Esozol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOZOL (ESOZOL)

Composition:

Active substance: esomeprazole;

1 vial contains 42.55 mg of esomeprazole sodium equivalent to 40 mg of esomeprazole;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Main physicochemical characteristics: white or almost white powder.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer.

Proton pump inhibitors. ATC code A02B C05.

Pharmacological Properties.

Pharmacodynamics.

Esomeprazole is the S-isomer of omeprazole; it reduces gastric acid secretion through a specific, targeted mechanism of action. Esomeprazole is a specific inhibitor of the acid pump in the parietal cell. The R- and S-isomers of omeprazole have equivalent pharmacodynamic activity.

Mechanism of Action

Esomeprazole is a weak base; it accumulates and is transformed into its active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the H⁺K⁺-ATPase enzyme of the acid pump, thereby suppressing both basal and stimulated acid secretion.

Effect on Gastric Acid Secretion

After five days of oral administration of esomeprazole at doses of 20 mg and 40 mg in patients with symptoms of gastroesophageal reflux disease (GERD), intragastric pH remained above 4 for an average of 13 hours and 17 hours, respectively. This effect is consistent regardless of the route of esomeprazole administration—oral or intravenous.

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

Over 24 hours, in healthy volunteers receiving an intravenous infusion of 80 mg esomeprazole over 30 minutes followed by a continuous intravenous infusion at a rate of 8 mg/hour, intragastric pH above 4 and above 6 was maintained on average for 21 hours and 11–13 hours, respectively.

Therapeutic Effects of Acid Secretion Inhibition

Treatment of reflux esophagitis with esomeprazole 40 mg demonstrates efficacy in 78% of patients after 4 weeks and in 93% of patients after 8 weeks of oral therapy.

Other Effects Related to Acid Secretion Inhibition

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion.

Chromogranin A (CgA) levels also rise due to decreased acidity of gastric juice. Because of elevated CgA levels, there may be an impact on laboratory test results used to detect neuroendocrine tumors. Published data indicate that treatment with proton pump inhibitors (PPIs) should be discontinued 5–14 days before measuring CgA levels, as this parameter may be elevated after PPI therapy.

In some patients, long-term oral treatment with esomeprazole is associated with an increase in the number of enterochromaffin-like (ECL) cells, which may be related to elevated serum gastrin levels.

An increased incidence of gastric polyps has been reported during long-term treatment with oral antisecretory agents. These changes are physiological consequences of sustained acid secretion suppression. They are benign and likely reversible.

Reduced gastric juice secretion resulting from any proton pump inhibitor leads to increased numbers of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors increases the risk of gastrointestinal infections (e.g., Salmonella, Campylobacter, or Clostridium difficile) in hospitalized patients.

Children

In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of esomeprazole were evaluated in patients with signs and symptoms of GERD. Esomeprazole at 1 mg/kg once daily was administered orally for 2 weeks (open-label phase), and 80 patients continued into an additional 4-week period (double-blind treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or discontinuation of treatment due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of esomeprazole were evaluated in patients with GERD. Esomeprazole at 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—the change in frequency of GERD symptoms compared to baseline.

Results from studies involving pediatric patients show that doses of esomeprazole at 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 < 4.0. The safety profile of esomeprazole in pediatric patients was similar to that observed in adults.

In a study involving pediatric patients with GERD (aged <1 to 17 years) receiving long-term proton pump inhibitor (PPI) therapy, 61% of children showed mild ECL-cell hyperplasia of unknown clinical significance; 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 via the cytochrome P450 (CYP) system. The major part of esomeprazole metabolism depends on the polymorphic isoenzyme CYP2C19, responsible for forming hydroxy- and desmethyl metabolites of esomeprazole. Another part is mediated by a different specific isoenzyme, CYP3A4, which is responsible for forming esomeprazole sulfone—the main metabolite in plasma.

The parameters listed below primarily reflect the pharmacokinetics in individuals with functional CYP2C19 enzyme (extensive metabolizers).

