Esomeprazole-mb: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOmeprazole-MB (Esomeprazole-MB)

Composition:

Active substance: esomeprazole; esomeprazole;

One vial contains sodium esomeprazole equivalent to esomeprazole 40 mg;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physico-chemical properties: porous mass or powder, white to almost white.

Pharmacotherapeutic group.

Agents for 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 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 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 acid pump—and suppresses both basal and stimulated acid secretion.

Effect on gastric acid secretion

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

Using AUC as a surrogate parameter for plasma drug concentration, a relationship 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, during a 24-hour interval.

Therapeutic effect of acid secretion inhibition

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

In a randomized, double-blind, placebo-controlled clinical trial, patients with endoscopically confirmed peptic ulcer of Forrest class Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively) were randomized to receive esomeprazole (n=375) or placebo (n=389). After endoscopic hemostasis, patients received either intravenous esomeprazole 80 mg as a 30-minute infusion followed by continuous infusion at 8 mg/hour or placebo for 72 hours. After the initial 72-hour period, all patients were switched to open-label oral esomeprazole 40 mg daily for 27 days to suppress acid secretion. The rate of recurrent bleeding within 3 days was 5.9% in the esomeprazole group and 10.3% in the placebo group. At 30 days after therapy, the rates of recurrent bleeding were 7.7% in the esomeprazole group and 13.6% in the placebo group.

Other effects related to acid secretion inhibition

During treatment with acid-suppressive agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric acidity. Elevated CgA levels may interfere with diagnostic investigations for neuroendocrine tumors. Available published data indicate that proton pump inhibitors should be discontinued between 5 days and 2 weeks before measuring CgA levels to allow CgA levels, which may be falsely elevated during PPI treatment, to return to baseline range.

An increase in enterochromaffin-like (ECL) cells, possibly related to elevated gastrin levels, has been observed in some patients during long-term treatment with oral esomeprazole. These findings are considered to have no clinical significance.

During long-term treatment with oral acid-suppressive agents, a slight increase in the frequency of gastric glandular cysts has been observed. These changes are considered a physiological consequence of pronounced inhibition of gastric acid secretion and are benign and reversible.

Reduced gastric acidity for any reason, including use of proton pump inhibitors, leads to increased bacterial load in the stomach, reflecting the normal flora of the gastrointestinal tract. Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Children

In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of esomeprazole in patients with signs and symptoms of GERD were evaluated. Esomeprazole at a dose of 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). There was no significant difference between esomeprazole and placebo regarding time to the primary endpoint due to discontinuation because of symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), efficacy and safety were evaluated in patients with symptoms of GERD. Esomeprazole 0.5 mg/kg once daily was administered orally for at least 10 days. No significant difference between esomeprazole and placebo was observed in the primary endpoint—the change in the number of GERD symptom occurrences from baseline.

Results from pediatric studies indicate 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 observed in adults.

In a study involving pediatric patients with GERD (aged 1 to 17 years) receiving long-term PPI treatment, mild ECL cell hyperplasia developed in 61% of children, with no known clinical significance and without development of atrophic gastritis or carcinoid tumors.

Pharmacokinetics.

Distribution

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

Metabolism and elimination

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

The parameters below primarily reflect the pharmacokinetics in individuals with functional CYP2C19 enzyme, i.e., rapid metabolizers.

Total plasma clearance is approximately 17 L/hour after a single dose and approximately 9 L/hour after repeated administration. The plasma elimination half-life is approximately 1.3 hours with repeated once-daily dosing.

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

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

Linearity/Non-linearity

Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear relationship between dose and AUC after repeated dosing. This time- and dose-dependent relationship is due to reduced presystemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

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

Special patient populations

Slow metabolizers

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

Gender

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

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

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

Elderly patients

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

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.
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 feasible, for example:
- gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

Hypersensitivity to the active substance esomeprazole, other substituted benzimidazoles, or to any of the excipients of this medicinal product.

Esomeprazole 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.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

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 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, Cmax, and Cmin by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant 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%.

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.

Increased serum concentrations of saquinavir (co-administered with ritonavir) (80–100%) were observed with concomitant administration of omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect darunavir (co-administered with ritonavir) or amprenavir (in combination with ritonavir) exposure. Esomeprazole 20 mg daily did not affect amprenavir exposure (with or without ritonavir). Omeprazole 40 mg daily did not alter lopinavir exposure (in combination with ritonavir).

Methotrexate

Methotrexate levels increased in some patients when used concomitantly with PPIs. Temporary discontinuation of esomeprazole may be required when high-dose methotrexate is administered.

Tacrolimus

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

Medicinal products with pH-dependent absorption

Suppression of gastric acid secretion during therapy with esomeprazole and other proton pump inhibitors (PPIs) may lead to reduced or enhanced absorption of drugs 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 digoxin absorption 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 of ten participants). Digoxin toxicity has been reported rarely. However, caution should be exercised when administering high doses of esomeprazole to elderly patients. Digoxin blood levels should be closely monitored.

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, phenytoin, etc., plasma concentrations of these drugs may increase, and dose reduction may be necessary. In vivo interaction studies using the intravenous formulation at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on drugs metabolized by CYP2C19 under such treatment regimens may be more pronounced, and patients should be closely monitored for adverse reactions during the three-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 minimum plasma phenytoin concentrations by 13% in epileptic patients. Monitoring of plasma phenytoin concentrations is recommended at the start and end of esomeprazole therapy.

Voriconazole

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

Cilostazol

Omeprazole, like esomeprazole, is a CYP2C19 inhibitor. In a crossover study in healthy volunteers, omeprazole 40 mg daily 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 the area under the concentration-time curve (AUC) by 32% and the elimination half-life (t1/2) by 31%, but no significant increase in maximum plasma concentration of cisapride was observed. The slight QTc interval prolongation observed with cisapride alone was not increased when cisapride was co-administered with esomeprazole.

Warfarin

During concomitant oral administration of 40 mg esomeprazole to patients receiving warfarin in a clinical study, blood coagulation time remained within the acceptable range. However, during the post-marketing period, several isolated cases of clinically significant INR increases 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

Studies in healthy volunteers have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (loading dose 300 mg followed by 75 mg daily) and esomeprazole (40 mg daily), resulting in an average 40% reduction in exposure to clopidogrel's active metabolite and an average 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, exposure to clopidogrel's active metabolite was reduced by nearly 40%. However, maximum levels of (ADP-induced) platelet aggregation inhibition were similar between the clopidogrel and clopidogrel + combination (esomeprazole + ASA) groups.

Observational and clinical studies have yielded conflicting data regarding the clinical significance of this PK/PD interaction in terms of major cardiovascular events. As a precautionary measure, concomitant use of clopidogrel and esomeprazole is not recommended.

Investigated medicinal products 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

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

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products inhibiting CYP2C19 and/or CYP3A4

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

Medicinal products inducing CYP2C19 and/or CYP3A4

Drugs capable of inducing CYP2C19 or CYP3A4 or both enzymes (such as rifampicin and St. John's wort) may reduce esomeprazole serum concentrations by enhancing its metabolism.

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use.

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

Gastrointestinal infections

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

Absorption of vitamin B12

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

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least 3 months, and in most cases, for a year or longer. Hypomagnesemia can manifest serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, but its onset may be gradual and remain unnoticed. In most patients with hypomagnesemia, condition improved after magnesium replacement therapy and discontinuation of PPIs.

For patients expected to undergo long-term treatment or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before initiating PPI therapy and periodically during treatment.

Fracture risk

Proton pump inhibitors, particularly when used at high doses and over 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 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 intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors have been associated with very rare cases of SCLE. If skin lesions develop, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical attention, and healthcare providers should consider discontinuing esomeprazole. Prior treatment with a proton pump inhibitor may increase the risk of developing SCLE upon subsequent use of other PPIs.

Concomitant use 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 PPIs is considered necessary, close patient monitoring 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. Potential interactions with drugs metabolized by CYP2C19 should be considered at the initiation and end of esomeprazole therapy. An interaction between clopidogrel and esomeprazole has been observed (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.

Serious cutaneous adverse reactions (SCARs)

Very rare cases of serious 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, have been reported in association with esomeprazole treatment.

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.

Esomeprazole treatment should be discontinued immediately upon the appearance of signs or symptoms of serious skin reactions, and additional medical care/monitoring should be provided as needed.

Patients with EM/SJS/TEN/DRESS should not be re-exposed to the drug.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole 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 discontinuation of proton pump inhibitor therapy.

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. Epidemiological studies using the racemic mixture of omeprazole in a large number of pregnant women do not indicate a lack of developmental malformations or fetotoxic effects. Animal studies have not revealed any direct or indirect harmful effects on embryofetal development. Studies in animals using the racemic mixture do not indicate adverse direct or indirect effects on pregnancy, delivery, or postnatal development. Esoméprazole-MB should be prescribed to pregnant women with caution.

A moderate amount of data from pregnant women (from 300 to 1000 pregnancy outcomes) indicates no evidence of developmental malformations or fetal/neonatal toxicity with esomeprazole. Animal studies do not indicate any direct or indirect harmful effects on reproductive toxicity.

Breastfeeding

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

Fertility

Animal studies using the racemic mixture of omeprazole administered orally do not indicate an effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Esomeprazole has a negligible influence on the ability to drive or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported. If these reactions occur, patients should not drive or operate machinery.

Method of 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.

Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding due to gastric or duodenal ulcer

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

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

Method of administration

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

Injections

Dose 40 mg

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

Dose 20 mg

Administer 2.5 mL or half of the reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Infusions

Dose 40 mg

Administer the reconstituted solution as an intravenous infusion over 10–30 minutes.

Dose 20 mg

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

Dose 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 (infusion rate calculated at 8 mg/hour; shelf life of reconstituted solution is specified in the section «Shelf life»).

Renal impairment

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

Hepatic impairment

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

Bleeding ulcers: dose adjustment is not required in patients with mild or moderate hepatic impairment; in patients with severe hepatic impairment, after administration of the initial 80 mg bolus dose of Esomeprazole-MB for infusion, subsequent 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

Dosage

Children aged 1–18 years

As an agent for inhibition of gastric secretion when oral administration of the drug 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 given in the table below).

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

Recommended intravenous doses of esomeprazole

Age group	Treatment of erosive reflux esophagitis	Symptomatic treatment of GERD
1-11 years	Body weight < 20 kg: 10 mg once daily Body weight ≥ 20 kg: 10 or 20 mg once daily	10 mg once daily
12-18 years	40 mg once daily	20 mg once daily

Method of administration

Instructions for preparing the reconstituted solution are provided in this section below ("Instructions for use, handling, and disposal (as 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. Any unused solution should be discarded.

Dose of 10 mg

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

Infusions

Dose 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. Any unused solution should be discarded.

Dose of 10 mg

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

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

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

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

Injection solution 40 mg

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

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

Infusion solution 40 mg

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

Infusion solution 80 mg

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

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

Children

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

Overdose

Experience with intentional overdose is currently very limited. Symptoms following oral intake of 280 mg included gastrointestinal disturbances and weakness. No adverse outcomes were observed after single oral doses of 80 mg esomeprazole or intravenous administration of 308 mg esomeprazole within 24 hours. There is no specific antidote. Esomeprazole-MB is highly plasma protein-bound and therefore not effectively removed by dialysis. As with any overdose, symptomatic treatment and general supportive measures should be provided.

Adverse reactions.

Summary of safety profile

Headache, abdominal pain, diarrhoea and nausea are among the most commonly reported adverse reactions during clinical trials (as well as during post-marketing use). Furthermore, the safety profile is similar across different formulations, indications, age groups and patient populations. Dose-dependent adverse reactions have not been identified.

List of adverse reactions

The following adverse drug reactions have been identified or suspected during the clinical development programme of esomeprazole with oral or intravenous administration, as well as during post-marketing surveillance of oral administration. Reactions are listed by system organ class and frequency categories: very common (≥ 1/10); 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).

Blood and lymphatic system disorders

Rare: leucopenia, thrombocytopenia.

Very rare: agranulocytosis, pancytopenia.

Immune system disorders

Rare: hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reactions/shock.

Metabolism and nutrition disorders

Uncommon: peripheral oedema.

Rare: hyponatraemia.

Frequency not known: hypomagnesaemia (see section "Special warnings and precautions for use"); severe hypomagnesaemia may correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.

Psychiatric disorders

Uncommon: insomnia.

Rare: agitation, confusion, depression.

Very rare: aggression, hallucinations.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, somnolence.

Rare: taste disturbance.

Eye disorders

Uncommon: blurred vision.

Ear and labyrinth disorders

Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders

Rare: bronchospasm.

Gastrointestinal disorders

Common: abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign).

Uncommon: dry mouth.

Rare: stomatitis, gastrointestinal candidiasis.

Frequency not known: microscopic colitis.

Hepatobiliary disorders

Uncommon: increased liver enzymes.

Rare: hepatitis, with or without jaundice.

Very rare: hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders

Common: infusion site reactions*.

Uncommon: dermatitis, pruritus, rash, urticaria.

Rare: alopecia, photosensitivity.

Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).

Frequency not known: subacute cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the hip, wrist or spine (see section "Special warnings and precautions for use").

Rare: arthralgia, myalgia.

Very rare: muscle weakness.

Renal and urinary disorders

Very rare: interstitial nephritis; in some patients, renal failure has been reported.

Reproductive system and breast disorders

Very rare: gynaecomastia.

General disorders and administration site conditions

Rare: malaise, increased sweating.

*Infusion site reactions were observed primarily in a study using high doses administered over 3 days (72 hours).

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

Paediatric population

A randomised, 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 (including 8 children aged 1–5 years) were included in the safety assessment. The safety profile of the drug was consistent with the known safety profile of esomeprazole, and no new safety concerns were identified.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

The reconstituted solution is chemically and physically stable for 12 hours when stored at a temperature not exceeding 30 °C. From a microbiological standpoint, the reconstituted solution should be used immediately.

Incompatibilities.

Do not use solvents not specified in the section "Dosage and method of administration". Do not mix with other medicinal products.

Packaging.

40 mg of the drug in a glass vial, stoppered with a rubber stopper and sealed with an aluminium crimp cap fitted with a flip-off cap providing a tamper-evident seal.

1 vial per cardboard carton.

Prescription status. Prescription only.

Manufacturer.

IMMACULE LIFESCIENCES PRIVATE LIMITED

Manufacturer's address.

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, IN 174101, India

Marketing Authorisation Holder.

M.BIOTECH LIMITED

Address of Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom