Sterepraz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STEPREZ

Composition:

Active substance: esomeprazole;

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

Excipients: edetate disodium, sodium hydroxide, water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole and inhibits gastric acid secretion through a specific, targeted mechanism of action. It is a specific inhibitor of the H+/K+-ATPase enzyme (the proton pump) in the 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 into its active form in the highly acidic environment of the secretory canaliculi of the parietal cells. There, it inhibits the H+/K+-ATPase enzyme (the proton pump), thereby suppressing both basal and stimulated acid secretion.

Effect on Gastric Acid Secretion

After 5 days of oral administration of 20 mg and 40 mg esomeprazole, gastric pH remained above 4 for an average of 13 hours and 17 hours, respectively, within a 24-hour interval in patients with symptomatic gastroesophageal reflux disease (GERD). The effect is similar regardless of whether esomeprazole is administered orally or intravenously.

Using AUC as a surrogate parameter for plasma drug concentration, a relationship between acid secretion inhibition and exposure has been demonstrated after oral administration of esomeprazole.

In healthy volunteers receiving intravenous esomeprazole at a dose of 80 mg as a 30-minute bolus infusion followed by a continuous infusion at 8 mg/hour for 23.5 hours, gastric pH remained above 4 and above 6 for an average of 21 hours and 11–13 hours, respectively, within a 24-hour interval.

Therapeutic Effect of Acid Secretion Inhibition

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 classified as Forrest classes Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively) were randomized to receive either esomeprazole infusion solution (n = 375) or placebo (n = 389). After endoscopic hemostasis, patients received either intravenous esomeprazole 80 mg as a 30-minute bolus infusion followed by a continuous infusion at 8 mg/hour, or placebo for 72 hours. After the initial 72-hour period, all patients received open-label oral esomeprazole 40 mg daily for 27 days to suppress acid secretion. The rate of recurrent bleeding within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, the rates of recurrent bleeding in the esomeprazole and placebo groups were 7.7% and 13.6%, respectively.

Other Effects Related to Acid Secretion Inhibition

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 indicate that treatment with proton pump inhibitors (PPIs) should be temporarily discontinued at least five days before measuring CgA levels to allow normalization, as these levels may remain elevated after PPI therapy. If CgA and gastrin levels do not normalize after the initial measurement, repeat testing should be performed 14 days after discontinuation of 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 treatment.

During prolonged treatment with oral acid-suppressing agents, a slight increase in the frequency of gastric glandular cysts has been noted. These changes are a physiological consequence of pronounced suppression of gastric acid secretion and are benign and reversible.

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial colonization in the stomach, particularly of bacteria normally present in the gastrointestinal tract. 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.

Children

In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of esomeprazole were evaluated in patients with signs and symptoms of GERD. Esomeprazole 1 mg/kg once daily was administered orally for 2 weeks (open phase), followed by an additional 4-week double-blind, placebo-controlled withdrawal phase involving 80 patients. No significant difference was observed between esomeprazole and placebo regarding the primary endpoint of symptom worsening after treatment cessation.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of esomeprazole in patients with GERD were evaluated. 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, defined as change in the number of GERD symptom episodes compared to baseline.

Results from pediatric studies 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 intraesophageal pH <4.0. The safety profile of esomeprazole in children was similar to that in adults.

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

Pharmacokinetics

Distribution

The steady-state volume of distribution 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 majority of esomeprazole metabolism depends on the polymorphic CYP2C19, responsible for forming hydroxy- and desmethyl-metabolites of esomeprazole. The remainder is mediated by another specific isoenzyme, CYP3A4, which forms esomeprazole sulfone—the main metabolite in plasma.

The following parameters primarily reflect pharmacokinetics in individuals with functional CYP2C19 enzyme activity (i.e., extensive metabolizers).

Total plasma clearance is approximately 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life of esomeprazole 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.

Total exposure (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 dosing. This time- and dose-dependent relationship is due to reduced presystemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

With repeated intravenous administration of esomeprazole 40 mg, 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. Intravenous administration results in a smaller increase (approximately 30%) in total exposure compared to oral administration. A linear, dose-dependent increase in exposure was observed with 30-minute intravenous infusions of esomeprazole (40 mg, 80 mg, or 120 mg) followed by continuous infusion at 4 mg/h or 8 mg/h for 23.5 hours.

Special Patient Populations

Slow Metabolizers

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

Gender

After a single 40 mg dose, 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

Esomeprazole metabolism may be impaired in patients with mild to moderate hepatic dysfunction. In patients with severe liver 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, a continuous infusion of esomeprazole at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not tend to accumulate with once-daily administration.

Renal Impairment

Studies in patients with renal impairment have not been conducted. Since the kidneys are responsible for excreting esomeprazole metabolites but not the parent compound, significant changes in metabolism are not expected in patients with renal impairment.

Elderly Patients

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

Children

In a randomized, open-label, international 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 children (including 7 aged 1 to 5 years) who completed the study.

The table presents systemic exposure to esomeprazole after 3-minute intravenous injection in pediatric patients and adult healthy volunteers. Values 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) of esomeprazole was measured 5 minutes after dosing in all pediatric age groups and 7 minutes after dosing in adults receiving 40 mg and after completion of the 20 mg infusion.

Age group	Dose group	AUC (μmol*hr/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 corrected 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 corrected age ≥ 44 completed weeks.

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

According to the constructed model, Css,max after 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 dosage groups, compared to Css,max after a 3-minute intravenous injection.

Preclinical safety data

Available preclinical data obtained from traditional safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies do not indicate any special hazard for humans.

Carcinogenicity studies in rats following oral administration of the racemic omeprazole mixture showed gastric hyperplasia and carcinoids. These gastric effects are the result of prolonged marked hypergastrinemia, secondary to reduced gastric acid production, and are observed in rats after long-term treatment with gastric acid secretion inhibitors. In preclinical studies of intravenous esomeprazole administration, no vascular irritation was observed; however, a slight inflammatory tissue reaction at the injection site was noted following subcutaneous injection.

Clinical characteristics.

Indications.

Adults

Antisecretory therapy in cases where oral administration is not possible, such as:

• 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.

Short-term support of hemostasis and 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 possible in gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

Hypersensitivity to esomeprazole, other substituted benzimidazoles, or any of the excipients in the formulation.

Esomeprazole should not be used concomitantly with atazanavir and nelfinavir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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 the CYP2C19 enzyme. Reduced serum levels of atazanavir and nelfinavir have been reported with concomitant use of omeprazole; therefore, co-administration of these drugs is not recommended. Concomitant use of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (reduction in AUC, Cmax, and Cmin by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant use 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. Concomitant use 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%. Given the similar 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.

Increased serum concentrations of saquinavir (in combination with ritonavir) (80–100%) were observed with concomitant use of omeprazole 40 mg daily. Omeprazole 20 mg daily did not affect exposure of darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily did not affect exposure of amprenavir (in combination with ritonavir or alone). Administration of omeprazole 40 mg daily did not alter exposure of lopinavir (in combination with ritonavir).

Methotrexate

When methotrexate is used concomitantly with PPIs, its levels may increase 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 dose adjustment of tacrolimus may be necessary.

Medicinal products whose absorption is pH-dependent

Suppression of gastric acid secretion during therapy with esomeprazole and other PPIs may lead to reduced or increased absorption of drugs whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of substances such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of digoxin may be enhanced during esomeprazole therapy. When omeprazole (20 mg daily) and digoxin were administered concomitantly to healthy volunteers, digoxin bioavailability increased by 10% (up to 30% in two out of ten participants). Toxic effects of digoxin were rarely observed. However, caution should be exercised when high doses of esomeprazole are used in elderly patients taking digoxin. Monitoring of digoxin blood concentrations should be intensified.

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, phenytoin, etc., their plasma concentrations may increase, and dose reduction may be required. In vivo interaction studies using the intravenous formulation at high doses (80 mg + 8 mg/h) have not been conducted. The effect of esomeprazole on drugs metabolized by CYP2C19 under such treatment regimens may be more pronounced, and patients should be closely monitored for adverse events during the three-day infusion period.

Diazepam

Concomitant oral administration of 30 mg esomeprazole reduced the clearance of the CYP2C19 substrate diazepam by 45%.

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased the minimum plasma concentrations 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, administration of either drug at a dose of 40 mg 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 the area under the plasma concentration-time curve (AUC) by 32% and the elimination half-life (t1/2) by 31%, but no increase in maximum plasma concentration of cisapride was observed. The slight QTc prolongation observed with cisapride alone was not increased when cisapride was administered in combination with esomeprazole.

Warfarin

In a clinical trial, co-administration of 40 mg esomeprazole orally with warfarin did not alter blood coagulation time beyond acceptable limits. However, during the post-marketing period, several isolated cases of clinically significant increases in INR (International Normalized Ratio) have been reported with concomitant use of these drugs. Monitoring is recommended at the beginning and end of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

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

In a study in healthy volunteers, when clopidogrel was administered concomitantly with a fixed-dose combination of esomeprazole and acetylsalicylic acid (ASA) (20 mg + 81 mg) compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. However, maximum levels of inhibition of ADP-induced platelet aggregation were similar in the group receiving clopidogrel alone 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.

Investigated medicinal products without clinically significant interaction

• Amoxicillin or quinidine. Esomeprazole was shown not to have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.
• Naproxen or rofecoxib. No pharmacokinetic interaction was observed in short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Clarithromycin and voriconazole

Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubled esomeprazole exposure (AUC). Concomitant administration of esomeprazole with combined inhibitors of CYP2C19 and CYP3A4 may increase esomeprazole exposure by more than two-fold. The 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 in cases requiring long-term treatment.

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

Drugs capable of inducing CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may reduce esomeprazole serum concentrations by enhancing its metabolism.

Children

Drug interaction studies have not been conducted in children.

Special precautions for use.

If any alarming symptoms occur (such as significant unexpected weight loss, recurrent vomiting, dysphagia, hematemesis or melena) or if gastric ulcer is suspected or present, malignancy must be ruled out, as esomeprazole may mask symptoms and delay diagnosis.

Gastrointestinal infections

Treatment with proton pump inhibitors (PPIs) 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 agents that inhibit gastric acid secretion, may impair absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low vitamin B12 reserves or risk factors for impaired absorption during long-term therapy.

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least three months, and in most cases, for one year or longer. Hypomagnesemia may present serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its onset may be insidious and go unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients expected to undergo long-term treatment, or those taking PPIs concomitantly with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before initiating PPI therapy and periodically during treatment.

Risk of fractures

Proton pump inhibitors, particularly when used at high doses and over prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPIs may increase the overall fracture risk by 10–40%. This increased risk 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 intake.

Subacute cutaneous lupus erythematosus

The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions occur, particularly in sun-exposed areas, and are accompanied by joint pain, the patient should seek immediate medical advice, and discontinuation of the drug should be considered. Previous development of subacute cutaneous lupus erythematosus during treatment with PPIs may increase the risk of recurrence when other PPIs are used.

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 co-administration of atazanavir with proton pump inhibitors is considered necessary, close monitoring of the patient is recommended, and the dose of atazanavir should be increased to 400 mg in combination with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19 should be considered at the start 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 skin adverse reactions

Very rare cases of severe skin adverse reactions, such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with esomeprazole treatment, which may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of severe skin reactions (EM/SJS/TEN/DRESS syndrome) and advised to seek immediate medical attention if any symptoms of these reactions occur.

If severe skin reactions develop, esomeprazole should be discontinued immediately, and additional medical care and close monitoring should be provided as needed.

Esomeprazole must not be re-administered to patients who have experienced severe skin reactions such as EM/SJS/TEN/DRESS syndrome.

Effect on laboratory test results

Elevated levels of chromogranin A (CgA) may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole treatment should be temporarily discontinued at least five days before measuring CgA levels. If CgA and gastrin levels have not normalized after the initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially "sodium-free" (3.6 mg/0.156 mmol per vial).

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of esomeprazole during pregnancy are limited. Epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy show no increased risk of congenital malformations or fetotoxic effects. Animal studies have not revealed any direct or indirect harmful effects on embryofetal development.

Data from animal studies with the racemic mixture of omeprazole do not indicate any adverse effects on pregnancy, labor, or postnatal development.

A moderate amount of data from pregnant women (from 300 to 1000 pregnancies) indicates no teratogenic effects or toxic effects of esomeprazole on the fetus or newborn health.

Animal studies indicate no direct or indirect harmful effects of the drug on reproductive function due to its toxicity.

Esomeprazole should be used during pregnancy only if clearly needed and with caution.

Breastfeeding

It is unknown whether esomeprazole is excreted in human milk. Studies in breastfeeding women have not been conducted.

The medicinal product should not be used during breastfeeding.

Reproductive function

Animal studies with the racemic mixture of omeprazole indicate no effect of omeprazole on reproductive function following oral administration.

Ability to affect reaction speed when driving or operating machinery.

Esomeprazole has minimal effect 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 or operating machinery.

Administration and Dosage

Instructions for preparing the reconstituted solution are provided below in this section («Instructions for Use, Handling, and Disposal (where applicable)»).

ADULTS

Dosing

Antisecretory therapy when oral administration is not feasible. The drug may be administered 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 of gastroesophageal reflux disease 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 receive a dose of 20 mg once daily.

Treatment via intravenous administration is generally 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 esomeprazole as a 30-minute intravenous bolus infusion, followed by a continuous infusion of 8 mg/hour for 3 days (72 hours).

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

Method of Administration

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 (½) of 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 30-minute intravenous infusion.

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; shelf life 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 drug in patients with severe renal impairment is limited, such 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 esomeprazole 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 an initial 80 mg bolus dose, a continuous infusion at 4 mg/hour for 71.5 hours may be sufficient (see section «Pharmacokinetics»).

Elderly Patients

No dose adjustment is required.

PEDIATRIC POPULATION

Dosing

Children aged 1–18 years

As an agent for inhibition of gastric secretion when oral administration is not possible

For patients unable to take the drug orally, parenteral administration once daily may be used throughout the full course of treatment for GERD (doses are specified in the table below).

Intravenous treatment is generally short-term, and patients should be switched to oral therapy as soon as possible.

Recommended intravenous doses of esomeprazole for pediatric patients

Age group	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

Injections

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

20 mg dose: Administer 2.5 ml (½) of reconstituted solution (8 mg/ml) as an intravenous injection over at least 3 minutes.

10 mg dose: Administer 1.25 ml (¼) of reconstituted solution (8 mg/ml) as an intravenous injection over at least 3 minutes.

Any unused solution must be discarded.

Infusions

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

20 mg dose: Administer half of the reconstituted solution as an intravenous infusion over 10–30 minutes.

10 mg dose: Administer a quarter of the reconstituted solution as an intravenous infusion over 10–30 minutes.

Any unused solution must be discarded.

Instructions for Administration, Use, and Disposal (where applicable)

Before administration, visually inspect the reconstituted solution 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 must be discarded in accordance with local requirements.

Preparation of Solutions

Injection Solution

Prepare an injection solution (8 mg/ml) by dissolving the contents of one vial (40 mg of esomeprazole) in 5 ml of 0.9% sodium chloride for intravenous use.

The reconstituted injection solution should be clear and colorless or slightly yellowish.

Infusion Solution 40 mg

Prepare an infusion solution by dissolving the contents of one vial (40 mg of esomeprazole) 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 vials (80 mg of esomeprazole) in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted injection solution should be clear and colorless or slightly yellowish.

Children

The medicinal product may be administered to children aged 1 year and older as an antisecretory agent when oral administration is not feasible.

Overdose

Information on overdose is currently very limited. Symptoms observed following oral administration of 280 mg of esomeprazole 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 consequences. There is no known specific antidote. Esomeprazole is highly protein-bound in plasma and therefore is poorly removed by dialysis.

As with any overdose, symptomatic treatment and general supportive measures should be administered in case of esomeprazole overdose.

Adverse Reactions

Summary of Safety Profile

The most commonly reported adverse effects observed in clinical trials (as well as during the post-marketing period) with esomeprazole include headache, abdominal pain, diarrhea, and nausea. Furthermore, the safety profile of esomeprazole is consistent across different dosage forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

The table below lists adverse reactions categorized by system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, with frequencies specified as follows: 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); and not known (frequency cannot be estimated from available data).

System Organ Classes	Frequency	Adverse Reactions
Blood and lymphatic system disorders	Uncommon	Leukopenia, thrombocytopenia
	Very rare	Agranulocytosis, pancytopenia
Immune system disorders	Uncommon	Hypersensitivity reactions such as fever, angioneurotic edema, anaphylactic reactions/shock
Metabolism and nutrition disorders	Uncommon	Peripheral edema
	Uncommon	Hypomagnesemia. Severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
	Frequency unknown	Hypomagnesemia. Severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
Psychiatric disorders	Uncommon	Insomnia
	Uncommon	Restlessness, 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	Bronchospasm
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	Liver 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	Multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
	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 has also been reported)
Reproductive system and breast disorders	Very rare	Gynaecomastia
General disorders and administration site conditions	Uncommon	Malaise, increased sweating

* Reactions at the injection site were observed primarily in the study using high doses administered over 3 days (72 hours).

Irreversible visual disturbances were rarely reported in critically ill patients receiving intravenous omeprazole (racemate), 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-dose intravenous administration of esomeprazole over 4 days with once-daily dosing in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients were included in the safety study (including 8 children aged 1–5 years). The data obtained were consistent with the known safety profile of esomeprazole, and no new safety concerns were identified.

Reporting of adverse reactions

It is important to report adverse reactions occurring after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists should report any adverse reactions.

Shelf life. 1.5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

The reconstituted solution should be used immediately from a microbiological standpoint.

Packaging.

1 or 10 vials with powder in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Steril-Jen Life Sciences (P) Ltd.

Manufacturer's address and site of operation.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India.