Ezoprotekt

INSTRUCTIONS for medical use of the medicinal product EZOPROTECT

Composition:

Active substance: esomeprazole;

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

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

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

Pharmacotherapeutic group. Drugs used in acid-related disorders. Agents for the treatment of peptic ulcer and gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs). ATC code A02BC05.

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole and inhibits gastric acid secretion through a specific and targeted mechanism of action. It is a specific inhibitor of the H+/K+-ATPase enzyme system—the so-called proton pump—on the secretory surface of gastric parietal cells. Both the R- and S-isomers of omeprazole have similar pharmacological activity.

Site and Mechanism of Action

Esomeprazole is a weak base that accumulates and is converted to its active form in the highly acidic environment of the secretory canaliculi of parietal cells. There, it inhibits the H+/K+-ATPase enzyme (proton pump), thereby suppressing both basal and stimulated gastric acid secretion.

Effect on Gastric Acid Secretion

After 5 days of oral administration of 20 mg and 40 mg esomeprazole, intragastric pH remained above 4 for a mean of 13 hours and 17 hours, respectively, over a 24-hour period in patients with symptomatic gastroesophageal reflux disease (GERD). The effect is similar regardless of whether esomeprazole is administered orally or intravenously. Using the area under the plasma concentration-time curve (AUC) as an indirect measure of drug exposure in plasma, a correlation between acid secretion inhibition and drug exposure after oral administration of esomeprazole has been demonstrated. In healthy volunteers receiving intravenous esomeprazole 80 mg as a 30-minute bolus infusion followed by a continuous intravenous infusion at 8 mg/hour for 23.5 hours, intragastric pH remained above 4 and above 6 for a mean of 21 hours and 11–13 hours, respectively, over a 24-hour period.

Therapeutic Effect of Acid Secretion Suppression

With oral administration of esomeprazole 40 mg, approximately 78% of patients with reflux esophagitis heal within 4 weeks and 93% within 8 weeks of treatment. In a randomized, double-blind, placebo-controlled clinical trial, patients with endoscopically confirmed peptic ulcer (Forrest class Ia, Ib, IIa, or IIb; 9%, 43%, 38%, and 10%, respectively) were randomized to receive intravenous esomeprazole (n=375) or placebo (n=389). After endoscopic hemostasis, patients received either esomeprazole 80 mg as a 30-minute intravenous infusion followed by a continuous infusion at 8 mg/hour, or placebo for 72 hours. After the initial 72-hour period, all patients were switched to open-label oral esomeprazole 40 mg once daily for 27 days to maintain acid suppression. The rebleeding rate within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, the rebleeding rates were 7.7% in the esomeprazole group and 13.6% in the placebo group.

Other Effects Related to Acid Secretion Suppression

During treatment with acid-suppressing agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also rise due to decreased gastric acidity. Elevated CgA levels may interfere with laboratory tests for neuroendocrine tumors. Published data suggest that proton pump inhibitor (PPI) treatment should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels to allow normalization, as CgA levels may remain elevated after PPI therapy.

An increase in enterochromaffin-like (ECL) cell numbers, possibly related to elevated gastrin levels, has been observed in some patients during long-term oral esomeprazole therapy. These findings are considered clinically insignificant.

During long-term treatment with oral acid-suppressing agents, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are considered a physiological consequence of profound acid secretion suppression and are benign and reversible.

Reduced gastric acidity, regardless of cause, including PPI use, leads to increased bacterial colonization in the stomach, particularly of organisms normally present in the gastrointestinal tract. PPI therapy may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly Clostridium difficile in hospitalized patients.

Children

In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of the drug were evaluated 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 continued for an additional 4 weeks (double-blind, treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or treatment discontinuation due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the drug were evaluated in patients with GERD. Esomeprazole 0.5 mg/kg once daily was administered orally for at least 10 days. No significant difference was observed between esomeprazole and placebo regarding the primary endpoint of change in the number of GERD symptom episodes compared to baseline.

Results from studies in pediatric patients indicate that esomeprazole doses of 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intragastric pH <4.0. The safety profile of the drug was similar to that observed in adults.

In a study involving pediatric patients with GERD (aged <1 to 17 years) receiving long-term PPI therapy, ECL cell hyperplasia of minor degree was observed in 61% of children, the clinical significance of which was unknown; no cases of atrophic gastritis or carcinoid tumors were reported.

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 Elimination

Esomeprazole is completely metabolized by the cytochrome P450 (CYP) system. The major part of esomeprazole metabolism is dependent on the polymorphic CYP2C19 enzyme, responsible for the formation of hydroxy- and desmethyl metabolites. The remainder is metabolized by another specific isoenzyme, CYP3A4, which mediates the formation of esomeprazole sulfone, the main metabolite in plasma.

The following parameters primarily reflect pharmacokinetics in individuals with functional CYP2C19 enzyme (i.e., extensive metabolizers). 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 with repeated once-daily dosing. Esomeprazole is completely cleared from plasma between doses, and no tendency for accumulation is observed with once-daily administration. The main metabolites of esomeprazole do not affect gastric acid secretion. Approximately 80% of an oral dose is excreted in urine as metabolites, and the remainder in feces. Less than 1% of the parent compound is excreted in urine. AUC increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a nonlinear relationship between dose and AUC after repeated dosing. This time- and dose-dependency is likely due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

After repeated administration of 40 mg esomeprazole as intravenous injections, the mean peak plasma concentration is approximately 13.6 µmol/L. The mean peak 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 to oral dosing. A linear, dose-dependent increase in exposure was observed after administration of esomeprazole as a 30-minute intravenous infusion (40 mg, 80 mg, or 120 mg) followed by continuous infusion (4 mg/h or 8 mg/h) for 23.5 hours.

Special Patient Groups

Slow Metabolizers

Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and are termed poor metabolizers. In these individuals, esomeprazole metabolism is likely primarily catalyzed by CYP3A4. After multiple oral doses of 40 mg esomeprazole once daily, mean total exposure was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). The mean peak plasma concentration was approximately 60% higher. Similar differences were observed with intravenous administration. These data do not necessitate dosage adjustments for esomeprazole.

Gender

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

Hepatic Impairment

Metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of total esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed a maximum dose of 20 mg. In cases of bleeding ulcer with severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.

Renal Impairment

No studies have been conducted in patients with impaired 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 renal impairment.

Elderly Patients

Esomeprazole metabolism is only slightly altered in elderly individuals (71–80 years).

Children

In a randomized, open-label, multinational, multiple-dose study, esomeprazole was administered as a 3-minute intravenous injection once daily for 4 days. A total of 59 children aged 0 to 18 years were enrolled, and pharmacokinetics were evaluated in 50 patients (including 7 children aged 1 to 5 years) who completed the study.

Table 1 presents the systemic exposure of esomeprazole after 3-minute intravenous injection in pediatric patients and healthy adult volunteers. Values in Table 1 are expressed as geometric means (range). The 20 mg dose in adults was administered as a 30-minute infusion. Maximum steady-state plasma concentration (Css,max) was measured 5 minutes after dosing in all pediatric age groups, and 7 minutes after dosing in adults receiving 40 mg, and at the end of the 20 mg infusion.

Table 1

Age group	Dose group	AUC (μmol×h/L)	Css, max (μmol/L)
0–1 month*	0.5 mg/kg (n = 6)	7.5 (4.5–20.5)	3.7 (2.7–5.8)
1–11 months*	1.0 mg/kg (n = 6)	10.5 (4.5–22.5)	8.7 (4.5–14.0)
1–5 years	10 mg (n = 7)	7.9 (2.9–16.6)	9.4 (4.4–17.2)
6–11 years	10 mg (n = 8)	6.9 (3.5–10.9)	5.6 (3.1–13.2)
	20 mg (n = 8)	14.4 (7.2–42.3)	8.8 (3.4–29.4)
	20 mg (n = 6)**	10.1 (7.2–13.7)	8.1 (3.4–29.4)
12–17 years	20 mg (n = 6)	8.1 (4.7–15.9)	7.1 (4.8–9.0)
	40 mg (n = 8)	17.6 (13.1–19.8)	10.5 (7.8–14.2)
Adults	20 mg (n = 22)	5.1 (1.5–11.8)	3.9 (1.5–6.7)
	40 mg (n = 41)	12.6 (4.8–21.7)	8.5 (5.4–17.9)

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

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

According to the developed model, Css,max after intravenous administration of esomeprazole via 10-minute, 20-minute, and 30-minute infusions will decrease by 37–49%, 54–66%, and 61–72%, respectively, across all age groups and dosing groups compared to Css,max after a 3-minute injection.

