Esomeprazole-pharmex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESMEPRAZOLE-PHARMEX (ESOMEPRAZOLE-PHARMEX)

Composition:

Active substance: esomeprazole;

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

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Main physicochemical properties: white to almost white lyophilized porous mass or powder.

Pharmacotherapeutic group.

Drugs used in acid-related disorders.

Agents for the treatment of peptic ulcer and gastroesophageal reflux disease.

Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties.

Pharmacodynamics.

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

Site and Mechanism of Action

Esomeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the H+/K+-ATPase enzyme (the proton pump), thereby suppressing both basal and stimulated gastric acid secretion.

Effect on Gastric Acid Secretion

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

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

Following 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 remained above 4 and above 6 for an average of 21 hours and 11–13 hours, respectively, within a 24-hour interval.

Therapeutic Effect of Acid Secretion Inhibition

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

Other Effects Related to Acid Secretion Inhibition

During treatment with acid-suppressing agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to decreased gastric acidity. Elevated CgA levels may affect laboratory test results for 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, to allow normalization of CgA, as this marker may be elevated after PPI therapy.

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

A slight increase in the incidence of gastric glandular polyps has been observed during long-term treatment with oral acid-suppressing agents. These changes are a physiological consequence of pronounced suppression of gastric acid secretion and are benign and reversible in nature.

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial counts in the stomach, normally present in the gastrointestinal tract. PPI therapy may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Children

Results from studies in pediatric patients show that esomeprazole doses of 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intraluminal esophageal pH <4.

The safety profile of the drug was similar to that in adults.

Pharmacokinetics.

Distribution

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

Metabolism and Elimination

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

The parameters described below predominantly 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 plasma elimination half-life (t1/2) is approximately 1.3 hours with repeated once-daily dosing. 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-dependent relationship is due to reduced pre-systemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

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

With repeated intravenous administration of 40 mg esomeprazole, 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 has been observed with esomeprazole administered 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.

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

Special Patient Groups

Slow Metabolizers

Approximately 2.9±1.5% of the population lacks functional CYP2C19 enzyme; these individuals are termed slow metabolizers. In these individuals, esomeprazole metabolism is likely primarily catalyzed by CYP3A4. After multiple oral doses of 40 mg esomeprazole once daily, the mean total exposure was approximately 100% higher in slow metabolizers compared to individuals with functional CYP2C19 (rapid metabolizers). The mean peak 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.

Sex

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

Hepatic Impairment

Metabolism of esomeprazole 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 the maximum dose of 20 mg. In cases of bleeding ulcer and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not 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 the elimination of esomeprazole metabolites, but not the parent compound, no changes in metabolism are expected in patients with renal impairment.

Elderly Patients

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

Clinical characteristics.

Indications.

Adults

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.

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 feasible, for example, GERD in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

Hypersensitivity to 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

Interactions between omeprazole and certain protease inhibitors have been observed. The clinical significance and mechanisms of these interactions are not always fully understood. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible due to inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been observed when omeprazole is administered concomitantly; therefore, co-administration of these drugs is not recommended. Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (reduction in AUC, maximum concentration [Cmax], and minimum concentration [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 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 when omeprazole (40 mg daily) was administered concomitantly. Omeprazole 20 mg daily did not affect the exposure of darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily did not affect the exposure of amprenavir (with or without ritonavir). Administration of omeprazole 40 mg daily did not alter the exposure of lopinavir (in combination with ritonavir). Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Methotrexate

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

Tacrolimus

Elevated serum levels of tacrolimus have been reported with concomitant use of esomeprazole. Close monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, 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. 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 subjects). Toxic effects of digoxin have been reported rarely. However, caution should be exercised when high doses of esomeprazole are administered to elderly patients. Monitoring of digoxin blood concentrations is necessary.

Medicinal products metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, and phenytoin, plasma concentrations of these drugs may increase, and dose reduction may be required.

In vivo interaction studies using intravenous formulations at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on medicinal products metabolized by CYP2C19 during 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 reduced the clearance of the CYP2C19 substrate diazepam by 45%.

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased the Cmin of phenytoin in plasma by 13% in patients with epilepsy. Monitoring of phenytoin plasma concentrations is recommended at the start of esomeprazole therapy and upon its discontinuation.

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. 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%.

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 Cmax of cisapride in plasma was observed. The slight QT interval prolongation observed with cisapride alone was not increased when cisapride was administered in combination with esomeprazole.

Warfarin

During a clinical study, when 40 mg esomeprazole was administered concomitantly with warfarin, blood coagulation time remained within the acceptable range. However, during the post-marketing period, several isolated cases of clinically significant increases in the international normalized ratio (INR) have been reported with concomitant use of these drugs. Monitoring is recommended at the beginning and end of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

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

In a study in healthy volunteers receiving clopidogrel together with esomeprazole and acetylsalicylic acid (ASA) in a fixed-dose combination (20 mg + 81 mg, respectively), compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. However, the maximum level of inhibition of (ADP-induced) platelet aggregation was 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 implications of the PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Medicinal products investigated without clinically significant interaction

Amoxicillin or quinidine

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

Naproxen or rofecoxib

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

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

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

Drugs (such as rifampicin and St. John's wort) capable of inducing CYP2C19 or CYP3A4, or both enzymes, 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 significant unexpected weight loss, recurrent vomiting, dysphagia, hematemesis or melena) or suspicion of, or existing, gastric ulcer, malignancy should be ruled out, since esomeprazole may mask symptoms and delay diagnosis.