Total plasma clearance is approximately 17 L/h after a single dose and about 9 L/h after repeated dosing. The elimination half-life in plasma is approximately 1.3 hours after repeated daily dosing. Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated dosing. This time- and dose-dependency is due to reduced first-pass metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

Esomeprazole is completely cleared from plasma between doses and does not tend to accumulate when administered once daily.

After repeated intravenous injections of 40 mg, the mean peak plasma concentration is approximately 13.6 µmol/L. Compared to oral administration, intravenous administration may result in a lower increase (approximately 30%) in total exposure.

The main metabolites of esomeprazole do not affect gastric acid secretion.

A linear, dose-dependent increase in exposure was observed following intravenous infusion of esomeprazole over 30 minutes (at doses of 40 mg, 80 mg, or 120 mg), followed by continuous infusion (at rates of 4 mg/h or 8 mg/h) for 23.5 hours.

Special Patient Populations

Slow Metabolizers

Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme (referred to as poor metabolizers). In these individuals, esomeprazole metabolism is likely mediated primarily by CYP3A4. After repeated oral administration of 40 mg esomeprazole once daily, mean total exposure was approximately 100% higher in poor metabolizers than in individuals with fully functional CYP2C19 (extensive metabolizers). Mean peak plasma concentrations were increased by approximately 60%. A similar difference was observed with intravenous administration of esomeprazole. However, these data do not affect esomeprazole dosing.

Elderly Patients

Esomeprazole metabolism does not undergo significant changes in elderly patients (aged 71 to 80 years).

Gender

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

Hepatic Impairment

Esomeprazole metabolism may be impaired in patients with mild or moderate liver dysfunction. Metabolism is slowed in patients with severe hepatic impairment, leading to a doubling of total esomeprazole exposure. Therefore, patients with GERD and severe liver impairment should not exceed the maximum dose of 20 mg. For patients with bleeding ulcers and severe hepatic impairment, after an initial 80 mg infusion of esomeprazole, a continuous intravenous infusion at 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not tend to accumulate when administered once daily.

Renal Impairment

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

Children

In a randomized, open-label, international, multiple-dose study, esomeprazole was administered as a 3-minute injection once daily for 4 days. A total of 59 children aged 0 to 18 years were enrolled, of whom 50 (including 7 children aged 1 to 5 years) completed the study and were included in the pharmacokinetic evaluation.

Table 1 presents the systemic effects of esomeprazole following intravenous injection over 3 minutes in pediatric patients and healthy adult volunteers. Values in Table 1 are expressed 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 measured 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 corrected age (the sum of gestational age and postnatal age in completed weeks) ≥ 32 completed weeks and < 44 completed weeks. The age group from 1 to 11 months included patients with corrected age ≥ 44 completed weeks.

** Two patients were excluded: one most likely due to reduced 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 on average by 37–49%, 54–66%, and 61–72%, respectively, across all age groups and dosing groups, compared to Css,max after a 3-minute injection.

Clinical characteristics.

Indications.

Adults

Antisecretory therapy when oral administration is not 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:

• gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

Hypersensitivity to esomeprazole or to any of the excipients of the medicinal product, or to substituted benzimidazoles.

Esomazole, like other proton pump inhibitors, should not be used concomitantly with atazanavir or nelfinavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Data on drug interactions are based on studies conducted only in adult patients.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent

Reduced gastric acidity during treatment with esomeprazole may increase or decrease the absorption of medicinal products if gastric pH affects their absorption mechanism.

As with other agents that reduce intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, whereas the absorption of drugs such as digoxin may be increased during treatment with esomeprazole. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (by 30% in two out of ten individuals). Digoxin toxicity has been reported rarely. However, caution should be exercised when administering high doses of esomeprazole to elderly patients. Monitoring of digoxin blood concentration should be intensified.

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported. 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 may involve inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been observed during 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 (approximately 75% reduction in AUC, Cmax, 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%.

Proton pump inhibitors, including esomeprazole, should not be administered concomitantly with atazanavir or nelfinavir.