Clinical characteristics.

Indications.

Adults:

• Antisecretory therapy when oral administration is not feasible, for example:

• gastroesophageal reflux disease (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.

• Prevention of recurrent bleeding 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 feasible, for example:

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

Contraindications.

• 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 medicinal products

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible via inhibition of CYP2C19. Reduced serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these medicinal products is not recommended. Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (decrease in AUC, maximum concentration [Cmax], and minimum concentration [Cmin] by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%. Increased serum concentrations of saquinavir (co-administered with ritonavir) (80–100%) were observed with concomitant omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect the exposure of darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily did not affect the exposure of amprenavir (with or without ritonavir). Administration of omeprazole 40 mg daily did not alter the exposure of lopinavir (in combination with ritonavir). Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Methotrexate.

When methotrexate is used concomitantly with PPIs, its levels have increased in some patients. Temporary discontinuation of esomeprazole may be required when high-dose methotrexate is administered.

Tacrolimus.

Elevated serum levels of tacrolimus have been reported with concomitant use of esomeprazole. Close monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and dosage adjustment of tacrolimus may be necessary.

Medicinal products whose absorption is pH-dependent.

Suppression of gastric secretion during therapy with esomeprazole and other PPIs may lead to reduced or enhanced absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of digoxin may be increased during esomeprazole therapy. In healthy volunteers, concomitant administration of omeprazole (20 mg daily) and digoxin increased digoxin bioavailability by 10% (up to 30% in two out of ten participants). Digoxin toxicity has been reported rarely. However, caution should be exercised when high doses of esomeprazole are used in elderly patients. Monitoring of digoxin blood concentrations is necessary.

Medicinal products metabolized by CYP2C19.

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, their plasma concentrations may increase, and dose reduction may be required. In vivo interaction studies using intravenous formulations at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on medicinal products metabolized by CYP2C19 during such treatment regimens may be more pronounced, and patients should be closely monitored for adverse events during the 3-day intravenous treatment period.

Diazepam.

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

Phenytoin.

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased the minimum plasma concentration of phenytoin in epileptic patients by 13%. Monitoring of phenytoin plasma concentrations is recommended at the initiation and discontinuation of esomeprazole therapy.

Voriconazole.

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

Cilostazol.

Omeprazole, like esomeprazole, is an inhibitor of CYP2C19. In a crossover study in healthy volunteers, omeprazole 40 mg daily increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Cisapride.

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

Warfarin.

During a clinical study, co-administration of 40 mg esomeprazole orally with warfarin resulted in blood clotting time remaining within the normal range. However, during the post-marketing period, several isolated cases of clinically significant increases in the international normalized ratio (INR) have been reported with concomitant use of these medicinal products. Monitoring is recommended at the start and end of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel.

Results from pharmacokinetic (PK)/pharmacodynamic (PD) interaction studies in healthy volunteers evaluating clopidogrel (loading dose 300 mg/maintenance dose 75 mg daily) and esomeprazole (oral 40 mg daily) showed a mean 40% reduction in exposure to the active metabolite of clopidogrel and a mean 14% reduction in maximum platelet aggregation inhibition (ADP-induced).

In a study in healthy volunteers, when clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in fixed-dose combination (20 mg + 81 mg, respectively) compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. However, maximum levels of platelet aggregation inhibition (ADP-induced) were similar between the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA. Observational and clinical studies have yielded conflicting data on the clinical implications of the PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Medicinal products studied without clinically significant interaction.

Amoxicillin or quinidine.

It has been demonstrated that esomeprazole does not have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib.

No pharmacokinetic interaction was observed during short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib.

Effect of other medicinal products on the pharmacokinetics of esomeprazole.

Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubled the AUC of esomeprazole. Concomitant administration of esomeprazole with combined inhibitors of CYP2C19 and CYP3A4 may increase esomeprazole exposure by more than twofold. The combined CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always necessary in such cases. However, it may be required in patients with severe hepatic impairment or when long-term treatment is indicated.

Medicinal products that induce CYP2C19 and/or CYP3A4 activity.

Rifampicin and St. John’s wort, for example, which can induce CYP2C19 and/or CYP3A4 activity, may reduce serum concentrations of esomeprazole by enhancing its metabolism.

Children.

Drug interaction studies have been conducted only in adults.

Special precautions for use.

In the event of any alarming symptoms (e.g., significant unanticipated weight loss, recurrent vomiting, dysphagia, hematemesis or melena) or suspicion of, or existing, gastric ulcer, malignancy should be ruled out, as Esoprotekt 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 "Pharmacodynamics").

Vitamin B12 absorption.

Esomeprazole, like all medicinal products that inhibit acid secretion, may suppress vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered in patients with low body stores of vitamin B12 or risk factors for impaired vitamin B12 absorption during long-term therapy.

Hypomagnesaemia.

Cases of severe hypomagnesaemia have been reported in patients treated with PPIs such as esomeprazole for at least three months, and in most cases, for over a year. Hypomagnesaemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its development may be gradual and remain unnoticed. In most patients with hypomagnesaemia, condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients requiring long-term treatment or those taking PPIs concomitantly with digoxin or medicinal products that may cause hypomagnesaemia (e.g., diuretics), it may be advisable to measure magnesium levels before starting PPI therapy and periodically during treatment.

Risk of fractures.

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

Subacute cutaneous lupus erythematosus.

PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Esoprotekt should be considered. Development of subacute cutaneous lupus erythematosus during previous PPI therapy may increase the risk of recurrence with other PPIs.

Combination with other medicinal products.

Concomitant use of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If combination of atazanavir with a PPI is considered essential, close monitoring of the patient is recommended, and the atazanavir dose should be increased to 400 mg in combination with 100 mg ritonavir; the esomeprazole dose should not exceed 20 mg. Esomeprazole is a CYP2C19 inhibitor. Potential interactions with medicinal products metabolized by CYP2C19 should be considered at the beginning and end of esomeprazole therapy. An interaction between clopidogrel and omeprazole has been reported (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction has not been fully established. As a precautionary measure, 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), some of which may be life-threatening, have been reported during esomeprazole treatment.

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

If signs or symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately, and additional medical care or close monitoring should be provided. Re-administration of the medicinal product is not recommended in patients with erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with neuroendocrine tumour diagnosis. To avoid this, esomeprazole should be temporarily discontinued at least five days before CgA measurement. If CgA and gastrin levels have not normalized after initial measurement, repeat measurements should be performed 14 days after stopping PPI treatment.

Important information about excipients.

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

Use during pregnancy or breastfeeding.

Data on the use of Esoprotekt during pregnancy are limited. Epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy provide somewhat more data, indicating no risk of congenital malformations or fetal toxicity. Animal studies have not shown direct or indirect harmful effects on embryofetal development. Studies in animals with the racemic mixture do not indicate any direct or indirect adverse effects on pregnancy, delivery, or postnatal development. Esoprotekt should be used during pregnancy only if clearly needed. A moderate amount of data in pregnant women (from 300 to 1000 pregnancy outcomes) indicates no malformative or toxic effects of esomeprazole on the fetus or newborn health. Animal studies indicate no direct or indirect harmful effect of the medicinal product on reproductive function due to its toxicological impact.

Period of breastfeeding.

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

Fertility.

Results from animal studies with the racemic mixture of omeprazole indicate no effect of omeprazole on fertility following oral administration.

Ability to influence reaction speed when driving or operating machinery.

Esomeprazole has minimal influence on the ability to drive or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section "Adverse reactions"). If such disorders occur, patients should refrain from driving vehicles or operating machinery.

Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not feasible
Administer the medicinal product intravenously 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 of gastroesophageal reflux disease (GERD) is 20 mg once daily.

