Mesopral

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEZOPRAL (MESOPRAL)

Composition:

Active substance: esomeprazole (esomeprazole);

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

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection and infusion.

Main physicochemical properties: porous white or almost white powder.

Pharmacotherapeutic group. Drugs used for acid-related disorders. Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole that inhibits gastric acid secretion through a specific and targeted mechanism of action. It is a specific inhibitor of the acid pump in parietal cells. Both the R- and S-isomers of omeprazole have similar pharmacological activity.

Site and Mechanism of Action

Esomeprazole is a weak base that accumulates and is converted to its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the enzyme H+/K+-ATPase—the proton pump—and thereby suppresses 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 period in patients with symptomatic GERD (gastroesophageal reflux disease). The effect is similar regardless of whether esomeprazole is administered orally or intravenously.

Using AUC as an indirect parameter of drug concentration in plasma, a relationship has been demonstrated between acid secretion inhibition and drug exposure following oral administration of esomeprazole.

After intravenous administration of esomeprazole to healthy volunteers at a dose of 80 mg as a 30-minute bolus infusion, followed by continuous intravenous 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 period.

Following 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 bleeding classified as 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 continuous infusion at 8 mg/hour or placebo for 72 hours. After the initial 72-hour period, all patients were switched to oral esomeprazole 40 mg daily for 27 days to maintain acid suppression. The rate of rebleeding within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, rebleeding rates were 7.7% in the esomeprazole group and 13.6% in the placebo group.

During treatment with acid-suppressing drugs, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also rise due to decreased gastric acidity. Because of elevated CgA levels, test results for neuroendocrine tumors may be affected. Published data indicate that proton pump inhibitor (PPI) treatment should be discontinued 5–14 days before measuring CgA levels to allow normalization, as CgA may be falsely elevated after PPI therapy.

During long-term esomeprazole therapy in both children and adults, an increase in enterochromaffin-like (ECL) cells has been observed, possibly due to elevated serum gastrin levels. These findings are considered clinically insignificant.

During prolonged treatment with oral acid-suppressing drugs, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are a physiological consequence of pronounced inhibition of gastric acid secretion, are benign, and resolve after discontinuation of treatment.

Reduced gastric acidity for any reason, including PPI use, leads to increased bacterial load in the stomach, normally present in the gastrointestinal tract. PPI treatment slightly increases the risk of gastrointestinal infections caused, for example, by 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 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-label phase), and 80 patients continued for an additional 4 weeks (double-blind treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or treatment discontinuation due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the drug were evaluated in patients with GERD symptoms. Esomeprazole at a dose of 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 pediatric studies 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 with intragastric pH < 4.0. The safety profile of the drug was similar to that observed in adults.

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

Pharmacokinetics

Distribution

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

Biotransformation

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

Elimination

The parameters below primarily reflect the pharmacokinetic profile in patients with functional CYP2C19 enzyme (extensive metabolizers).

Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after repeated administration. The plasma elimination half-life is approximately 1.3 hours with once-daily repeated 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 of esomeprazole is excreted in urine as metabolites, the remainder in feces. Less than 1% of unchanged esomeprazole is found in urine.

Linearity/Non-linearity

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

With repeated administration of 40 mg esomeprazole as intravenous injections, the mean peak plasma concentration is approximately 13.6 µmol/L. The mean peak plasma concentration after corresponding oral doses is approximately 4.6 µmol/L. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared to oral administration. A linear, dose-dependent increase in exposure was observed after intravenous infusion of esomeprazole over 30 minutes (40 mg, 80 mg, or 120 mg), followed by continuous infusion (4 mg/h or 8 mg/h) for 23.5 hours.

Special Patient Groups

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

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

Hepatic Impairment. Esomeprazole metabolism may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of total esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed a maximum dose of 20 mg. In cases of bleeding ulcer with severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a maximum rate of 4 mg/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. No studies have been conducted in patients with impaired renal function. Since the kidneys are responsible for excretion of esomeprazole metabolites, but not the parent compound, no changes in metabolism are expected in patients with renal impairment.

