Pompezo lyophilisate for solution for injection 40 mg No. 1

Instructions for Pompezo lyophilisate for solution for injection 40 mg No. 1

Composition

active ingredient: esomeprazole;

1 vial contains esomeprazole (as esomeprazole sodium) 40 mg;

excipients: disodium edetate, sodium hydroxide.

Dosage form

Lyophilisate for solution for injection.

Main physicochemical properties: white lyophilized powder; prepared solution: clear colorless or light yellow solution.

Pharmacotherapeutic group

Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02B C05.

Pharmacological properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion by a specific, targeted mechanism of action. It is a specific proton pump inhibitor (PPI) of the parietal cell. Both the R- and S-isomers of omeprazole exhibit similar pharmacodynamic activity.

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 proton pump and suppresses both basal and stimulated acid secretion.

Pharmacodynamic effects

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.

A relationship between acid suppression and AUC after oral administration of esomeprazole has been demonstrated using a proxy parameter of drug concentration in blood plasma, the area under the pharmacokinetic concentration-time curve (AUC).

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 over a 24-hour period, respectively.

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.

During treatment with antisecretory agents, plasma gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that PPI treatment should be discontinued 5–14 days before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment.

An increase in the number of enterochromaffin-like cells (ECL) was observed in both children and adults during long-term treatment with esomeprazole, which was possibly due to an increase in plasma gastrin levels. These findings are considered to be of no clinical significance.

Against the background of long-term use of antisecretory agents, a slight increase in the frequency of gastric glandular cysts has been noted. Such changes are a physiological consequence of pronounced inhibition of gastric juice secretion; they are benign in nature and resolve after completion of treatment.

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, such as Salmonella and Campylobacter, in hospitalized patients, and possibly also Clostridium difficile.

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

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.

Breeding

The parameters below reflect predominantly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, i.e. the pharmacokinetics of extensive metabolizers.

Total plasma clearance is approximately 17 l/h after a single dose and approximately 9 l/h after repeated administration. The plasma half-life (t½) of esomeprazole is approximately 1.3 hours after repeated 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 rest in the feces. Less than 1% of the parent compound is excreted in the urine.

Linearity/nonlinearity

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, probably due to inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

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

Special patient groups

Patients with CYP2C19 enzyme polymorphism

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 doses of 40 mg esomeprazole once daily, the mean AUC was approximately 100% higher in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). The mean Cmax 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.

Patients with liver dysfunction

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 AUC of esomeprazole. Therefore, in patients with GERD and severe hepatic impairment, the maximum dose of 20 mg should not be exceeded. In patients with bleeding ulcers and severe hepatic impairment, after an initial bolus dose of 80 mg, a continuous intravenous infusion of esomeprazole at a maximum rate of 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.

Patients with renal impairment

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 the metabolism of esomeprazole are expected in patients with impaired renal function.

Elderly patients

The metabolism of esomeprazole is slightly altered in elderly patients (71-80 years).

Gender differences

After a single dose of 40 mg esomeprazole, the mean AUC in women is approximately 30% higher than in men. There is no gender difference when esomeprazole is administered once daily. These findings do not impact the dosage of esomeprazole.

Indication

Adults

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

GERD in patients with esophagitis and/or severe reflux symptoms; treatment of gastric ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) therapy; prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.

Short-term maintenance of hemostasis and 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:

GERD in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindication

Hypersensitivity to the active substance, to other substituted benzimidazoles or to other components of the drug.

Concomitant use with atazanavir, nelfinavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Interaction studies have only been conducted in adults.

Effect of esomeprazole on the pharmacokinetics of other drugs

Protease inhibitors

Interactions of omeprazole with some protease inhibitors have been reported. 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 mechanisms of interaction are possible through inhibition of CYP2C19.

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 atazanavir dose 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 the AUC of atazanavir by approximately 30% compared to the AUC observed with atazanavir (300 mg/ritonavir 100 mg daily) without omeprazole (20 mg daily).

Concomitant use of omeprazole (40 mg daily) reduced 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%.

Due to the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of esomeprazole and atazanavir is not recommended (see section 4.4). The concomitant use of esomeprazole and nelfinavir is contraindicated (see section 4.3).

Increased plasma levels (80-100%) of saquinavir (in combination with ritonavir) were observed with concomitant use with omeprazole (40 mg daily).

Omeprazole (20 mg daily) had no effect on the AUC of darunavir (co-administered with ritonavir) and amprenavir (co-administered with ritonavir).

Esomeprazole (20 mg daily) had no effect on the AUC of amprenavir (in combination with ritonavir or alone).

The use of omeprazole (at a dose of 40 mg per day) did not change the AUC of lopinavir (in combination with ritonavir).

Methotrexate

Some patients have experienced increased plasma levels of methotrexate when co-administered with PPIs. Temporary discontinuation of esomeprazole should be considered when high doses of methotrexate are being used.

Tacrolimus

Increased plasma levels of tacrolimus have been reported with concomitant use of esomeprazole. In case of concomitant use, increased monitoring of tacrolimus plasma levels and renal function (creatinine clearance) should be performed and the tacrolimus dose adjusted if necessary.