Increased serum concentrations of saquinavir (co-administered with ritonavir) (80–100%) were observed during 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 (with or without ritonavir). Administration of omeprazole 40 mg/day did not alter the exposure of lopinavir (in combination with ritonavir). Due to similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration 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 co-administered with drugs metabolized by the CYP2C19 enzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., plasma concentrations of these drugs may increase, necessitating dose reduction. In vivo interaction studies using the intravenous formulation at high doses (80 mg + 8 mg/h) have not been conducted. The effect of esomeprazole on drugs metabolized by CYP2C19 during such treatment regimens may be more pronounced, and patients should be closely monitored for adverse events during the 3-day intravenous treatment period.

Diazepam

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

Phenytoin

Concomitant administration of 40 mg esomeprazole and phenytoin increased plasma phenytoin levels by 13% in patients with epilepsy. Plasma phenytoin concentrations should be monitored at the initiation or discontinuation of esomeprazole therapy.

Voriconazole

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

Cilostazol

Esomeprazole, like omeprazole, is an inhibitor of CYP2C19. Administration of omeprazole 40 mg to healthy volunteers increased Cmax and area under the concentration-time curve (AUC) for cilostazol by 18% and 26%, respectively, and for one of its active metabolites by 29% and 69%, respectively.

Warfarin

Concomitant administration of 40 mg esomeprazole in patients taking warfarin showed that coagulation time remained within acceptable limits. However, post-marketing experience with oral esomeprazole use reports several isolated cases of clinically significant increases in the international normalized ratio (INR) during concomitant administration of esomeprazole and warfarin. Therefore, monitoring of INR is recommended at the beginning and after discontinuation of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Cisapride

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride increased the area under the concentration-time curve (AUC) by 32% and prolonged the elimination half-life (t½) by 31%, but no significant increase in peak plasma levels of cisapride was observed. With cisapride alone, a slight prolongation of the QTc interval was observed, which did not further increase when cisapride was administered in combination with esomeprazole.

Tacrolimus

Elevated serum levels of tacrolimus have been reported during concomitant administration of esomeprazole. Intensified monitoring of tacrolimus concentration and renal function (creatinine clearance) is required; dose adjustment of tacrolimus may be necessary.

Methotrexate

Increased blood levels of methotrexate have been reported in some patients during concomitant use with proton pump inhibitors. If high-dose methotrexate is required, temporary discontinuation of esomeprazole should be considered.

Clopidogrel

Due to pharmacokinetic/pharmacodynamic (PK/PD) interaction between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and esomeprazole (40 mg daily orally), exposure to the active metabolite of clopidogrel is reduced by an average of 40%, and maximum inhibition of (ADP-induced) platelet aggregation is reduced by an average of 14%.

In a study involving healthy volunteers, when clopidogrel was administered 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, maximum levels of inhibition of (ADP-induced) platelet aggregation were similar in the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA. Observational and clinical studies have yielded conflicting data regarding the clinical relevance of the PK/PD interaction between esomeprazole and major cardiovascular events. Concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin or quinidine

Esomeprazole has no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

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

Medicinal products inducing CYP2C19 and/or CYP3A4 activity

Agents that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin or St. John's wort) may lead to decreased serum levels of esomeprazole by accelerating its metabolism.

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use

In the presence of any alarm symptom (e.g., marked unintentional weight loss, recurrent nausea, dysphagia, hematemesis, or melena) and when gastric ulcer is suspected or present, malignancy must be excluded, as treatment with Esosol may alleviate symptoms and delay correct diagnosis.

Gastrointestinal infections

Proton pump inhibitor therapy slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B12 absorption

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

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least three months, and in most cases, for a year or longer. Hypomagnesemia may present serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its development may be insidious and go unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

Patients who are expected to undergo long-term treatment or who are taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics) may benefit from measurement of magnesium levels before initiation of PPI therapy and periodically during treatment.

Risk of fractures

Proton pump inhibitors, particularly when used at high doses and for prolonged periods (>1 year), are associated with a slightly increased risk of hip, wrist, and spine fractures, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPIs 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 vitamin D and calcium supplementation.

Subacute cutaneous lupus erythematosus

The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of the drug should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous treatment with PPIs indicates an increased risk of recurrence with other PPIs.

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 proton pump inhibitors is considered essential, 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 a CYP2C19 inhibitor. 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 is not fully established. 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 have not normalized after initial measurement, repeat testing should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Each vial contains less than 1 mmol of sodium, i.e., Esosol is practically sodium-free.

Use during pregnancy or breastfeeding

Data on the use of Esosol during pregnancy are limited. Animal studies with esomeprazole have not shown any direct or indirect harmful effects on embryonic/fetal development. Animal studies using the racemic mixture have not indicated any direct or indirect adverse effects on pregnancy, delivery, or postnatal development. However, Esosol should be prescribed to pregnant women only with special caution.

Data from pregnant women (from 300 to 1000 pregnancy cases) indicate no malformative effects or toxic influence of esomeprazole on the fetus or newborn's health.

Results of animal studies indicate no direct or indirect harmful effects of the drug on reproductive function.

Breastfeeding

It is unknown whether esomeprazole is excreted in human breast milk. Studies in breastfeeding women have not been conducted. Therefore, Esosol should not be used during breastfeeding.

Fertility

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

Ability to influence reaction speed when driving or operating machinery

Esosol 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 not drive vehicles or operate machinery.

Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients who cannot take the drug orally, parenteral administration of esomeprazole at a dose of 20–40 mg once daily is recommended. Patients with reflux esophagitis should receive a dose of 40 mg once daily. Patients with gastroesophageal reflux disease (GERD) receiving symptomatic treatment should be given a dose of 20 mg once daily.

For treatment of gastric and duodenal ulcers associated with NSAID use, the usual dose is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be given 20 mg once daily.

Intravenous treatment is usually short-term, after which patients should be switched to oral therapy as soon as possible.

Short-term maintenance of hemostasis and prevention of recurrent bleeding from gastric and duodenal ulcers

After endoscopic treatment of acute bleeding from gastric or duodenal ulcers, an 80 mg dose should be administered as an intravenous infusion over 30 minutes, followed by continuous intravenous infusion at a rate of 8 mg/hour for 3 days (72 hours).

After parenteral therapy, oral therapy aimed at acid secretion suppression should be continued for 4 weeks.

Administration method

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

If not all of the reconstituted contents of the vial are used, any unused solution should be discarded according to local requirements.

The reconstituted solution for infusion and injection is a clear, colorless to yellowish solution.

Injections

As an intravenous injection, Esosol 40 mg should be administered over 3 minutes. The injection solution is prepared by adding 5 mL of 0.9% sodium chloride solution to the vial containing esomeprazole. For administration of a 20 mg dose, half of the prepared solution should be used. The unused portion must be discarded.

Infusions

Dose of 40 mg

As an intravenous infusion, Esosol 40 mg should be administered over 10–30 minutes. The infusion solution is prepared by dissolving the contents of one vial containing 40 mg esomeprazole in 100 mL of 0.9% sodium chloride solution for intravenous use.

Dose of 20 mg

For administration of a 20 mg dose, half of the prepared solution should be used. Any unused portion of the solution must be discarded.

Bolus infusion of 80 mg

The 80 mg infusion solution is prepared by dissolving the contents of two vials, each containing 40 mg esomeprazole, in up to 100 mL of 0.9% sodium chloride solution for intravenous use.

The prepared solution should be administered as a continuous intravenous infusion over 30 minutes.

Dose of 8 mg/hour

The prepared solution should be administered as a continuous intravenous infusion over 72 hours (calculated for an infusion rate of 8 mg/hour).

Special patient groups

Renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment. Due to limited experience in patients with severe renal impairment, such patients should be treated with caution (see section "Pharmacokinetics").

Hepatic impairment

Gastroesophageal reflux disease: dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the maximum daily 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. For patients with severe hepatic impairment, after the initial 80 mg intravenous dose of esomeprazole administered over 30 minutes, a continuous intravenous infusion of 4 mg/hour over 72 hours may be sufficient (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required in elderly patients.

Children

Dosage

Children aged 1–18 years

Antisecretory therapy when oral administration is not possible

For patients unable to take the drug orally, parenteral administration of the drug once daily may be prescribed as part of treatment for gastroesophageal reflux disease (dosage – see Table 2).

Intravenous treatment should usually be short-term, after which patients should be switched to oral therapy as soon as possible.

Table 2.

Recommended intravenous doses of esomeprazole

Method of Administration

Injection

Dose of 40 mg

5 ml of reconstituted solution (8 mg/ml) should be administered as an intravenous injection over a period of not less than 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 a period of not less than 3 minutes. Any unused portion must be discarded.

Dose of 10 mg

1.25 ml of reconstituted solution (8 mg/ml) should be administered as an intravenous injection over a period of not less than 3 minutes. Any unused portion must be discarded.

Infusion

Dose of 40 mg

The reconstituted solution should be administered as an intravenous infusion over a period of 10 to 30 minutes.

Dose of 20 mg

Half of the reconstituted solution should be administered as an intravenous infusion over a period of 10 to 30 minutes. Any unused portion must be discarded.

Dose of 10 mg

A quarter of the reconstituted solution should be administered as an intravenous infusion over a period of 10 to 30 minutes. Any unused portion must be discarded.

Children

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

Overdose

Data regarding overdose are limited and relate to intentional overdosage. Gastrointestinal disturbances and weakness have been reported following oral administration of esomeprazole at a dose of 280 mg. Single oral doses of esomeprazole up to 80 mg and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any symptoms. There is no known specific antidote. Esomeprazole is highly protein-bound and therefore not readily dialyzed. As in any case of overdose, treatment should be symptomatic and include general supportive measures.

Adverse reactions.

Among the 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. In addition, the safety profile of the drug is consistent across different dosage forms, treatment indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

During clinical trials and following the introduction of esomeprazole into widespread medical practice, the adverse effects listed below have been reported. Adverse events were classified according to their frequency of occurrence: common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

*Reactions at the injection site were mainly observed in the study with high-dose administration over 3 days (72 hours). Intravenous administration of esomeprazole was not associated with vascular irritation; however, slight inflammatory reaction in the subcutaneous (perivenous) tissue at the injection site was noted. The degree of tissue irritation was concentration-dependent.

Isolated cases of irreversible visual disturbances have been reported in critically ill patients receiving intravenous injections of omeprazole (racemate), particularly at high doses; however, a causal relationship has not been established.

Pediatric population

The safety profile of the medicinal product in children corresponds to the known safety profile of esomeprazole in adult patients.

Reporting of adverse reactions

It is important to report adverse reactions after the medicinal product has been marketed. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Physicians and pharmacists should report any adverse reactions.

Shelf life. 18 months.

Storage period after reconstitution

Chemical and physical in-use stability has been demonstrated under conditions of use for 12 hours at 30 °C. From a microbiological standpoint, the product should be used immediately.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Incompatibilities.

Other diluents should not be used for reconstitution except those specified in the section "Dosage and administration".

Packaging.

Pack size № 1. Lyophilisate for solution for injection and infusion in a clear glass vial stoppered with a butyl rubber stopper and sealed with an aluminum flip-off cap. 1 vial in a cardboard pack.

Pack size № 10. Lyophilisate for solution for injection and infusion in a clear glass vial stoppered with a butyl rubber stopper and sealed with an aluminum flip-off cap. 10 vials in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

STERIL-GENE LIFE SCIENCES (P) LTD / Steril-Gene Life Sciences (P) Ltd.

Manufacturer's address.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India.

Marketing Authorization Holder. JIVDHARA PHARMA PRIVATE LIMITED.

Address of the Marketing Authorization Holder. 504, Block-B, Shiv Angan Complex, Sallaiya, Bhopal, Bhopal, Madhya Pradesh, 462026, India.