeks) ≥32 completed weeks and <44 completed weeks. The age group 1 to 11 months included patients with adjusted ages ≥44 completed weeks.

**Two patients were excluded: one, more likely due to reduced CYP2C19 isoenzyme activity, the second due to concomitant use of a CYP3A4 isoenzyme inhibitor.

According to the constructed model, Css, max after intravenous administration of esomeprazole by 10-minute, 20-minute and 30-minute infusion will decrease on average by 37-49%, 54-66% and 61-72%, respectively, in all age groups and dosage groups compared to the Css, max value after a 3-minute injection.

Indication

Adults:

Antisecretory therapy when oral administration is not possible, for example:

gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe reflux symptoms;

treatment of stomach ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) therapy;

prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.

Prevention of rebleeding in patients after endoscopic treatment of acute bleeding due to gastric or duodenal ulcer.

Children aged 1 to 18 years:

Antisecretory therapy when oral administration is not possible, for example:

Gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindication

Hypersensitivity to the active substance esomeprazole, other substituted benzimidazoles or to any of the excipients of this medicinal product.

Esomeprazole, like other PPIs, should not be used concomitantly with atazanavir and nelfinavir (see section “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions

Effect of esomeprazole on the pharmacokinetics of other drugs

Omeprazole has been reported to interact with some protease inhibitors. The clinical significance and mechanisms of these interactions are not always known. The increase in gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other possible mechanisms of interaction include inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole, and concomitant use of these drugs is therefore not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers decreased atazanavir exposure by approximately 30% compared to the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Co-administration of omeprazole (40 mg daily) decreased the mean AUC, Cmax, and Cmin of nelfinavir by 36-39% and the mean AUC, Cmax, and Cmin of the pharmacologically active metabolite M8 by 75-92%. Increased serum concentrations of saquinavir (co-administered with ritonavir) (80-100%) were observed with co-administration of omeprazole (40 mg daily). Omeprazole 20 mg daily had no effect on the exposure of darunavir (co-administered with ritonavir) and amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily had no effect on the exposure of amprenavir (in combination with ritonavir or alone). Omeprazole 40 mg daily did not alter the exposure of lopinavir (in combination with ritonavir). Due to the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Methotrexate.

Methotrexate levels have been increased in some patients when used with PPIs. Temporary discontinuation of esomeprazole may be necessary when high doses of methotrexate are used.

Tacrolimus.

Increased serum tacrolimus levels have been reported with concomitant use of esomeprazole. Increased monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required and the tacrolimus dosage should be adjusted if necessary.

Drugs whose absorption depends on pH.

Suppression of gastric secretion during therapy with esomeprazole and other PPIs may lead to a decrease or increase in the absorption of drugs whose absorption depends on the pH of the gastric juice. As with other drugs that reduce the acidity of gastric juice, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced and the absorption of digoxin may be increased during the period of use of esomeprazole. When omeprazole (20 mg per day) was co-administered with digoxin in healthy volunteers, the bioavailability of digoxin increased by 10% (up to 30% in two out of ten participants). Toxic effects of digoxin have been observed rarely. However, caution should be exercised when using high doses of esomeprazole in elderly patients. Monitoring of the concentration of digoxin in the patient's blood should be increased. Drugs metabolized by CYP2C19.

Esomeprazole inhibits CYP2C19, the main enzyme that metabolizes esomeprazole. Therefore, when esomeprazole is combined with drugs that are metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, the plasma concentrations of these drugs may increase and a dose reduction may be required. In vivo interaction studies with the high-dose intravenous formulation (80 mg + 8 mg/hour) have not been performed. The effect of esomeprazole on drugs that are metabolized by CYP2C19 may be more pronounced with this regimen, and patients should be closely monitored for adverse events during the 3-day intravenous period.

Diazepam.

Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in the clearance of the CYP2C19 substrate diazepam.

Phenytoin.

When 40 mg of esomeprazole was co-administered with phenytoin, the trough plasma concentration of phenytoin in epileptic patients increased by 13%. It is recommended to monitor phenytoin plasma concentrations at the beginning and end of esomeprazole therapy.

Voriconazole.

Omeprazole (40 mg once daily) increased the Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively.

Cilostazol.

Omeprazole, like esomeprazole, is an inhibitor of CYP2C19. In a cross-over study in healthy volunteers, the use of omeprazole at a dose of 40 mg resulted in an increase in Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%.

Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers resulted in a 32% increase in AUC and a 31% increase in t1/2, but no significant increase in plasma Cmax of cisapride was observed. The slight prolongation of the QTc interval observed with cisapride alone was not increased when cisapride was given in combination with esomeprazole.

Warfarin.

When esomeprazole 40 mg was co-administered orally in patients taking warfarin in a clinical trial, clotting times remained within the acceptable range. However, in the post-marketing period, a few isolated cases of clinically significant increases in international normalised ratio (INR) have been reported with oral esomeprazole when these medicinal products were co-administered. Monitoring is recommended at the start and end of co-administration of esomeprazole and warfarin or other coumarin derivatives. Clopidogrel.

The results of the pharmacokinetic (PK)/pharmacodynamic (PD) interaction assessment between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg orally daily) obtained during studies in healthy volunteers showed a decrease in the exposure of the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibition rate (induced by ADP) of platelet aggregation by an average of 14%.

In a study in healthy volunteers, when clopidogrel was administered with esomeprazole and acetylsalicylic acid (ASA) in a fixed dose combination (20 mg + 81 mg, respectively) compared with clopidogrel alone, there was a decrease in exposure to the active metabolite of clopidogrel by almost 40%. However, the maximum levels of inhibition of (ADP-induced) platelet aggregation in these subjects were the same in the clopidogrel monotherapy group and in the clopidogrel plus esomeprazole and ASA group. Observational and clinical studies have provided conflicting data on the clinical aspects of the PK/PD interaction of esomeprazole with respect to major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Investigational medicinal products without clinically significant interactions.

Amoxicillin or quinidine.

Esomeprazole has been shown to have no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib.

No pharmacokinetic interactions were observed during short-term studies of concomitant use of esomeprazole with naproxen or rofecoxib. Effects of other medicinal products on the pharmacokinetics of esomeprazole.

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) resulted in a doubling of esomeprazole AUC. Concomitant administration of esomeprazole and a combined CYP2C19 and CYP3A4 inhibitor may result in a more than two-fold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always necessary in these situations. However, it may be necessary in patients with severe hepatic impairment and in cases where long-term treatment is indicated.

Drugs that induce CYP2C19 and/or CYP3A4 activity.

Rifampicin and St. John's wort, for example, are capable of inducing CYP2C19 or CYP3A4 or both enzymes and may reduce the serum concentration of esomeprazole by increasing its metabolism.

Children.

Drug interaction studies have only been conducted in adults.

Application features

In the event of any alarming symptoms (e.g. significant unexpected weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and if gastric ulcer is suspected or present, malignancy should be excluded, as Ezoprotect may mask symptoms and delay diagnosis.

Gastrointestinal infections.

PPI therapy may slightly increase the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section 5.1).

Vitamin B12 absorption.

Esomeprazole, like all acid-blocking drugs, may inhibit the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with reduced body stores or risk factors for impaired vitamin B12 absorption during long-term therapy.

Hypomagnesemia.

Cases of severe hypomagnesemia have been reported in patients taking PPIs such as esomeprazole for at least three months, and in most cases for a year. Hypomagnesemia can have serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, but its development may be gradual and go unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of the PPI.

In patients who are expected to be on long-term treatment or who are taking PPIs with digoxin or drugs that can cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before starting PPI therapy and periodically during treatment.

PPIs, especially when used at high doses and for long periods (>1 year), may slightly increase the risk of hip, wrist, and spine fractures, mainly in elderly patients or those with other risk factors. Review studies suggest that PPIs may increase the overall risk of fractures by 10–40%. This increase may be partly due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and should receive adequate vitamin D and calcium.

Subacute cutaneous lupus erythematosus.

The use of PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and this is accompanied by arthralgia, the patient should immediately consult a doctor who will consider the need to discontinue the drug Ezoprotect. The occurrence of subacute cutaneous lupus erythematosus in patients during previous PPI therapy may increase the risk of its development with the use of other PPIs.

Combination with other drugs.

The use of esomeprazole with atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a PPI is considered necessary, close monitoring of the patient is recommended and the dose of atazanavir should be increased to 400 mg with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg. Esomeprazole is a CYP2C19 inhibitor. The possibility of interactions with medicinal products metabolised by CYP2C19 should be considered when initiating and ending esomeprazole therapy. An interaction between clopidogrel and omeprazole has been observed (see section 4.5). The clinical significance of this interaction is not fully established. As a precautionary measure, the concomitant use of esomeprazole and clopidogrel is not recommended.

Severe cutaneous adverse reactions (SCARs).

Very rare cases of severe cutaneous adverse reactions (SCARs), including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening, have been reported during treatment with esomeprazole.

Patients should be informed of the possible signs and symptoms of EM/SJS/TEN/DRESS severe cutaneous adverse reactions and should seek immediate medical advice if any characteristic signs or symptoms occur.

