Nexopral

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEXOPRAL

Composition:

Active substance: esomeprazole;

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

Excipients: edetate disodium, sodium hydroxide, nitrogen.

Pharmaceutical form: Powder for solution for injection and infusion.

Main physico-chemical properties: white or almost white, porous lyophilized powder.

Pharmacotherapeutic group: Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties

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

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, where it inhibits the H+/K+-ATPase enzyme—the proton pump—thereby suppressing both basal and stimulated acid secretion.

Pharmacodynamics

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 24 hours 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 a surrogate parameter for drug exposure in plasma, a relationship between acid secretion inhibition and exposure after oral administration of esomeprazole has been demonstrated.

In healthy volunteers, during intravenous administration of 80 mg esomeprazole as a 30-minute bolus infusion followed by continuous intravenous infusion at 8 mg/hour for 23.5 hours, intragastric pH above 4 and pH above 6 was maintained for a mean of 21 hours and 11–13 hours, respectively, over a 24-hour period.

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 bleeding of Forrest class 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 80 mg esomeprazole as an intravenous bolus over 30 minutes followed by 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 for 27 days to maintain acid suppression. The rate of recurrent bleeding within 3 days was 5.9% in the esomeprazole group compared to 10.3% in the placebo group. At 30 days after treatment, the rate of recurrent bleeding was 7.7% in the esomeprazole group versus 13.6% in the placebo group.

During treatment with acid-suppressing 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 interfere with laboratory tests for detecting neuroendocrine tumors. Available published data indicate that treatment with proton pump inhibitors (PPIs) should be discontinued between 5 days and 2 weeks before measuring CgA levels. This is necessary to allow CgA levels, which may be falsely elevated after PPI treatment, to return to baseline levels.

An increase in enterochromaffin-like (ECL) cells, possibly related to elevated serum gastrin levels, has been observed in both children and adults during long-term oral esomeprazole therapy. These findings are not considered clinically significant.

With prolonged oral treatment with acid-suppressing agents, a slight increase in the incidence of gastric glandular cysts has been reported. These changes are a physiological consequence of pronounced suppression of gastric acid secretion, are benign in nature, and resolve after discontinuation of treatment.

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial colonization in the stomach, as bacteria normally present in the gastrointestinal tract proliferate. PPI treatment may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter, and in hospitalized patients, possibly Clostridioides difficile.

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 at a dose of 1 mg/kg once daily was administered orally for 2 weeks (open phase), and 80 patients continued into an additional 4-week double-blind treatment-withdrawal phase. There was no significant difference between esomeprazole and placebo in time to reach the primary endpoint before 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 symptoms. Esomeprazole at a dose of 0.5 mg/kg once daily was administered orally for at least 10 days. No statistically significant difference was observed between esomeprazole and placebo in the primary endpoint, which was the change from baseline in the number of GERD symptom occurrences.

Results from pediatric studies also show that doses of 0.5 mg/kg and 1.0 mg/kg of esomeprazole in infants aged <1 month and 1 to 11 months, respectively, reduced the mean percentage of time with intraesophageal pH < 4. The safety profile was similar to that observed in adults.

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

Pharmacokinetics

Distribution

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

Biotransformation

Esomeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of esomeprazole metabolism is dependent on the polymorphic CYP2C19, responsible for forming hydroxy- and desmethyl-metabolites of esomeprazole. The remaining portion is dependent on another specific isoenzyme, CYP3A4, responsible for forming esomeprazole sulfone, the main metabolite in plasma.

Elimination

The parameters below primarily reflect pharmacokinetics in individuals with functional CYP2C19 enzyme (extensive metabolizers), in whom metabolism occurs rapidly.

Total plasma clearance is approximately 17 L/h after single administration and approximately 9 L/h after repeated administration. The plasma elimination half-life is approximately 1.3 hours after repeated once-daily dosing.

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

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 drug is recovered in urine.

Linearity/Non-linearity

Total AUC increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated dosing. This time- and dose-dependence is due to reduced first-pass metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

After repeated administration of a 40 mg dose given as a 30-minute intravenous infusion, 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 after intravenous administration compared to oral administration. A linear, dose-dependent increase in total exposure is observed after intravenous administration of esomeprazole as a 30-minute infusion (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 Groups

Poor Metabolizers

Approximately 2.9 ± 1.5% of the population lack functional CYP2C19 enzyme and are termed poor metabolizers. In these individuals, esomeprazole metabolism is likely primarily catalyzed by CYP3A4. After repeated once-daily oral administration of 40 mg esomeprazole, 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 findings do not require dose adjustments for esomeprazole.

