Ezom

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOМ (ESOM)

Composition:

Active substance: esomeprazole;

1 vial contains sodium esomeprazole equivalent to esomeprazole 40 mg;

Excipients: edetate disodium, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection and infusion.

Main physicochemical properties: white or almost white porous lump or powder.

Pharmacotherapeutic group. Drugs used in acid-related disorders. Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors (PPI). 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 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 into its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the enzyme H⁺K⁺-ATPase—the acid pump—and suppresses both basal and stimulated acid secretion.

Effect on gastric juice secretion

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

Using the area under the plasma concentration-time curve (AUC) as an indirect parameter of drug concentration in blood plasma, a relationship between acid secretion inhibition and exposure after oral administration of esomeprazole has been demonstrated.

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

Therapeutic effect of acid secretion inhibition

With oral administration of esomeprazole 40 mg, approximately 78% of patients with reflux esophagitis heal within 4 weeks, and 93% within 8 weeks of treatment.

In a randomized, double-blind, placebo-controlled clinical trial in patients with endoscopically confirmed peptic ulcer class Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively) according to Forrest classification, patients were randomized to receive esomeprazole infusion (n = 375) or placebo (n = 389). After endoscopic hemostasis, patients received either esomeprazole 80 mg as a 30-minute intravenous 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 open-label oral esomeprazole 40 mg for 27 days to suppress acid secretion. The rate of recurrent bleeding within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, the rates of recurrent bleeding in the esomeprazole and placebo groups were 7.7% and 13.6%, respectively.

Other effects related to acid secretion inhibition

During treatment with acid-suppressing drugs, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity. Because of elevated CgA levels, there may be an impact on laboratory test results for detecting neuroendocrine tumors. Published data indicate that treatment with proton pump inhibitors (PPIs) should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels, so that CgA levels can normalize, as this parameter may be elevated after PPI treatment.

An increase in enterochromaffin-like (ECL) cell numbers, possibly related to increased gastrin levels, has been observed in some patients during long-term treatment with oral esomeprazole.

During long-term treatment with oral acid-suppressing drugs, a slight increase in the frequency of gastric glandular cyst formation has been noted. These changes are a physiological consequence of pronounced suppression of gastric juice secretion and are benign and reversible in nature.

Reduced gastric juice acidity for any reason, including PPI use, leads to increased bacterial colonization in the stomach, normally present in the gastrointestinal tract. PPI treatment may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and in hospitalized patients, possibly also by Clostridium 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 1 mg/kg once daily was administered orally for 2 weeks (open-label phase), and 80 patients were included for an additional 4 weeks (double-blind, treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or treatment discontinuation due to symptom worsening.

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

Results from studies involving 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 average percentage of time with intragastric pH <4.0. The safety profile of the drug was similar to that in adults.

In a study conducted in 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 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 volunteers is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Metabolism and elimination

Esomeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of esomeprazole metabolism 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 isoform, CYP3A4, 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/hour after a single dose and approximately 9 L/hour after repeated administration. The elimination half-life (t_1/2) of the drug in plasma is approximately 1.3 hours with repeated once-daily dosing.

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

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

Total 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.

With repeated administration of 40 mg esomeprazole as intravenous injections, the mean maximum plasma concentration is approximately 13.6 µmol/L. The mean maximum 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 administration of esomeprazole as a 30-minute intravenous 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

Slow metabolizers

Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and are referred to as 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 (rapid metabolizers). Mean maximum plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dose adjustments for esomeprazole.

Gender

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

Liver function impairment

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

Renal function 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.

Elderly patients

Metabolism of esomeprazole is only slightly altered in elderly patients (71–80 years).

Children

In a randomized, open-label, international multiple-dose study, esomeprazole was administered as a 3-minute 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 of esomeprazole.

Table 1 presents the results of systemic exposure to esomeprazole after intravenous administration as a 3-minute 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. Maximum steady-state plasma concentration (C_ss,max) was assessed 5 minutes after dosing in all pediatric age groups, and 7 minutes after dosing in adult patients receiving 40 mg and at the end of the 20 mg infusion.

Table 1

* 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, probably 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 after 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 to any of the excipients of this medicinal product.

Esomeprazole must not be used concomitantly with atazanavir or 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

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 interaction mechanisms are possible via inhibition of CYP2C19. Reduced serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these agents 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 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 daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30 % compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39 %, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92 %.

Increased serum concentrations of saquinavir (co-administered with ritonavir) (80–100 %) were observed with concomitant omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir) exposure. Esomeprazole 20 mg daily did not affect amprenavir exposure (with or without ritonavir). Omeprazole 40 mg daily did not alter lopinavir exposure (in combination with ritonavir). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Methotrexate

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

Tacrolimus

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

Medicinal products whose absorption is pH-dependent

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

Medicinal products metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, 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 under such treatment regimens may be more pronounced, and patients should be closely 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 increased the minimum plasma concentration of phenytoin in epileptic patients by 13 %. Monitoring of phenytoin plasma concentrations is recommended at the initiation and discontinuation of esomeprazole therapy.

Voriconazole

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

Cilostazol

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

Cisapride

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

Warfarin

In a clinical study, co-administration of 40 mg esomeprazole orally with warfarin did not alter blood coagulation time beyond 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 these drugs. Monitoring is recommended at the initiation and termination of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

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

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

Medicinal products investigated without clinically significant interaction

Amoxicillin or quinidine

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

Naproxen or rofecoxib

In short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib, no pharmacokinetic interaction was observed.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

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

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

Drugs such as rifampicin and St. John's wort, which can induce CYP2C19 and/or CYP3A4 activity, may reduce esomeprazole serum concentrations by enhancing its metabolism.

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use

In the presence of any alarming symptoms (such as, for example, significant unexplained weight loss, recurrent vomiting, dysphagia, hematemesis or melena) or suspicion of, or existing gastric ulcer, malignancy should be excluded, as esomeprazole may mask symptoms and delay diagnosis.

Gastrointestinal infections

Treatment with PPIs may slightly increase the risk of gastrointestinal infections such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B₁₂ absorption

Esomeprazole, like all acid-suppressing medications, 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.

Hypomagnesaemia

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

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

Risk of fractures

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

Subacute cutaneous lupus erythematosus

The use of PPIs 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 the drug should be considered. Development of subacute cutaneous lupus erythematosus during prior treatment with a PPI may increase the risk of its occurrence 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 PPI is considered necessary, close monitoring of the patient is recommended and the dose of atazanavir should be increased to 400 mg in combination with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19. The potential for interaction with drugs metabolized by CYP2C19 should be considered at the beginning and end of esomeprazole therapy. An interaction between clopidogrel and omeprazole has been reported (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction has not been fully established. As a precautionary measure, concomitant use of esomeprazole and clopidogrel is not recommended.

Severe cutaneous adverse reactions (SCARs)

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

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

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

Re-administration of the drug should not be considered in 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 tumours. To avoid this, esomeprazole treatment should be discontinued temporarily at least five days before measuring CgA levels. If CgA and gastrin levels have not normalized after the initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI therapy.

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

Use during pregnancy or breastfeeding

Data on the use of esomeprazole during pregnancy are limited. A somewhat larger amount of epidemiological data on the use of the racemic mixture of omeprazole during pregnancy indicates no risk of congenital malformations or fetotoxic effects. Animal studies have not revealed direct or indirect harmful effects on embryofetal development.

Animal studies with the racemic mixture do not indicate any direct or indirect harmful effects on pregnancy, delivery, or postnatal development. Esomeprazole should be prescribed to pregnant women with caution.

A moderate amount of data in pregnant women (from 300 to 1000 pregnancy cases) indicates absence of teratogenic effects or toxic influence of esomeprazole on the fetus/newborn.

Results of animal studies indicate no direct or indirect harmful effect of the drug on reproductive function due to its toxic effects.

Period of breastfeeding

It is unknown whether esomeprazole passes into breast milk. Studies in breastfeeding women have not been conducted. Esomeprazole should not be used during breastfeeding.

Fertility

Results of 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 disorders occur, patients should refrain from driving vehicles and operating machinery.

Method of Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients unable to take the medicinal product 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. To prevent gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be given the medicinal product at a dose of 20 mg once daily.

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

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

Following endoscopic therapy for acute bleeding from gastric or duodenal ulcers, administer 80 mg of the drug as a 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 (see "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.

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

Special Patient Populations

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 insufficiency is limited, these patients should be treated with caution (see section "Pharmacokinetics").

Hepatic Impairment

GERD: dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the maximum dose of the drug 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 intravenous esomeprazole, subsequent administration as a continuous intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly Patients

Dose adjustment is not required.

Children

Dosage

Children aged 1–18 years

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

For patients unable to take the drug orally, parenteral administration once daily may be used during the full course of treatment for GERD (doses are specified in Table 2).

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

Table 2

Recommended intravenous doses of esomeprazole

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 40 mg

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

Dose 10 mg

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

Infusions

Dose 40 mg

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

Dose 20 mg

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

Dose 10 mg

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

Instructions for use, handling and disposal (where applicable)

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

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

Injection solution 40 mg

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

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

Children

Can be used in children aged 1 year and older as an agent for antisecretory therapy when oral administration is not possible.

Overdose

Experience with intentional overdose is very limited to date. Symptoms observed after oral ingestion of 280 mg included gastrointestinal effects and weakness. Single oral doses of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours have not resulted 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 taken.

Adverse reactions.

Summary of safety profile

Based on available literature data, it is known that during clinical trials (as well as in the post-marketing period) the most commonly observed adverse reactions were headache, abdominal pain, diarrhea, and nausea. Furthermore, the safety profile of the drug is consistent across different dosage forms, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been identified.

The adverse reactions listed below (see Table 3) were reported or suspected in clinical trials of esomeprazole following oral or intravenous administration, as well as during post-marketing surveillance of oral administration of the drug. 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).

Table 3

*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 omeprazole (racemate) as intravenous injection, particularly at high doses; however, a causal relationship has not been established.

Pediatric population

A randomized, open-label, international study was conducted to evaluate the pharmacokinetics of multiple intravenous 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 in the safety assessment. The safety profile of the drug was consistent with the known safety profile of esomeprazole, and no new patient safety concerns were identified.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

After reconstitution, store for up to 12 hours at 25 °C.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Store in a light-protected place.

Keep out of reach of children.

Incompatibilities.

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

Packaging. 1 vial in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Nobel Ilac Sanai Ve Ticaret A.S.

Manufacturer's address and location of its business operations.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Highway No:299, 81100 Duzce, Turkey.