For treatment of gastric ulcers associated with NSAID use, the usual dose is 20 mg once daily.

For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be given the medicinal product at a dose of 20 mg once daily. Treatment with the intravenous medicinal product is usually short-term; patients should be switched to oral therapy as soon as possible.

Short-term maintenance of hemostasis and prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers

Following endoscopic therapy for acute bleeding from gastric or duodenal ulcers, administer 80 mg of the medicinal product as an intravenous bolus infusion over 30 minutes, followed by continuous intravenous infusion of the medicinal product at a rate of 8 mg/hour for 3 days (72 hours).

After parenteral treatment, therapy should be continued with oral acid-suppressive agents.

Administration method

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

Injections

Dose of 40 mg
Administer 5 mL of reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes.

Dose of 20 mg
Administer 2.5 mL, or half of the reconstituted solution (8 mg/mL), as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Infusions

Dose of 40 mg
Administer the reconstituted solution as an intravenous infusion over 10–30 minutes.

Dose of 20 mg
Administer half of the reconstituted solution as an intravenous infusion over 10–30 minutes. Any unused solution should be discarded.

Bolus dose of 80 mg
Administer the reconstituted solution as a continuous intravenous infusion over 30 minutes.

Dose of 8 mg/hour
Administer the reconstituted solution as a continuous intravenous infusion over 71.5 hours (infusion rate calculated at 8 mg/hour; the stability period of the reconstituted solution is specified in the section «Shelf life»).

Special patient groups

Renal impairment
Dose adjustment is not required in patients with renal impairment. However, since experience with the medicinal product in patients with severe renal impairment is limited, these patients should be treated with caution (see section «Pharmacokinetics»).

Hepatic impairment
GERD: dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the maximum dose of Esoprotec should not exceed 20 mg (see section «Pharmacokinetics»).
Bleeding ulcers: dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, after administration of the initial 80 mg bolus dose of Esoprotec for infusion, continued administration as a continuous intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section «Pharmacokinetics»).

Elderly patients
Dose adjustment is not required.

Children

Dosage

Children aged 1–18 years

As an agent for inhibition of gastric secretion when oral administration of the medicinal product is not possible
For patients unable to take medicinal products orally, parenteral administration once daily is recommended throughout the full course of GERD treatment (doses are specified in Table 2).

Treatment with the intravenous medicinal product is usually short-term; patients should be switched to oral therapy as soon as possible.

Table 2
Recommended intravenous doses of esomeprazole

Age group	Treatment of erosive reflux esophagitis	Symptomatic treatment of GERD
1–11 years	Body weight <20 kg: 10 mg once daily Body weight ≥20 kg: 10 or 20 mg once daily	10 mg once daily
12–18 years	40 mg once daily	20 mg once daily

Method of administration.

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

Injections.

Dose of 40 mg.

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

Dose of 20 mg.

2.5 ml or half of the reconstituted solution (8 mg/ml) should be administered as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Dose of 10 mg.

1.25 ml of reconstituted solution (8 mg/ml) should be administered as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Infusions.

Dose of 40 mg.

The reconstituted solution should be administered as an intravenous infusion over 10–30 minutes.

Dose of 20 mg.

Half of the reconstituted solution should be administered as an intravenous infusion over 10–30 minutes. Any unused solution should be discarded.

Dose of 10 mg.

A quarter of the reconstituted solution should be administered as an intravenous infusion over 10–30 minutes. Any unused solution should be discarded.

Instructions for use, handling and disposal (where applicable).
Before administration, the reconstituted solution should be inspected visually for particulate matter and discoloration. Only clear solutions should be used. The solution is intended for single use only. If the entire reconstituted content of the vial is not required, any unused solution should be discarded according to local requirements.

Injection solution 40 mg.

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

The reconstituted injection solution is clear and colourless or slightly yellow.

Infusion solution 40 mg.

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

Infusion solution 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 infusion solution is clear and colourless or slightly yellow.

Children.

Can be used in children from the age of 1 year as an antisecretory agent when oral administration is not possible.

Overdose.