Gender

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

Hepatic Impairment

Metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. Metabolism is reduced in patients with severe hepatic impairment, leading to a doubling of total esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed the maximum dose of 20 mg. For patients with bleeding ulcers and severe hepatic impairment, after an initial 80 mg bolus dose, a maximum prolonged intravenous infusion rate of 4 mg/h 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

Studies in patients with impaired renal function have not been conducted. Since the kidneys are responsible for excretion of esomeprazole metabolites, but not the parent compound, esomeprazole metabolism is not expected to be altered in patients with renal impairment.

Elderly Patients

Esomeprazole metabolism is not significantly altered in elderly individuals (71–80 years of age).

Children

In a randomized, open-label, multinational, multiple-dose study, esomeprazole was administered as a 3-minute intravenous injection once daily for four days. The study included a total of 59 children aged 0 to 18 years, of whom 50 patients (7 children aged 1 to 5 years) completed the study and were included in the pharmacokinetic evaluation.

The table below describes systemic exposure to esomeprazole after intravenous administration as a 3-minute injection in children across all age groups and in healthy adult volunteers. Values in the table are geometric means (ranges). The 20 mg adult dose 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 administration of the 40 mg dose in adults, as well as at the end of the infusion for the 20 mg dose in adults.

* The age group from 0 to 1 month was defined as patients with corrected age ≥ 32 completed weeks and < 44 completed weeks, where corrected age was the sum of gestational age and postnatal age in completed weeks. The age group from 1 to 11 months included patients with corrected age ≥ 44 completed weeks.

** Two patients were excluded, one of whom was likely a poor metabolizer of the CYP2C19 isoenzyme, and one patient was receiving concomitant treatment with a CYP3A4 isoenzyme inhibitor.

Model-based predictions indicate that Css,max after intravenous administration of esomeprazole as 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 when the dose is administered as a 3-minute injection.

Clinical Characteristics

Indications

Adults

• Gastric 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 and adolescents aged 1 to 18 years

• Gastric antisecretory therapy when oral administration is not feasible, for example:
  • Gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe reflux symptoms.

Contraindications

• Hypersensitivity to the active substance or to other substituted benzimidazoles or to any of the excipients of the medicinal product.
• Esomeprazole should not be used concomitantly with 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 reported interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible due to inhibition of CYP2C19 activity.

For atazanavir and nelfinavir, decreased serum levels have been reported when co-administered with omeprazole; therefore, their concomitant use 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 (approximately 75 % decrease in AUC, Cmax, and minimum concentration [Cmin]). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers led to approximately 30 % reduction in atazanavir exposure compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg once daily. Concomitant administration of omeprazole (40 mg once daily) reduced mean AUC, Cmax, and Cmin of nelfinavir by 36–39 %, and mean AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 were reduced by 75–92 %. Due to similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended (see section "Special precautions for use"), and concomitant use of esomeprazole and nelfinavir is contraindicated (see section "Contraindications").

For saquinavir (with concomitant ritonavir), increased serum levels (80–100 %) have been reported with concomitant omeprazole therapy (40 mg once daily). Omeprazole treatment at a dose of 20 mg once daily did not affect exposure of darunavir (with concomitant ritonavir) or amprenavir (with concomitant ritonavir). Esomeprazole treatment at a dose of 20 mg once daily did not affect amprenavir exposure (with or without concomitant ritonavir). Omeprazole treatment at a dose of 40 mg once daily did not affect lopinavir exposure (with concomitant ritonavir).

Methotrexate

Elevated methotrexate levels have been reported in some patients when co-administered with PPIs. Temporary discontinuation of esomeprazole may be necessary when high-dose methotrexate is administered.

Tacrolimus

Concomitant use of esomeprazole has been reported to increase serum tacrolimus levels. Close monitoring of tacrolimus concentrations, renal function (creatinine clearance), and dose adjustment of tacrolimus as needed are recommended.

Medicinal products whose absorption is pH-dependent

Suppression of gastric acidity during treatment with esomeprazole and other PPIs may decrease or increase the 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 digoxin absorption may be increased during esomeprazole therapy. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10 % (up to 30 % in two of ten participants). Digoxin toxicity has been rarely reported. However, caution should be exercised when using high-dose esomeprazole in elderly patients. Enhanced monitoring of digoxin blood concentrations is recommended.