Gastrointestinal infections

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

Vitamin B12 absorption

Esomeprazole, like all acid secretion-blocking agents, may inhibit absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced 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 PPIs such as esomeprazole for at least three months, and in most cases, for a year. Hypomagnesemia may present serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, and its development may be gradual and remain unnoticed. In most patients with hypomagnesemia, condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

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

Risk of fractures

PPIs, particularly when used at high doses and for prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Results of observational studies suggest that PPIs may increase the overall fracture risk by 10–40%. This increased risk may be partly attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should receive adequate amounts 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, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should immediately consult a physician who will consider the necessity of discontinuing esomeprazole. Development of subacute cutaneous lupus erythematosus during previous PPI therapy may increase the risk of recurrence when other PPIs are used.

Combination with other medicinal products

Concomitant use of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If combination of atazanavir with PPIs 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 esomeprazole dose 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.

Effect on laboratory test results

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

Severe cutaneous adverse reactions (SCARs)

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

Patients should be informed about the signs and symptoms of severe skin reactions (EM/SJS/TEN/DRESS) and the need to seek immediate medical advice from their physician if any such signs or symptoms appear. Esomeprazole should be discontinued immediately upon the appearance of signs or symptoms of severe skin reactions, and additional medical care and careful monitoring should be provided as needed. Re-administration of esomeprazole to patients with EM/SJS/TEN/DRESS is not recommended.

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

Use during pregnancy or breastfeeding.

Data on the use of esomeprazole during pregnancy are limited. A somewhat larger amount of epidemiological data on the use of racemic omeprazole during pregnancy indicates no risk of congenital malformations or fetotoxic effects. Animal studies have not revealed any 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 used during pregnancy only if clearly needed and with caution.

A moderate amount of data in pregnant women (from 300 to 1000 pregnancy cases) indicates no malformative effects or toxic effects of esomeprazole on the fetus/newborn child's health.

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. Therefore, 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.

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. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be prescribed the medicinal product at a dose of 20 mg once daily.

Treatment with the intravenous medicinal product 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 ulcer

After endoscopic therapy of acute bleeding from gastric or duodenal ulcer, administer 80 mg of the medicinal product as an intravenous bolus infusion over 30 minutes, followed by continuous intravenous infusion at a rate of 8 mg/hour for 3 days (72 hours).

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

Administration method

Instructions for preparation of the reconstituted solution are provided below in this section («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 (calculated infusion rate of 8 mg/hour).

Patients in special populations

Renal impairment

Dose adjustment is not required in patients with renal impairment. As experience with use of the drug in patients with severe renal impairment is limited, such patients should be treated with caution (see section «Pharmacokinetics»).

Hepatic impairment

GERD: dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the maximum dose of esomeprazole should not exceed 20 mg (see section «Pharmacokinetics»).

Bleeding ulcers: dose adjustment is not required in patients with mild to moderate hepatic impairment; in patients with severe hepatic impairment, after administration of the initial 80 mg intravenous bolus dose of esomeprazole, subsequent 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 to 18 years

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

For patients unable to take the drug orally, the drug may be administered parenterally once daily during the full course of treatment of GERD (doses are indicated in Table 1).

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

Table 1

Recommended intravenous doses of esomeprazole

Method of administration

Instructions for the preparation of reconstituted solution are provided in the section below («Instructions for use, handling and disposal (where applicable)»).

Injections

• 40 mg dose

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

• 20 mg dose

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

• 10 mg dose

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

Infusions

• 40 mg dose

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

• 20 mg dose

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

• 10 mg dose

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

Instructions for use, handling and disposal (where applicable)

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

Any unused solution should be disposed of according to local requirements.

• 40 mg injection solution

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

• 40 mg infusion solution

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

• 80 mg infusion solution

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

Storage after reconstitution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25 °C. From a microbiological standpoint, the product should be used immediately.

Children

Administered to children aged 1 year and older as an antisecretory agent when oral administration is not feasible.

Overdose

Experience with intentional overdose is currently very limited. Symptoms observed following oral administration of a 280 mg dose included gastrointestinal effects and weakness. Single oral doses of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any sequelae. 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 adopted.

Adverse reactions.

Summary of safety profile

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

List of adverse reactions

The adverse reactions listed below have been identified or suspected in the clinical development program of esomeprazole during its 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 (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Table 2

*Reactions at the injection site were observed primarily in the 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 an intravenous injection, particularly at high doses; however, a causal relationship has not been established.

Reporting of adverse reactions

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

Paediatric population

There are data from studies using esomeprazole for 4 days with once-daily administration in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients (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.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

This medicinal product should not be used with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

40 mg in a vial, 1 vial in a carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and place of business.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.