Ezolong

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOZOLONG® (EZOLONG®)

Composition:

Active substance: esomeprazole;

1 vial contains 42.60 mg of sodium esomeprazole, equivalent to 40 mg of esomeprazole;

Excipients: disodium edetate (Trilon B), sodium hydroxide.

Pharmaceutical form. Powder for solution for injection or infusion.

Main physico-chemical properties: porous and homogeneous lyophilized powder, white or almost white in color.

Pharmacotherapeutic group.
Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Esomeprazole. 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.

Mechanism of action. Esomeprazole is a weak base. After entering the body, esomeprazole accumulates and is converted into its active form in the highly acidic environment of the secretory canaliculi of parietal cells. This is precisely where inhibition of the enzyme H⁺K⁺-ATPase—the "proton pump"—is required. This leads to suppression of both basal and stimulated gastric acid secretion.

Effect on gastric juice secretion. After 5 days of oral administration of 20 mg and 40 mg esomeprazole, the gastric 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 extent of therapeutic effect does not depend on the route of esomeprazole administration—oral or intravenous.

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

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

Therapeutic significance of acid secretion inhibition. With oral administration of esomeprazole 40 mg, healing was observed in approximately 78% of patients with reflux esophagitis after 4 weeks and in 93% after 8 weeks of treatment.

According to published results of a randomized, double-blind, placebo-controlled clinical study in patients with endoscopically confirmed peptic ulcer classified as Forrest Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively), a nearly 2-fold reduction in the frequency of rebleeding within the first 72 hours was observed with intravenous esomeprazole compared to placebo.

Other effects related to acid secretion inhibition. During treatment with antisecretory agents, serum gastrin levels increase. This is a physiological response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity.

In some patients, prolonged treatment with oral esomeprazole has been associated with an increased number of enterochromaffin-like (ECL) cells, possibly related to elevated gastrin levels. There is also a slight increase in the frequency of glandular cysts in the gastric mucosa. These changes are a physiological consequence of pronounced inhibition of gastric juice secretion and are benign and reversible in nature.

Reduced gastric acidity from any cause, including use of proton pump inhibitors (PPIs), leads to increased numbers of bacteria 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 by Clostridium difficile.

Children

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 pH <4 in the esophagus.

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

Pharmacokinetics

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

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

The parameters listed below primarily reflect pharmacokinetics in individuals with functional CYP2C19 enzyme, i.e., those in whom esomeprazole metabolism occurs more rapidly.

Total plasma clearance is approximately 17 L/hour after a single dose and approximately 9 L/hour after repeated administration. The elimination half-life from plasma 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 non-linear 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.

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

With repeated administration of 40 mg via intravenous injection, the mean peak plasma concentration is approximately 13.6 µmol/L. The mean peak plasma concentration after corresponding oral doses is approximately 4.6 µmol/L. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared to oral administration. A linear, dose-dependent increase in exposure is observed when esomeprazole is administered as a 30-minute intravenous infusion (at doses of 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 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.

Special patient groups. Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and is classified as poor metabolizers. In these individuals, esomeprazole metabolism is likely catalyzed predominantly by CYP3A4. After multiple oral doses of esomeprazole 40 mg once daily, mean total exposure was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). Mean peak plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dosage adjustments for esomeprazole.

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

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

Esomeprazole metabolism may be altered in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of total esomeprazole exposure. Therefore, in patients with GERD and severe hepatic impairment, the maximum dose should not exceed 20 mg. In cases of bleeding ulcer and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a rate of up to 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.

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

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 due to gastric or duodenal ulcer.

Children aged 1 to 18 years:

• Antisecretory therapy when oral administration is not possible, 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 the medicinal product.

The medicinal product Esolong® must not be used concomitantly with nelfinavir or atazanavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adults.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

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

Interaction of omeprazole with certain protease inhibitors. 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 possible mechanisms of interaction involve inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been observed with concomitant administration of omeprazole; therefore, co-administration of these drugs is not recommended. Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (reduction in AUC, 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%.

Elevated serum concentrations of saquinavir (co-administered with ritonavir) were observed (80–100% increase) with concomitant administration of omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect the exposure of darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily did not affect the exposure of amprenavir (in combination with ritonavir or alone). Administration of omeprazole 40 mg daily did not alter the exposure of lopinavir (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.

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, their plasma concentrations may increase, and dose reduction may be necessary. Concomitant oral administration of 30 mg esomeprazole reduced the clearance of the CYP2C19 substrate diazepam by 45%. With concomitant oral administration of 40 mg esomeprazole and phenytoin, the minimum plasma concentration of phenytoin in epileptic patients increased by 13%. Monitoring of phenytoin plasma concentration is recommended at the beginning and end of esomeprazole therapy.