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, and phenytoin, plasma concentrations of these drugs may be increased, and dose reduction may be necessary. In vivo interaction studies with high-dose intravenous administration (80 mg + 8 mg/h) have not been conducted. The effect of esomeprazole on medicinal products metabolized by CYP2C19 may be more pronounced during this treatment regimen; therefore, patients should be carefully monitored for adverse reactions 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 resulted in a 13 % increase in the minimum plasma phenytoin level in patients with epilepsy. Plasma phenytoin concentrations should be monitored when initiating or discontinuing esomeprazole therapy.

Voriconazole

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

Cilostazol

Omeprazole, as well as esomeprazole, acts as an inhibitor of CYP2C19. Omeprazole administered at 40 mg doses to healthy volunteers in a crossover study increased Cmax and AUC of cilostazol by 18 % and 26 %, respectively, and one of its active metabolites by 29 % and 69 %, respectively.

Cisapride

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32 % increase in AUC and a 31 % prolongation of elimination half-life (t1/2), but without a significant increase in peak plasma cisapride levels. The slightly prolonged QTc interval observed after cisapride administration alone was not further prolonged when cisapride was administered in combination with esomeprazole.

Warfarin

A clinical study showed that concomitant oral administration of 40 mg esomeprazole to patients taking warfarin resulted in blood coagulation times within the acceptable range. However, during the post-marketing period, several isolated cases of clinically significant increases in international normalized ratio (INR) have been reported with concomitant use of oral esomeprazole. Monitoring is recommended at the start and upon discontinuation of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

Results from studies in healthy subjects showed a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg daily), resulting in an average 40 % reduction in exposure to the active metabolite of clopidogrel and an average 14 % reduction in maximum inhibition of (ADP-induced) platelet aggregation. In a study in healthy volunteers, concomitant administration of clopidogrel with a fixed-dose combination of esomeprazole 20 mg + acetylsalicylic acid (ASA) 81 mg, compared to clopidogrel monotherapy, resulted in nearly a 40 % reduction in exposure to the active metabolite of clopidogrel. However, the maximum level of inhibition of (ADP-induced) platelet aggregation was similar between the clopidogrel monotherapy and clopidogrel + combination (esomeprazole + ASA) groups.

Observational and clinical studies have yielded conflicting data on the clinical outcomes of the PK/PD interaction between esomeprazole in terms of major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin and quinidine

Esomeprazole has been shown not to have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen and rofecoxib

Short-term studies evaluating concomitant administration of esomeprazole with naproxen or rofecoxib did not reveal any clinically significant PK interactions.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products that inhibit CYP2C19 and/or CYP3A4

Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) resulted in a doubling of esomeprazole AUC. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may lead to more than a twofold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC by 280 %. Dose adjustment of esomeprazole is not always required in such situations. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases where long-term treatment is indicated.

Medicinal products that induce CYP2C19 and/or CYP3A4

Medicinal products known to induce CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased esomeprazole serum levels by increasing esomeprazole metabolism.

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use

In the presence of any alarming symptom (e.g., significant unexplained weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) and in suspected or confirmed gastric ulcer, malignancy should be ruled out, as treatment with the medicinal product Nexopral may mask symptoms and delay diagnosis.

Gastrointestinal infections

Treatment with PPIs may lead to a slightly increased risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B12 absorption

Esomprazole, like all acid-suppressing drugs, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body stores or risk factors for reduced vitamin B12 absorption during long-term therapy.

Hypomagnesemia

Severe hypomagnesemia has been reported in patients treated with PPIs such as esomprazole for at least three months, and in most cases for a year or longer. Serious manifestations of hypomagnesemia may include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, but symptoms may develop gradually and remain unnoticed. In most patients with hypomagnesemia, condition improved with magnesium supplementation and discontinuation of PPI therapy.

Patients who are expected to undergo long-term treatment or who are taking PPIs with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics) should have magnesium levels assessed before starting esomprazole and periodically during treatment.

Risk of fractures

PPIs, particularly when used at high doses and over prolonged periods (>1 year), may moderately increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other recognized risk factors.

Observational studies suggest that PPIs may increase the overall risk of fractures by 10–40%. This increase may be partly related to other risk factors. Patients at risk of developing osteoporosis should receive medical management according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

PPI treatment has been associated with very rare cases of SCLE. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical attention, and the physician should consider discontinuing Nexopral. Development of SCLE after prior PPI treatment may increase the risk of SCLE with subsequent use of other PPIs.

Combination with other medicinal products

Concomitant use of esomprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If co-administration of atazanavir with PPIs cannot be avoided, close clinical monitoring is recommended in combination with increasing the atazanavir dose to 400 mg with 100 mg ritonavir, and the esomprazole dose should not exceed 20 mg.

Esomprazole is an inhibitor of CYP2C19. The potential for interaction with medicinal products metabolized via CYP2C19 should be considered at the start or end of esomprazole treatment. An interaction between clopidogrel and omeprazole has been observed (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction is uncertain. As a precautionary measure, concomitant use of esomprazole and clopidogrel is not recommended.

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), which may be life-threatening, have been reported.

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 from their physician if any characteristic signs or symptoms appear.

If signs or symptoms of severe skin reactions occur, esomprazole should be discontinued immediately and additional medical care/careful monitoring should be provided as needed.

Esomprazole should not be re-administered to patients with EM/SJS/TEN/DRESS.

Effect on laboratory test results

Elevated CgA levels may interfere with investigations of neuroendocrine tumors. To avoid this, treatment with Nexopral should be discontinued at least 5 days before measuring CgA (see section "Pharmacodynamics"). If CgA and gastrin concentrations have not returned to the reference range after the initial measurement, the test should be repeated 14 days after discontinuation of esomprazole.

Information on excipients

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

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient clinical data on the use of esomprazole-containing medicinal products during pregnancy. Epidemiological data from larger numbers of pregnant women using the racemic mixture omeprazole do not indicate malformations or fetal toxicity. Animal studies with esomprazole have not shown direct or indirect harmful effects on embryonal/fetal development. Animal studies with the racemic mixture have not shown direct or indirect harmful effects on the course of pregnancy, delivery, or postnatal development. Caution should be exercised when prescribing Nexopral to pregnant women.

A moderate amount of data on use in pregnant women (from 300 to 1000 pregnancy cases) indicates no risk of congenital malformations or toxic effects of esomprazole on the fetus/newborn child's health. Animal studies do not indicate direct or indirect harmful effects regarding reproductive toxicity.

Breastfeeding

It is unknown whether esomprazole passes into breast milk. Studies in breastfeeding women have not been conducted. Therefore, the medicinal product Nexopral should not be used during breastfeeding.

Fertility

Animal studies with orally administered racemic omeprazole did not indicate effects on fertility.

Ability to influence reaction speed in driving and operating machinery

Esomprazole has negligible influence on the ability to drive and 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 not drive or operate machinery.

Method of Administration and Dosage

Adults

Dosage

Gastric antisecretory treatment when oral administration is not possible

For patients unable to take the medication orally, parenteral administration of 20–40 mg once daily is possible. Patients with reflux esophagitis should be given 40 mg of esomeprazole once daily. Patients receiving symptomatic treatment for gastroesophageal reflux disease should be given 20 mg once daily.

For healing of gastric ulcers associated with NSAID therapy, the usual dose of esomeprazole is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be given 20 mg once daily. The duration of intravenous treatment is usually short-term; therefore, transition to oral therapy should be performed as soon as possible.

Prevention of recurrent peptic ulcer bleeding

Following therapeutic endoscopy for acute bleeding from gastric or duodenal ulcers, administer 80 mg of esomeprazole as an intravenous bolus infusion over 30 minutes, followed by continuous intravenous infusion of 8 mg/hour for 3 days (72 hours).

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

Method of Administration

Instructions for preparing the reconstituted solution are provided in this section below; see section "Special precautions for disposal and handling of unused medicinal product".

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.

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.

Bolus dose of 80 mg

The reconstituted solution should be administered as a prolonged intravenous infusion over 30 minutes.

Dose of 8 mg/hour

The reconstituted solution should be administered as a prolonged intravenous infusion over 71.5 hours (calculated infusion rate of 8 mg/hour); see section below "Special precautions for disposal and handling of unused medicinal product". The shelf life of the reconstituted solution is indicated in the section "Shelf Life".

Special Patient Populations

Patients with Renal Impairment

Dose adjustment is not required in patients with renal impairment. However, due to limited experience in treating patients with severe renal insufficiency, these patients should be treated with caution (see section "Pharmacokinetics").

Patients with Hepatic Impairment

GERD: Dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the maximum daily dose of Nexopral 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 the initial 80 mg bolus dose of Nexopral, a prolonged 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 in elderly patients.

Children

Dosage

Children and adolescents aged 1 to 18 years

Gastric antisecretory treatment when oral administration is not possible

Patients who cannot take the medication orally may be treated parenterally once daily as part of the full treatment course for GERD (see doses in the table below).

The duration of intravenous treatment should usually be short-term, and transition to oral therapy should be performed as soon as possible.

Recommended doses of esomeprazole for intravenous administration

Method of Administration

Instructions for the preparation of the reconstituted solution are provided in this section below (see section “Special precautions for disposal and handling of unused medicinal product”).

Injections

Dose 40 mg

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

Dose 20 mg

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

Dose 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 40 mg

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

Dose 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 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.

Special precautions for disposal and handling of unused medicinal product

The reconstituted solution should be visually inspected for the presence of particulate matter and discoloration prior to administration. Only clear solution should be used. Do not use if any particles are present in the reconstituted solution. For single use only.

If the entire content of the reconstituted vial is not required, any unused solution should be disposed of according to local requirements.

Injection solution 40 mg

The injection solution (8 mg/ml) is prepared by adding 5 ml of 0.9% sodium chloride for intravenous use to the vial containing 40 mg of esomeprazole.

The reconstituted injection solution is clear, ranging from colorless to very slightly yellow.

Infusion solution 40 mg

The infusion solution is prepared by dissolving the contents of one vial containing 40 mg of esomeprazole in 100 ml of 0.9% sodium chloride for intravenous use.

Infusion solution 80 mg

The infusion solution is prepared by dissolving the contents of two vials of esomeprazole 40 mg each in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted infusion solution is clear, ranging from colorless to very slightly yellow.

Any unused medicinal product or waste should be disposed of according to local requirements.

Children

Used in children and adolescents aged 1 to 18 years as gastric antisecretory therapy when oral administration is not possible.

Overdose

To date, experience with intentional overdose is very limited. Symptoms described following an oral dose of 280 mg were gastrointestinal reactions and weakness. A single oral dose of 80 mg of esomeprazole and intravenous administration of 308 mg of esomeprazole over 24 hours were not associated with complications. No specific antidote is known. Esomeprazole is highly plasma protein-bound and therefore not dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be employed.

Adverse Reactions

Summary of safety profile

Headache, abdominal pain, diarrhea, and nausea are among the most commonly reported adverse reactions in clinical trials (as well as in post-marketing use). Furthermore, the safety profile is similar across different dosage forms, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been observed.

List of adverse reactions in tabular form

The following adverse reactions have been identified or suspected in the clinical trial program of orally or intravenously administered esomeprazole, as well as in post-marketing surveillance with oral administration. Reactions are classified according to their frequency: very common (≥ 1/10); common (≥ 1/100 – <1/10); uncommon (≥ 1/1,000 – <1/100); rare (≥ 1/10,000 – <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

*Reactions at the injection site were mainly observed in a study using high doses of esomeprazole for 3 days (72 hours).

There have been isolated reports of irreversible visual disturbances in critically ill patients receiving intravenous omeprazole (racemate), particularly at high doses, but a causal relationship has not been established.

Pediatric population

A randomized, open-label, multinational study was conducted to evaluate the pharmacokinetics of repeated intravenous administration of esomeprazole once daily for 4 days in children up to 18 years of age (see section "Pharmacokinetics"). A total of 57 patients (including 8 children aged 1–5 years) were included for safety evaluation. The safety data were consistent with the known safety profile of esomeprazole, and no new safety signals 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, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after reconstitution: Chemical and physical in-use stability has been demonstrated under conditions of use for 12 hours at 30 °C.

From a microbiological standpoint, the medicinal product should be used immediately.

Storage conditions

Keep out of the reach of children.

Store at temperatures not exceeding 30 °C in the original package to protect from light.

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

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those specified in the section "Instructions for use, handling and disposal" ("Special precautions for disposal and handling of unused medicinal product").

Packaging

Powder for solution for injection and infusion in a vial. 1 vial per cardboard box.

Prescription status

Prescription only.

Manufacturer

Laboratorios Normon S.A.

Manufacturer's address and place of business

Ronda de Valdecarrizo 6, Tres Cantos, 28760, Spain.