If signs and symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately and additional medical attention or close monitoring of the patient should be provided. The drug should not be re-administered to patients with erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms.

Impact on laboratory test results.

Elevated CgA levels may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole should be temporarily discontinued for at least five days before CgA measurement. If CgA and gastrin levels have not returned to normal after the initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

Important information about excipients.

Each vial of the medicinal product contains less than 1 mmol sodium, i.e. Esoprotect is essentially sodium-free.

Use during pregnancy or breastfeeding

Data on the use of Ezoprotect during pregnancy are limited. A somewhat larger number of epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy indicate no risk of birth defects and fetotoxic effects. Animal studies have not shown direct or indirect harmful effects on embryofetal development. Animal studies of the racemic mixture do not indicate direct or indirect harmful effects on pregnancy, childbirth or postnatal development. Ezoprotect should be prescribed to pregnant women with caution. A moderate amount of data on pregnant women (from 300 to 1000 pregnancy outcomes) indicate no malformative effects or toxic effects of esomeprazole on the condition of the fetus/health of the newborn. The results of animal studies indicate no direct or indirect harmful effects of the drug on reproductive function due to its toxic effects.

Breastfeeding period.

It is not known whether esomeprazole passes into breast milk. No studies have been conducted in breastfeeding women. Esomeprazole should not be used during breastfeeding.

Fertility.

Animal studies of the racemic mixture of omeprazole indicate no effect of omeprazole on fertility when administered orally.

Ability to influence reaction speed when driving vehicles or other mechanisms

Esomeprazole has minimal influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section 4.8). If such disorders occur, patients should not drive or use machines.

Method of administration and doses

Dosage.

Adults.

Antisecretory therapy when oral administration is not possible Patients are given the drug parenterally at a dose of 20–40 mg once daily. The dose for patients with reflux esophagitis is 40 mg once daily. The dose for patients receiving symptomatic treatment for reflux disease is 20 mg once daily.

In the treatment of gastric ulcers caused by the use of NSAIDs, the usual dose is 20 mg once a day.

To prevent gastric and duodenal ulcers caused by NSAID therapy, patients at risk are prescribed the drug at a dose of 20 mg once a day. Usually, treatment with the drug for intravenous administration is short-term, patients should be transferred to oral administration of the drug as soon as possible.

Short-term maintenance of hemostasis and prevention of rebleeding in patients after endoscopic treatment of acute bleeding due to gastric or duodenal ulcer

After therapeutic endoscopy of acute bleeding gastric or duodenal ulcers, 80 mg of the drug is administered as a bolus infusion lasting 30 minutes, after which the drug is continued as a continuous intravenous infusion at a rate of 8 mg/hour for 3 days (72 hours).

After parenteral treatment, therapy should be continued with oral agents that suppress acid secretion.

Method of application.

Instructions for preparing the reconstituted solution are provided in this section below (“Instructions for use, handling and disposal (where applicable)”).

Injections.

Dose 40 mg.

5 ml of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes.

Dose 20 mg.

2.5 ml, or half of the reconstituted solution (8 mg/ml), is administered as an intravenous injection over at least 3 minutes. Discard any unused solution.

Infusions.

Dose 40 mg.

The reconstituted solution is administered as an intravenous infusion over 10–30 minutes. Dose 20 mg.

Half of the reconstituted solution is administered as an intravenous infusion over 10-30 minutes. Any unused solution is discarded.

Bolus dose of 80 mg.

The reconstituted solution is administered as a continuous intravenous infusion over 30 minutes.

Dose 8 mg/hour.

The reconstituted solution is administered as a continuous intravenous infusion over 71.5 hours (calculated infusion rate 8 mg/hour; the shelf life of the reconstituted solution is indicated in the “Expiration Date” section).

Patients of special groups.

Kidney dysfunction.

No dose adjustment is necessary for patients with renal impairment. Since experience in patients with severe renal impairment is limited, such patients should be treated with caution (see section 5.2). Hepatic impairment.

GERD: No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment should not exceed the maximum dose of Ezoprotect 20 mg (see section 5.2). Bleeding ulcers: No dose adjustment is required in patients with mild or moderate hepatic impairment; in patients with severe hepatic impairment, after an initial bolus dose of Ezoprotect for infusion 80 mg, a continuous intravenous infusion of 4 mg/hour for 71.5 hours may be sufficient (see section 5.2).

Elderly patients.

No dose adjustment is required.

Children.

Dosage.

Children aged 1–18 years.

As a means of oppression