Drugs whose absorption depends on pH

The suppression of gastric acidity during treatment with esomeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption depends on gastric pH. As with other agents 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 during treatment with esomeprazole. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (in 2 out of 10 subjects - up to 30%). Rare cases of digoxin-induced toxicity have been reported. However, caution should be exercised when using high doses of esomeprazole in elderly patients. Therapeutic drug monitoring of digoxin 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, 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 effects during the 3-day period of intravenous esomeprazole administration.

Diazepam

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

Phenytoin

With simultaneous oral administration of esomeprazole (40 mg) in patients with epilepsy, an increase in Cmin of phenytoin in blood plasma by 13% was observed. It is recommended to monitor phenytoin plasma levels at the beginning and after the end of therapy with esomeprazole.

Voriconazole

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

Cilostazol

Omeprazole and esomeprazole act as inhibitors of CYP2C19. In a cross-over study, omeprazole (40 mg) in healthy volunteers increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.

Cisapride

In healthy volunteers, when co-administered orally with esomeprazole (40 mg), the AUC increased by 32% and the t½ increased by 31%, but there was no significant increase in Cmax of cisapride. The slight prolongation of the QTc interval observed with cisapride alone was not observed when cisapride was co-administered with esomeprazole.

In a clinical study, it was shown that concomitant oral administration of esomeprazole 40 mg in patients on warfarin therapy maintained coagulation times within acceptable limits. However, in the post-marketing period, a few isolated cases of clinically significant increases in the international normalized ratio (INR) have been reported during concomitant oral administration of these agents. Monitoring is recommended at the beginning and after the end of concomitant administration of esomeprazole with warfarin or other coumarin derivatives.

Clopidogrel

The results of the pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (loading dose – 300 mg/maintenance dose – 75 mg per day) and esomeprazole (oral dose 40 mg per day), obtained in the course of studies with the participation of healthy volunteers, showed a decrease in the AUC of the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibition index (induced by ADP) of platelet aggregation by an average of 14%.

In a study in healthy volunteers, when clopidogrel was used together with esomeprazole and acetylsalicylic acid (ASA) in a fixed dose combination (20 mg + 81 mg, respectively) compared with clopidogrel as monotherapy, a decrease in the AUC of the active metabolite of clopidogrel by almost 40% was observed. However, the maximum levels of inhibition of (ADP-induced) platelet aggregation in these subjects were the same in the group using clopidogrel as monotherapy and in the group using clopidogrel together with esomeprazole and ASA.

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.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Drugs that inhibit CYP2C19 and/or CYP3A4 activity

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 2-fold increase in esomeprazole AUC. The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not usually necessary in any of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Drugs that induce CYP2C19 and/or CYP3A4 activity

Agents known to induce the activity of CYP2C19 or CYP3A4 or both enzymes (such as rifampicin and St. John's wort) may lead to decreased plasma levels of esomeprazole by increasing its rate of metabolism.

Investigational medicinal products without clinically significant interactions

Amoxicillin and quinidine

It was noted that esomeprazole had 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.

Application features

In the presence of any alarming symptoms (such as significant unexpected weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and in the presence or suspicion of gastric ulcer, malignancy should be excluded, as esomeprazole may mask symptoms and delay diagnosis.

Gastrointestinal infections

The use of PPIs may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B12 absorption

Esomeprazole, like all acid-blocking agents, 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 present with serious manifestations such as fatigue, tetany, delirium, seizures, dizziness and ventricular arrhythmias, but may develop gradually and go unnoticed. Most patients with hypomagnesemia improve 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 appropriate 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 are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing the drug. The occurrence of subacute cutaneous lupus erythematosus in patients on previous PPI therapy may increase the risk of its development with other PPIs.

Concomitant use with other medicines

The concomitant 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. When initiating and ending therapy with esomeprazole, the possibility of interactions with drugs metabolized by CYP2C19 should be considered. An interaction between clopidogrel and omeprazole has been reported (see section 4.5). The clinical significance of this interaction is not yet fully established. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Impact on laboratory test results

Elevated CgA levels may interfere with the results of diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with the drug should be temporarily discontinued for at least 5 days before CgA levels are measured (see section 5.1). If CgA and gastrin levels have not returned to the normal range after the initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

1 vial contains less than 1 mmol sodium.

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 these symptoms occur, patients should not drive or use machines.

Use during pregnancy or breastfeeding

Pregnancy

There are currently no adequate data on the use of esomeprazole during pregnancy. A somewhat larger number of epidemiological studies of the use of the racemic mixture of omeprazole during pregnancy indicate the absence of congenital malformations and fetotoxic effects. Animal studies of esomeprazole did not reveal direct or indirect negative effects on embryonal/fetal development. Animal studies of the racemic mixture did not reveal direct or indirect effects on pregnancy, parturition or postnatal development. The drug should be used with caution during pregnancy.

A moderate amount of data on pregnant women (300 to 1000 pregnancy outcomes) indicate no malformative or foeto/neonatal toxicity of esomeprazole.