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

In a clinical study, concomitant oral administration of 40 mg esomeprazole to patients receiving warfarin resulted in blood coagulation time remaining within the normal range. However, in the post-marketing period, several isolated cases of clinically significant INR elevation have been reported with concomitant use of these drugs. Monitoring is recommended at the initiation and discontinuation of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Increased serum levels of tacrolimus have been reported with concomitant administration of esomeprazole.

Close monitoring of tacrolimus concentration and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Omeprazole, like esomeprazole, is an inhibitor of CYP2C19. In a cross-over 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.

Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers increased AUC by 32% and half-life (T1/2) by 31%, but no significant increase in cisapride Cmax in plasma was observed. The slight QTc interval prolongation observed with cisapride alone was not increased when cisapride was administered in combination with esomeprazole.

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

Interaction studies evaluating the concomitant use of esomeprazole with naproxen or rofecoxib did not reveal any clinically significant pharmacokinetic interactions during short-term studies.

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 medicinal products metabolized by CYP2C19 under such treatment regimens may be more pronounced, and patients should be closely monitored for adverse reactions during the three-day intravenous treatment period.

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

When clopidogrel was administered together with a fixed-dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel monotherapy in a study in healthy volunteers, a nearly 40% reduction in exposure to clopidogrel's active metabolite was observed. However, the maximum level of inhibition of (ADP-induced) platelet aggregation was similar in the clopidogrel and clopidogrel + combination therapy (esomeprazole + ASA) groups.

Both observational and clinical studies have yielded conflicting data regarding the clinical consequences of the PK/PD interaction between esomeprazole and clopidogrel in terms of serious cardiovascular events.

Unknown mechanism of interaction with methotrexate. When methotrexate is administered concomitantly with PPIs, its levels have increased in some patients. Temporary discontinuation of esomeprazole may be required when high-dose methotrexate is administered.

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 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 situations. However, it may be required in patients with severe hepatic impairment and in cases requiring long-term treatment.

Medicinal products capable of inducing CYP2C19 and/or CYP3A4 (rifampicin and St. John's wort) may reduce esomeprazole serum concentrations by enhancing its metabolism.

Special precautions for use.

In the presence of any alarming symptoms (e.g., significant unexplained weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) or suspicion of, or existing gastric ulcer, malignancy should be excluded, as the medicinal product Esolong® may mask symptoms and delay diagnosis.

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

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 PPIs is considered mandatory, 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, like all acid secretion inhibitors, may impair vitamin B12 (cyanocobalamin) absorption 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.

Esomeprazole is an inhibitor of CYP2C19. Potential interactions 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.

Cases of severe hypomagnesemia have been reported in patients treated with PPIs such as esomeprazole for at least 3 months, and in most cases, for over a year. Hypomagnesemia may present with serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, but its onset may be gradual and remain unnoticed. In most patients with hypomagnesemia, condition improved with magnesium supplementation and discontinuation of PPI therapy.

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

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. Observational studies indicate that PPIs may increase the overall risk of fractures by 10–40%. This increased risk 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.

The use of PPIs has been associated with very rare cases of subacute cutaneous systemic lupus erythematosus (SCLE). If skin lesions develop, particularly in sun-exposed areas and accompanied by arthralgia, the patient should seek immediate medical attention and discontinue use of Esolong®. The treating physician should consider the appropriateness of continuing Esolong®, taking into account prior experience with PPIs associated with SCLE development.

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

Patients should be informed about the signs and symptoms of severe skin reactions (EM/SJS/TEN/DRESS) and advised to seek immediate medical attention from their physician if any such signs or symptoms occur.

Treatment with esomeprazole should be discontinued immediately upon the appearance of signs or symptoms of severe skin reactions, and additional medical care and close monitoring should be provided as needed. Esomeprazole should not be re-administered to patients with a history of EM/SJS/TEN/DRESS.

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking formulations containing esomeprazole and naproxen and may occur at any time during Esolong® therapy.

Acute tubulointerstitial nephritis may progress to renal failure. Esolong® should be discontinued if TIN is suspected, and appropriate treatment should be initiated immediately.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole therapy should be temporarily discontinued at least five days before measuring CgA levels. If CgA and gastrin levels have not returned to the reference range after initial measurement, the test should be repeated 14 days after stopping PPI therapy.

Each vial of this medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

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 toxic effects of the drug on the fetus.