Experience with intentional overdose is currently very limited.

Symptoms. Symptoms observed after oral administration of a 280 mg dose included gastrointestinal effects and weakness. A single oral dose of 80 mg of esomeprazole and intravenous administration of 308 mg of esomeprazole over 24 hours did not result in any adverse outcomes.

Treatment. There is no specific antidote. Esomeprazole is highly protein-bound in plasma and therefore is poorly dialysed. As with any overdose, symptomatic treatment and general supportive measures should be employed.

Adverse reactions.

Summary of the safety profile for the active substance

Among the adverse reactions most commonly observed during clinical trials (as well as in the post-marketing period of esomeprazole use), headache, abdominal pain, diarrhea, and nausea were reported. In addition, the safety profile of esomeprazole is consistent across different pharmaceutical forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified. List of adverse reactions (see Table 3).

The adverse reactions listed below have been identified or suspected in the clinical development program of esomeprazole following its oral or intravenous administration, as well as during post-marketing surveillance of oral esomeprazole use.

All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Table 3

System organ class	Frequency	Adverse reaction
Blood and lymphatic system disorders	Uncommon	Leukopenia, thrombocytopenia
	Very rare	Agranulocytosis, pancytopenia
Immune system disorders	Uncommon	Hypersensitivity reactions, e.g. fever, angioneurotic oedema and anaphylactic reactions/shock
Metabolism and nutrition disorders	Uncommon	Peripheral oedema
	Uncommon	Hypomagnesaemia (see section "Special warnings and precautions for use"); severe hypomagnesaemia may correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
	Frequency unknown	Hypomagnesaemia (see section "Special warnings and precautions for use"); severe hypomagnesaemia may correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
Psychiatric disorders	Uncommon	Insomnia
	Uncommon	Excitement, confusion, depression
	Very rare	Aggression, hallucinations
Nervous system disorders	Common	Headache
	Uncommon	Dizziness, paraesthesia, somnolence
	Uncommon	Taste disturbance
Eye disorders	Uncommon	Blurred vision
Ear and labyrinth disorders	Uncommon	Vertigo
Respiratory, thoracic and mediastinal disorders	Uncommon	Respiratory depression
Gastrointestinal disorders	Common	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign)
	Uncommon	Dry mouth
	Uncommon	Stomatitis, gastrointestinal candidiasis
	Frequency unknown	Microscopic colitis
Hepatobiliary disorders	Uncommon	Elevated liver enzymes
	Uncommon	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
	Uncommon	Alopecia, photosensitivity
	Very rare	Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)
	Frequency unknown	Subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use")
Musculoskeletal and connective tissue disorders	Uncommon	Femur, wrist or spine fracture (see section "Special warnings and precautions for use")
	Uncommon	Arthralgia, myalgia
	Very rare	Muscle weakness
Renal and urinary disorders	Very rare	Interstitial nephritis (in some patients renal failure was also reported)
Reproductive system and breast disorders	Very rare	Gynaecomastia
General disorders and administration site conditions	Uncommon	Malaise, increased sweating

*Injection site reactions were observed primarily in a study using high doses of the medicinal product administered over 3 days (72 hours).

Irreversible visual disturbances have been reported in isolated cases in critically ill patients receiving omeprazole (racemate) as intravenous injection, particularly at high doses; however, a causal relationship has not been established. Pediatric population. A randomized, open-label, international study was conducted to evaluate the pharmacokinetics of multiple intravenous administrations of esomeprazole once daily over 4 days in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients (including 8 children aged 1–5 years) were included in the safety assessment. The safety data were consistent with the known safety profile of esomeprazole, and no new patient safety concerns were identified.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

A vial stored without original packaging may be kept for up to 24 hours at a temperature not exceeding 25 °C. Storage after reconstitution: from a microbiological point of view, the prepared solution should be used immediately.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities. This medicinal product should not be mixed with other medicinal products except those specified in the section "Method of administration and dosage."

Packaging. 40 mg in a vial, 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

VEM Ilac San. ve Tic. A.S.

Manufacturer's address and location of operations.

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Boulevard No 38, Kapakli / Tekirdag / Turkey.