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

Children. In a randomized, open-label, international multiple-dose study, esomeprazole was administered as a 3-minute 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 and were included in the pharmacokinetic evaluation.

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

Table 1

Age group	Dose group	AUC (μmol⁎g/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 activity of the CYP2C19 isoenzyme, 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 would decrease on average by 37–49%, 54–66%, and 61–72%, respectively, across all age groups and dosing groups compared to Css,max after a 3-minute injection.

Clinical characteristics

Indications

Adults

• Antisecretory therapy when oral administration is not 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.

• Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcer.

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, other substituted benzimidazoles, or to any of the excipients listed in the section "Composition".

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

Interaction with other medicinal products and other types of interactions

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

An interaction between omeprazole and certain protease inhibitors has 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 mechanisms of interaction may involve inhibition of CYP2C19 activity.

It has been reported that concomitant use of omeprazole reduces serum levels of atazanavir and nelfinavir; 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 (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 values of nelfinavir by 36–39% and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%.

Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole with atazanavir is not recommended (see section "Special precautions for use"); concomitant use of esomeprazole with nelfinavir is contraindicated (see section "Contraindications").

Increased serum concentrations of saquinavir (co-administered with ritonavir) by 80–100% were observed with concomitant use of omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect exposure of darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily did not affect exposure of amprenavir (with or without ritonavir). 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. When high-dose methotrexate is administered, temporary discontinuation of esomeprazole should be considered.

Tacrolimus

Increased 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 whose absorption is pH-dependent

Reduced 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 absorption of digoxin may be increased during esomeprazole treatment. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in two out of ten participants). Toxic effects of digoxin were rarely observed. However, caution should be exercised when administering high doses of esomeprazole to elderly patients. Monitoring of digoxin blood concentrations should be intensified.

Medicinal products metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme metabolizing esomeprazole. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, plasma concentrations of these drugs may increase, and dose reduction may be required. In vivo interaction studies using intravenous esomeprazole at high doses (80 mg + 8 mg/h) 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 administration period.

Diazepam

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

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased minimum plasma concentrations 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.

Cilostazol

Omeprazole, like esomeprazole, is an inhibitor of CYP2C19. In a crossover study in healthy volunteers, administration of omeprazole 40 mg increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and 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 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. No prolongation of the QTc interval, which was slightly observed during cisapride monotherapy, was noted when cisapride was administered in combination with esomeprazole.

Warfarin

In a clinical study, coagulation time remained within acceptable limits when esomeprazole 40 mg was administered orally concomitantly with warfarin. However, during the post-marketing period, several isolated cases of clinically significant increases in INR (International Normalized Ratio) were reported with concomitant use of these medicinal products. 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 assessments between clopidogrel (loading dose 300 mg/maintenance dose 75 mg daily) and esomeprazole (40 mg orally daily) in studies involving healthy volunteers showed a 40% reduction in exposure to the active metabolite of clopidogrel and a 14% reduction in maximum inhibition of ADP (adenosine diphosphate)-induced platelet aggregation.

In a study involving healthy volunteers where clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in fixed combination doses (20 mg + 81 mg, respectively), exposure to the active metabolite of clopidogrel was reduced by nearly 40% compared to clopidogrel monotherapy. However, maximum levels of inhibition of ADP-induced platelet aggregation 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 implications of the PK/PD interaction of esomeprazole on serious cardiovascular events. Concomitant use of esomeprazole and clopidogrel should be avoided.

Medicinal products with no clinically significant interaction

Amoxicillin or quinidine

It has been shown that esomeprazole does not clinically significantly affect the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

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

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

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 inhibitors of CYP2C19 and CYP3A4 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 situations. However, it may be necessary for patients with severe hepatic impairment or when long-term treatment is indicated.

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

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

Children

Drug interaction studies have only been conducted in adults.

Special precautions for use

In the event of any alarming symptoms (such as significant unpredictable weight loss, recurrent vomiting, dysphagia, hematemesis or melena), as well as in suspected or confirmed gastric ulcer, malignancy should be ruled out, since the medicinal product Mезопрал may mask symptoms and delay diagnosis.

Gastrointestinal infections

Treatment with proton pump inhibitors (PPIs) slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Absorption of vitamin B12

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

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least three months, mostly after a year of treatment. Hypomagnesemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, 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.

If prolonged treatment is expected, or if the patient is taking PPIs together with digoxin or medicinal products that may cause hypomagnesemia (e.g. diuretics), it may be advisable to measure magnesium levels before starting PPI therapy and periodically during treatment.

Fracture risk

Proton pump inhibitors, particularly when used at high doses and for long durations (>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 partly be due to other 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

The use of proton pump inhibitors 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 Mезопрал should be considered. Development of subacute cutaneous lupus erythematosus during previous treatment with PPIs increases 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 a proton pump inhibitor cannot be avoided, close clinical monitoring 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 a CYP2C19 inhibitor. Potential interactions with medicinal products 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 is not 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, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), some of which may be life-threatening, have been reported with esomeprazole treatment.

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

If signs or symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately and additional medical care / close monitoring should be provided.

Re-administration of the medicinal product should not be considered in patients who have experienced EM/SJS/TEN/DRESS syndrome.

Effect on laboratory test results

Due to increased chromogranin A (CgA) levels, test results for neuroendocrine tumors may be affected. To avoid this, esomeprazole should be temporarily discontinued at least five days before CgA measurement. 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

Each vial of the medicinal product Mезопрал contains approximately 3.28 mg of sodium, which can be considered negligible in terms of sodium content.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of the medicinal product Mезопрал during pregnancy are limited. Epidemiological data on the use of the racemic mixture of omeprazole during pregnancy suggest no risk of congenital malformations or toxic effects of the drug on the fetus. Animal studies with esomeprazole did not reveal any direct or indirect harmful effects on embryonic/fetal development.

Animal studies with the racemic mixture did not show direct or indirect adverse effects on pregnancy, delivery, or postnatal development. Mезопрал should be used with caution in pregnant women.

Available data on the use of the medicinal product in pregnant women (from 300 to 1000 pregnancy cases) indicate no risk of congenital malformations or toxic effects of esomeprazole on fetal/neonatal health.

Animal studies did not reveal any direct or indirect harmful effects of the drug on reproductive function.

Breastfeeding

It is unknown whether esomeprazole passes into breast milk. Information on the effects of esomeprazole on neonates/infants is insufficient. Esomeprazole should not be used during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

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

Administration and Dosage

Adults

Dosage

Antisecretory therapy when oral administration is not feasible

For patients who cannot take esomeprazole 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 given the drug at a dose of 20 mg once daily.

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

Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers

After endoscopic therapy of acute bleeding from gastric or duodenal ulcers, administer 80 mg of the drug as a 30-minute intravenous bolus infusion, followed by continuous intravenous infusion of the drug at a rate of 8 mg/hour for 3 days (72 hours).

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

Administration method

Instructions for preparation of the reconstituted solution are provided below — see section "Instructions for preparation, use and disposal of the medicinal product".

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. Discard any unused solution.

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. Discard any unused solution.

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

Patients with renal impairment

Dose adjustment is not required in patients with impaired renal function. Since experience with esomeprazole in patients with severe renal impairment is limited, 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 dose of Mezopral should not exceed 20 mg (see section "Pharmacokinetics").

Bleeding ulcers: Dose adjustment is not required in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, after the initial 80 mg intravenous bolus dose of Mezopral, continued administration as a continuous intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required.

Children aged 1–18 years

Dosage

Antisecretory therapy when oral administration is not feasible

For patients who cannot take esomeprazole orally, the drug may be administered parenterally once daily during the full course of treatment of GERD (doses are indicated in Table 2).

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

Table 2

Recommended doses of esomeprazole for intravenous administration

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 below — see section "Instructions for preparation, use and disposal of the medicinal product".

Injections

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

Dose 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.

Dose 10 mg: Administer 1.25 ml of reconstituted solution (8 mg/ml) as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Infusions

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

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

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

Instructions for preparation, use and disposal of the medicinal product

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

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

Injection solution 40 mg

To prepare an injection solution (8 mg/ml), add 5 ml of 0.9% sodium chloride for intravenous use to a vial containing 40 mg of esomeprazole lyophilisate.

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

Infusion solution 40 mg

To prepare an infusion solution, dissolve the contents of one vial containing 40 mg of esomeprazole in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted infusion solution should be clear, colorless or slightly yellowish.

Infusion solution 80 mg

To prepare an infusion solution, dissolve the contents of two vials containing 40 mg of esomeprazole each in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted infusion solution should be clear, colorless or slightly yellowish.

Children. Can 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 very limited to date. Gastrointestinal symptoms and weakness have been reported after oral intake of 280 mg. A single oral dose of 80 mg of esomeprazole and intravenous administration of 308 mg of esomeprazole over 24 hours did not result in serious adverse effects. There is no specific antidote. Esomeprazole is highly bound to plasma proteins and therefore is poorly dialyzable. As with any overdose, symptomatic treatment and general supportive measures should be administered.

Adverse Reactions

Summary of safety profile

Among the adverse reactions most commonly observed during clinical trials and in the post-marketing period are headache, abdominal pain, diarrhea, and nausea. The safety profile of esomeprazole is consistent across different pharmaceutical forms, indications, age groups, and other patient populations. No dose-dependent adverse reactions have been identified.

List of adverse reactions

The adverse reactions listed below were identified or suspected during clinical trials of esomeprazole administered orally or intravenously, as well as during post-marketing surveillance of oral esomeprazole. Reactions are classified according to frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Table 3

Body systems	Frequency	Adverse reactions
Blood and lymphatic system	Uncommon	Leukopenia, thrombocytopenia
	Very rare	Agranulocytosis, pancytopenia
Immune system	Uncommon	Hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reactions/shock
Metabolism and nutrition	Uncommon	Peripheral edema
	Uncommon	Hypomagnesemia (see section "Special precautions"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
	Frequency unknown	Hypomagnesemia (see section "Special precautions"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
Psychiatric	Uncommon	Insomnia
	Uncommon	Agitation, confusion, depression
	Very rare	Aggression, hallucinations
Nervous system	Common	Headache
	Uncommon	Dizziness, paraesthesia, somnolence
	Uncommon	Taste disturbance
Eye organs	Uncommon	Blurred vision
Ear and labyrinth disorders	Uncommon	Vertigo
Respiratory, thoracic and mediastinal disorders	Uncommon	Bronchospasm
Gastrointestinal system	Common	Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign)
	Uncommon	Dry mouth
	Uncommon	Stomatitis, gastrointestinal candidiasis
	Frequency unknown	Microscopic colitis
Hepatobiliary system	Uncommon	Elevated liver enzymes
	Uncommon	Hepatitis, with or without jaundice
	Very rare	Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue	Common	Injection site reactions*
	Uncommon	Dermatitis, pruritus, rash, urticaria
	Uncommon	Alopecia, photosensitivity
	Very rare	Polymorphic 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 precautions")
Musculoskeletal and connective tissue	Uncommon	Fracture of femur, wrist or spine (see section "Special precautions")
	Uncommon	Arthralgia, myalgia
	Very rare	Muscle weakness
Renal and urinary system	Very rare	Interstitial nephritis (in some patients, renal failure also occurred simultaneously)
Reproductive system and breast	Very rare	Gynecomastia
General disorders and administration site conditions	Uncommon	Malaise, increased sweating

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

Irreversible visual disturbances were reported in isolated cases 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 intravenous doses of esomeprazole administered once daily over 4 days in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients (including 8 children aged 1–5 years) were included for safety assessment. The safety profile of the medicinal product was consistent with the known safety profile of esomeprazole, and no new risks were identified.

Reporting of adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions

Store in the original packaging to protect from light. Vials may be kept under normal room lighting without the cardboard box for up to 24 hours.

Store at a temperature not exceeding 30 °C.

Keep out of the 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 glass vials with powder in a 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