Animal studies with esomeprazole have not shown direct or indirect harmful effects on embryonic/fetal development.

Animal studies with the racemic mixture do not indicate direct or indirect adverse effects on pregnancy, labor, or postnatal development. Esolong® should be used during pregnancy only if clearly needed and with caution.

A moderate amount of data on the use of the drug in pregnant women (from 300 to 1000 pregnancy cases) suggests no risk of congenital malformations or toxic effects of esomeprazole on the fetus or newborn's health.

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

Period of breastfeeding

It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the effects of esomeprazole on newborns/infants. Therefore, Esolong® should not be used during breastfeeding.

Fertility

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

Ability to influence reaction speed when driving or operating machinery.

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

Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients who cannot 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 administration of the drug 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 of 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 using oral agents that suppress acid secretion.

Administration method

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

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. Discard any unused solution.

Dose 80 mg

Administer the reconstituted solution as a prolonged intravenous infusion over 30 minutes.

Dose 8 mg/hour

Administer the reconstituted solution as a prolonged intravenous infusion over 71.5 hours (calculated infusion rate of 8 mg/hour; the shelf life of the reconstituted solution is specified in the section "Shelf life").

Injections

Dose 40 mg

Inject 5 mL of the reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes.

Dose 20 mg

Inject 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.

Renal impairment

Dose adjustment is not required in patients with renal impairment. Since experience with the use of the drug in patients with severe renal impairment 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 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 Esolong® for infusion, continued administration as a prolonged intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required.

Children

Children aged 1 to 18 years

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

For patients who cannot take the drug orally, the drug may be administered parenterally once daily during the full course of treatment of GERD (doses are listed in the table below).

Treatment with the intravenous drug is usually short-term. Patients should be switched to oral administration of the medicinal product as soon as possible.

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 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.

Dose of 10 mg

Administer 1.25 ml of 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.

Dose of 10 mg

Administer a quarter of the reconstituted solution as an intravenous infusion over 10–30 minutes. Discard any unused solution.

Instructions for use, handling, and disposal (where applicable)

Before administration, visually inspect the reconstituted solution for particles and discoloration. Only use clear solutions. The solution is intended for single use only.

If not the entire reconstituted content of the vial is required, any unused solution should be discarded 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 the vial containing 40 mg of esomeprazole.

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

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.

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

Children

The drug is used in children aged 1 year and older as an antisecretory agent when oral administration is not possible.

Overdose

Experience with intentional overdose is very limited to date. Symptoms observed after oral administration of a 280 mg dose included gastrointestinal disturbances and weakness. No adverse effects were observed after a single oral dose of 80 mg esomeprazole or intravenous administration of 308 mg esomeprazole over 24 hours. There is no known specific antidote. Esomeprazole is highly bound to plasma proteins and therefore is poorly dialyzable. As in any case of overdose, symptomatic treatment and general supportive measures should be provided.

Adverse reactions.

The adverse reactions listed below have been identified or suspected in clinical trials of esomeprazole during its oral or intravenous administration, as well as during post-marketing surveillance of the oral use of the drug. Reactions are categorized by frequency: very common (≥1/10); common (≥1/100 – <1/10); uncommon (≥1/1000 – <1/100); rare (≥1/10,000 – <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

*Local reactions were observed primarily in the study using high doses administered over 3 days (72 hours). In the preclinical intravenous esomeprazole program, no vascular irritation was observed; however, minimal tissue inflammatory reaction was noted at the site of subcutaneous (perivenous) injection. Preclinical study results indicated that the clinical manifestation of tissue irritation was concentration-dependent.

Irreversible visual disturbances have been 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.

Paediatric population

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

Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage period after reconstitution

The physicochemical stability of the reconstituted solution has been demonstrated for 12 hours at 25 °C. However, from a microbiological standpoint, the solution should be used immediately.

Storage conditions.

Keep the vial in the outer carton at a temperature not exceeding 25 °C. Vials may be stored without secondary packaging under normal room lighting for up to 24 hours.

Keep out of reach and sight of children.

Incompatibilities.

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

Packaging. 1 or 10 vials with powder in a carton.

Prescription status. Prescription only.

Manufacturer.

Sofarimex – Industria Quimica e Farmaceutica, S.A. /
Sofarimex – Industria Quimica e Farmaceutica, S.A.

Manufacturer's address and location of operations.
Av. das Industrias – Alto do Colaride, Cacem, 2735-213, Portugal /
Av. das Industrias – Alto do Colaride, Cacem, 2735-213, Portugal.