Ezonexa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESONEXA® (ESONEXA)

Composition:

Active substance: esomeprazole;

One vial contains sodium esomeprazole 42.5 mg, equivalent to esomeprazole 40 mg;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Main physicochemical properties: porous lyophilized powder of white or almost white color.

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

ATC code: A02BC05.

Pharmacological Properties.

Pharmacodynamics.

Esomeprazole is the S-isomer of omeprazole that inhibits gastric acid secretion through a specific, targeted mechanism of action. It is a specific inhibitor of the H+/K+-ATPase enzyme (proton pump) in the parietal cells. Both the R- and S-isomers of omeprazole have similar pharmacological activity.

Mechanism and Site 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, where it inhibits the H+/K+-ATPase enzyme (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, 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 following both oral and intravenous administration.

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

Following intravenous administration of esomeprazole 80 mg as a 30-minute bolus infusion followed by a continuous intravenous infusion at 8 mg/hour for 23.5 hours in healthy volunteers, 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 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 in patients with endoscopically confirmed peptic ulcer (Forrest class Ia, Ib, IIa, or IIb; 9%, 43%, 38%, and 10%, respectively), patients were randomized to receive esomeprazole infusion (n = 375) or placebo (n = 389). After endoscopic hemostasis, patients received either intravenous esomeprazole 80 mg as a 30-minute 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-suppressive agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric acidity. Elevated CgA levels may affect laboratory test results for neuroendocrine tumor detection. Published data indicate that proton pump inhibitor (PPI) treatment should be discontinued for a period of 5 days to 2 weeks prior to CgA measurement to allow normalization of CgA levels, as this parameter may be 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 treatment with oral esomeprazole.

A slight increase in the frequency of gastric glandular cyst formation has been observed during long-term treatment with oral acid-suppressive agents. These changes are a physiological consequence of pronounced inhibition 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, including bacteria normally present in the gastrointestinal tract. PPI treatment slightly increases the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also 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 in patients with signs and symptoms of GERD were evaluated. Esomeprazole 1 mg/kg once daily was administered orally for 2 weeks (open phase), and 80 patients continued into an additional 4-week period (double-blind treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or discontinuation due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the drug in patients with GERD were assessed. 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 show 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 during which intraluminal esophageal pH < 4.

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 treatment, ECL cell hyperplasia of mild degree was observed in 61% of children; the clinical significance of this finding 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 main part of esomeprazole metabolism depends on the polymorphic CYP2C19, responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remainder is mediated by another specific isoenzyme, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in plasma.

The parameters below primarily reflect the pharmacokinetics in individuals with functional CYP2C19 enzyme (i.e., rapid 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 is approximately 1.3 hours with repeated once-daily dosing.

Total exposure (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 due to reduced presystemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

Esomeprazole is completely cleared from plasma between doses, and no tendency for accumulation is observed with once-daily administration.

With repeated intravenous administration of 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. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared to oral administration. A linear, dose-dependent increase in exposure is observed when esomeprazole is administered 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.

The main metabolites of esomeprazole do not affect gastric acid secretion. Approximately 80% of an oral dose of esomeprazole is excreted in urine as metabolites, and the remainder in feces. Less than 1% of the parent compound is excreted in urine.

Special Patient Populations

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 esomeprazole 40 mg once daily, mean total exposure was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). Mean peak plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dosage adjustments for esomeprazole.

Elderly Patients

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

Gender

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

Hepatic Impairment

Metabolism of esomeprazole may be altered 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 esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed the 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 tend 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 elimination of esomeprazole metabolites but not the parent compound, changes in metabolism are not expected in patients with renal impairment.

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, of whom 50 (including 7 children aged 1 to 5 years) completed the study. Pharmacokinetics of esomeprazole were evaluated based on study results.

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 presented as geometric means (range). The 20 mg dose in adults was administered as a 30-minute infusion. The 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 weeks and < 44 weeks. The age group from 1 to 11 months included patients with postmenstrual age ≥ 44 weeks.

** Two patients were excluded: one most likely due to reduced CYP2C19 isoenzyme activity, and 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 dose groups, compared to Css,max after a 3-minute injection.

Clinical characteristics.

Indications.

Adults

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

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

• treatment of 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 recurrent bleeding in patients following endoscopic treatment of acute bleeding from gastric or duodenal ulcers.

Children aged 1 to 18 years

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

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

Contraindications.

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

Esomeprazole should not be used concomitantly with atazanavir or 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 been conducted only in adults.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent. Suppression of gastric acid secretion during therapy with esomeprazole and other proton pump inhibitors (PPIs) may lead to reduced or increased 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 treatment. In healthy volunteers, concomitant administration of omeprazole (20 mg daily) and digoxin increased digoxin bioavailability by 10% (up to 30% in two of ten participants). Digoxin toxicity has been reported rarely. However, caution should be exercised when administering high doses of esomeprazole to elderly patients. Monitoring of digoxin blood concentrations is recommended.

Protease inhibitors. Interactions between omeprazole and certain protease inhibitors have been observed. 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. Decreased serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these drugs 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 (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 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 use of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin 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/day 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. Methotrexate levels increased in some patients when used concomitantly with PPIs. Temporary discontinuation of esomeprazole may be necessary 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; dose adjustment of tacrolimus may be 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, phenytoin, etc., plasma concentrations of these drugs may increase, and dose reduction may be required. In vivo interaction studies using the intravenous formulation at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on drugs 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 reduced the clearance of diazepam (a CYP2C19 substrate) by 45%.

Phenytoin. Concomitant oral administration of 40 mg esomeprazole and phenytoin increased the minimum plasma concentration of phenytoin in epileptic patients by 13%. Monitoring of plasma phenytoin 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.

Warfarin. In a clinical study, concomitant oral administration of 40 mg esomeprazole to patients taking 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. Results from pharmacokinetic (PK)/pharmacodynamic (PD) interaction studies in healthy volunteers receiving clopidogrel (loading dose 300 mg / maintenance dose 75 mg daily) and esomeprazole (40 mg orally daily) showed a mean 40% reduction in exposure to clopidogrel's active metabolite and a mean 14% reduction in maximum platelet aggregation inhibition (ADP-induced).

In a study in healthy volunteers, when clopidogrel was administered with esomeprazole and acetylsalicylic acid (ASA) in fixed combination doses (20 mg + 81 mg, respectively), exposure to clopidogrel's active metabolite decreased by nearly 40% compared to clopidogrel monotherapy. 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 regarding the clinical significance of this PK/PD interaction in terms of major cardiovascular events. Concomitant use of esomeprazole and clopidogrel should be avoided.

Cilostazol. Omeprazole, like esomeprazole, is a CYP2C19 inhibitor. 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%.

Cisapride. Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers increased the area under the concentration-time curve (AUC) by 32% and the elimination half-life (t1/2) by 31%, but no significant increase in maximum plasma concentration of cisapride was observed. The slight QTc prolongation observed with cisapride alone was not increased when cisapride was administered with esomeprazole.

Medicinal products studied 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 during short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib.

Effect of other medicinal products on esomeprazole pharmacokinetics

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 use of esomeprazole with combined CYP2C19 and CYP3A4 inhibitors may increase esomeprazole exposure by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always required in such cases. However, it may be necessary in patients with severe hepatic impairment or when long-term treatment is indicated.

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

Medicinal products capable of inducing CYP2C19 and/or CYP3A4 activity (such as rifampicin and St. John's wort) may reduce serum concentrations of esomeprazole due to enhanced metabolism.

Special precautions for use.

In case of any alarming symptoms (such as significant unexpected weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be ruled out, since Esoneksa® may mask symptoms and delay diagnosis.

Gastrointestinal infections

PPI therapy slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B12 absorption

Esomeprazole, like all acid secretion-blocking agents, may impair vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered when treating patients with low body stores of vitamin B12 or with risk factors for impaired vitamin B12 absorption during long-term therapy.

Combination with other medicinal products

Concomitant use of esomeprazole and atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If co-administration 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 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. Concomitant use of esomeprazole and clopidogrel is not recommended.

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 or longer. Hypomagnesemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, but its onset may be gradual and remain unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients requiring long-term PPI therapy or those taking PPIs concomitantly with digoxin or medications capable of causing hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before initiating PPI therapy and periodically during treatment.

Fracture risk

PPIs, particularly when used at high doses and for prolonged periods (>1 year), are associated with a slightly increased 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 increase may be partly attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should receive adequate intake of vitamin D and calcium.

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, patients should seek immediate medical advice, and discontinuation of Esoneksa® should be considered. Previous occurrence of subacute cutaneous lupus erythematosus during prior PPI therapy increases the risk of recurrence with other PPIs.

Severe cutaneous adverse reactions (SCARs)

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

Patients should be informed about signs and symptoms of severe skin reactions

EM/SJS/TEN/DRESS and the need to seek immediate medical attention from their physician if any of these signs or symptoms occur. Esomeprazole therapy should be discontinued immediately upon the first signs or symptoms of severe skin reactions, and additional medical care and close monitoring should be provided as needed. Esomeprazole should not be re-administered to patients who have experienced EM/SJS/TEN/DRESS.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels 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 are not normalized after the initial measurement, repeat testing should be performed 14 days after discontinuation of PPI therapy.

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

Use during pregnancy or breastfeeding.

Data on the use of esomeprazole during pregnancy are limited. A larger amount of epidemiological data on the use of racemic omeprazole during pregnancy suggests no 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 do not indicate any direct or indirect adverse effects on pregnancy, delivery, or postnatal development; however, Esoneksa® should be used during pregnancy only with caution.

Data from pregnant women (from 300 to 1000 pregnancy cases) indicate no teratogenic effects or toxic influence of esomeprazole on the fetus or the health of the newborn.

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

Breastfeeding

It is unknown whether esomeprazole passes into breast milk. No studies have been conducted in breastfeeding women; therefore, Esoneksa® should not be used during breastfeeding.

Fertility

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

Method of Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients who cannot take the medication orally, 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 be prescribed the drug at a dose of 20 mg once daily.

Treatment with the intravenous formulation of the drug 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 the drug as an intravenous bolus infusion over 30 minutes, followed by continuous intravenous infusion at a rate of 8 mg/hour for 3 days (72 hours).

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

Method of Administration

Instructions for preparing the reconstituted solution are provided below in this section («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 an intravenous infusion over 30 minutes.

Dose of 8 mg/hour

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

Renal Impairment

Dose adjustment is not required in patients with renal impairment. However, since experience with the use of the drug in patients with severe renal impairment is limited, the drug should be used with caution in such patients (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 Nexium® should not exceed 20 mg (see section «Pharmacokinetics»).

Bleeding ulcers: dose adjustment is not required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, after administration of the initial 80 mg bolus dose of Nexium®, continued 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 is not possible

For children who cannot take the drug orally, parenteral administration once daily may be used throughout the full course of treatment for GERD (doses are specified in Table 2).

Intravenous esomeprazole treatment is generally short-term, and children should be switched to oral medication 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 must 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 must 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 must 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 must 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 for single use only.

Any unused solution should be disposed of 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 40 mg esomeprazole vial.

The reconstituted injection solution is clear and colorless or slightly yellowish.

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 colorless or slightly yellowish.

Children

Esomeprazole may be used in children aged 1 year and older as an antisecretory agent when oral administration is not feasible.

Overdose

Experience with intentional overdose is currently very limited. Symptoms observed after oral administration of a 280 mg dose included gastrointestinal disturbances and weakness. A single oral dose of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any adverse outcomes. There is no specific antidote. Esomeprazole is highly bound to plasma proteins and therefore is not effectively removed by dialysis. As with any overdose, symptomatic treatment and general supportive measures should be applied.

Adverse Reactions

The most commonly reported adverse reactions during clinical trials and post-marketing use include headache, abdominal pain, diarrhea, and nausea. The safety profile is consistent across different dosage forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

The adverse reactions listed below were observed or suspected in clinical trials of esomeprazole following oral or intravenous administration, as well as during post-marketing surveillance of oral use. Reactions are categorized by 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); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: leukopenia, thrombocytopenia;
Very rare: agranulocytosis, pancytopenia.

Immune system disorders:

Rare: hypersensitivity reactions, e.g., fever, angioedema, anaphylactic reactions/shock.

Metabolism and nutrition disorders:

Uncommon: peripheral edema;
Rare: hyponatremia;
Frequency not known: hypomagnesemia (see section "Special Warnings and Precautions for Use"); severe hypomagnesemia may be associated with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders:

Uncommon: insomnia;
Rare: agitation, confusion, depression;
Very rare: aggression, hallucinations.

Nervous system disorders:

Common: headache;
Uncommon: dizziness, paraesthesia, somnolence;
Rare: taste disturbance.

Eye disorders:

Uncommon: blurred vision.

Ear and labyrinth disorders:

Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders:

Rare: bronchospasm.

Gastrointestinal disorders:

Common: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign);
Uncommon: dry mouth;
Rare: stomatitis, gastrointestinal candidiasis;
Frequency not known: microscopic colitis.

Hepatobiliary disorders:

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: infusion site reactions*;
Uncommon: dermatitis, pruritus, rash, urticaria;
Rare: alopecia, photosensitivity;
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS);
Frequency not known: subacute cutaneous lupus erythematosus (see section "Special Warnings and Precautions for Use").

Musculoskeletal and connective tissue disorders:

Uncommon: fractures of the hip, wrist, or spine (see section "Special Warnings and Precautions for Use");
Rare: arthralgia, myalgia;
Very rare: muscle weakness.

Renal and urinary disorders:

Very rare: interstitial nephritis; in some patients, renal failure has been observed.

Reproductive system and breast disorders:

Very rare: gynecomastia.

General disorders and administration site conditions:

Rare: malaise, increased sweating.

*Infusion site reactions were mainly observed in a study using high doses over 3 days (72 hours).

Irreversible visual disturbances have been reported in isolated cases in critically ill patients receiving intravenous omeprazole (racemate), particularly at high doses; however, a causal relationship has not been established.

Paediatric population

A randomized, open-label international study was conducted to evaluate the pharmacokinetics of multiple-dose intravenous esomeprazole administered once daily for 4 days in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients were included in the safety assessment (including 8 children aged 1–5 years). Results were consistent with the known safety profile of esomeprazole, and no new safety concerns were identified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life.

2 years.

Storage period after reconstitution: Chemical and physical in-use stability has been demonstrated for 12 hours at 30°C. From a microbiological standpoint, the product should be used immediately.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Vials may be kept without secondary packaging under normal indoor lighting for up to 24 hours.

Keep out of reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and Administration."

Packaging. 10 ml in a vial. 1, 5, or 10 vials per carton (manufactured from bulk packaging by Laboratorios Normon S.A., Spain).

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.