The results of animal studies indicate the absence of direct or indirect negative effects of esomeprazole on reproductive function due to its toxic effects.

Breastfeeding period

It is not known whether esomeprazole is excreted in human milk. There is insufficient information on the effects of esomeprazole on newborns/infants. Therefore, the drug should not be used during breast-feeding.

Fertility

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

Method of administration and doses

Adults

Dosage

Antisecretory therapy when oral esomeprazole is not possible Patients who cannot take esomeprazole orally can be given the drug parenterally at a dose of 20–40 mg once daily.

For patients with reflux esophagitis, the recommended dose is 40 mg once daily.

For patients receiving symptomatic treatment for reflux disease, the dose 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.

Treatment with intravenous esomeprazole is usually short-term and patients should be switched to oral administration 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

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

20 mg dose: 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.

Dose 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 is 8 mg/hour; the shelf life of the reconstituted solution is indicated in the “Expiration Date” section).

Patients with renal impairment

No dose adjustment is required for patients with renal impairment. As experience with esomeprazole in patients with severe renal impairment is limited, the drug should be used with caution in such patients (see section 5.2).

Patients with liver dysfunction

GERD: No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment should not exceed a maximum dose of 20 mg (see Pharmacokinetics).

Bleeding ulcers: No dose adjustment is required in patients with mild or moderate hepatic impairment; in patients with severe hepatic impairment, an initial bolus dose of 80 mg followed by a continuous intravenous infusion of 4 mg/hour for 71.5 hours may be sufficient (see Pharmacokinetics).

Elderly patients

No dose adjustment is required.

Children aged 1-18 years

Dosage

As a means of suppressing gastric secretion when oral esomeprazole is not possible

For patients who cannot take the drug orally, the drug can be administered parenterally once a day during the complete treatment period for GERD (doses are listed in the table below).

Treatment with intravenous esomeprazole should usually be short-term and patients should be switched to oral esomeprazole as soon as possible.

Recommended doses of esomeprazole for intravenous administration

Method of application

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

Injections

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

20 mg dose: 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.

10 mg dose: 1.25 ml of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes. Any unused solution is discarded.

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. Discard any unused solution.

Dose 10 mg: One-quarter of the reconstituted solution is administered as an intravenous infusion over 10-30 minutes. Discard any unused solution.

Instructions for use, handling and disposal (where applicable)

The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solutions should be used. The solution is for single use only.

If the entire reconstituted vial contents are not required, any unused solution should be disposed of in accordance with local requirements.

Prepare a solution for injection (8 mg/ml) by adding 5 ml of 0.9% sodium chloride for intravenous use to a vial of esomeprazole 40 mg.

The reconstituted solution for injection is clear and colorless to slightly yellowish.

Solution for infusion 40 mg

Prepare a solution for infusion by dissolving the contents of one vial of esomeprazole 40 mg in 100 ml of 0.9% sodium chloride for intravenous use.

Solution for infusion 80 mg

Prepare an infusion solution by dissolving the contents of two 40 mg esomeprazole vials in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted solution for infusion is clear and colourless or slightly yellowish.

Children

The drug should be used in children over 1 year of age as an antisecretory therapy when oral administration of esomeprazole is not possible.

Overdose

There is currently very limited information on intentional overdose. Symptoms reported with esomeprazole 280 mg have included gastrointestinal symptoms and weakness. A single oral dose of 80 mg esomeprazole and an intravenous dose of 308 mg esomeprazole over 24 hours were without adverse effects. No specific antidote is known. Esomeprazole is highly bound to plasma proteins and therefore dialysis is of little benefit. In the event of overdose, symptomatic and general supportive treatment should be provided.

Adverse reactions

The most common adverse reactions observed in clinical trials and post-marketing experience with esomeprazole include headache, abdominal pain, diarrhoea and nausea. In addition, the safety profile of esomeprazole is consistent across dosage forms, indications, age groups and patient populations. No dose-related adverse reactions have been observed.

The following adverse reactions to esomeprazole have been reported or suspected during clinical trials with oral or intravenous administration and in the post-marketing period with oral administration. The reactions are listed according to their frequency: very common (> 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders:

rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia.

On the part of the immune system:

Rare: hypersensitivity reactions, such as fever, angioedema and anaphylactic reaction/shock.

From the side of metabolism and nutrition:

uncommon - peripheral edema; rare - hyponatremia; frequency unknown - hypomagnesemia (see section "Special instructions for use"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

From 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:

infrequently - blurred vision.

On the part of the organs of hearing and balance:

infrequently - vertigo.

From the respiratory system, chest organs and mediastinum:

rarely - bronchospasm.

From the digestive tract:

often - abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign); infrequently - dry mouth; rarely - stomatitis, gastrointestinal candidiasis; frequency unknown - microscopic colitis.

From the hepatobiliary system:

uncommon - increased liver enzymes; rare - hepatitis with or without jaundice; very rare - hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders:

Common: injection site reactions*; uncommon: dermatitis, pruritus, rash, urticaria; rare: alopecia, photosensitivity; very rare: