Pompezo

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

Composition:

Active substance: esomeprazole;

1 vial contains esomeprazole (as esomeprazole sodium) 40 mg;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Main physicochemical properties: lyophilized white powder; prepared solution: clear colorless or slightly yellow solution.

Pharmacotherapeutic group. Drugs 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, which reduces gastric acid secretion through a specific, targeted mechanism of action. It is a specific inhibitor of the proton pump (PPI) in parietal cells. Both the R- and S-isomers of omeprazole exhibit similar pharmacodynamic 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 proton pump—and suppresses both basal and stimulated acid secretion.

Pharmacodynamic effects. After 5 days of oral administration of esomeprazole at doses of 20 mg and 40 mg, intragastric pH remained above 4 for an average of 13 hours and 17 hours, respectively, during a 24-hour period in patients with symptomatic gastroesophageal reflux disease (GERD). The effect of esomeprazole is similar following oral and intravenous administration.

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

In healthy volunteers receiving intravenous esomeprazole at a dose of 80 mg as a 30-minute bolus infusion followed by a continuous intravenous infusion at 8 mg/hour for 23.5 hours, intragastric pH remained above 4 and above 6 for an average of 21 hours and 11–13 hours, respectively, during a 24-hour period.

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

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

During treatment with acid-suppressing agents, plasma gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that PPI treatment should be discontinued 5–14 days before measuring CgA levels. This allows CgA levels to return to normal ranges, as they may be falsely elevated during PPI therapy.

During long-term esomeprazole therapy, both in children and adults, an increase in the number of enterochromaffin-like (ECL) cells has been observed, possibly due to elevated plasma gastrin levels. These findings are considered clinically insignificant.

With prolonged use of acid-suppressing agents, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are a physiological consequence of pronounced suppression of gastric juice secretion; they are benign in nature and resolve after discontinuation of therapy.

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial load in the stomach, particularly of organisms normally present in the gastrointestinal tract. PPI therapy slightly increases 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 the drug were evaluated in patients with signs and symptoms of GERD. Esomeprazole 1 mg/kg once daily was administered orally for 2 weeks (open 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 treatment discontinuation due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the drug were evaluated in patients with GERD symptoms. Esomeprazole 0.5 mg/kg once daily was administered orally for at least 10 days. There was no significant difference between esomeprazole and placebo in the primary endpoint—change in frequency of GERD symptoms—compared to 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 < 4.0. The safety profile of the drug was similar to that in adults.

In a study involving pediatric patients with GERD (aged <1 to 17 years) receiving long-term proton pump inhibitor (PPI) therapy, ECL-cell hyperplasia of mild degree was observed in 61% of children; its clinical significance was unknown. No cases of atrophic gastritis or carcinoid tumors were reported.

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

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

Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after repeated administration. The plasma elimination half-life (t½) of esomeprazole 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. Approximately 80% of an oral dose of esomeprazole is excreted in urine as metabolites, and the remainder in feces. Less than 1% of the parent compound is excreted in urine.

Linearity/Non-linearity. 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 likely due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

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

Special patient groups

Patients with CYP2C19 enzyme polymorphism. Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and are termed poor metabolizers. In these individuals, esomeprazole metabolism is likely catalyzed predominantly by CYP3A4. After multiple doses of esomeprazole 40 mg once daily, the mean AUC was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). The mean C_max was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These differences do not require dose adjustments for esomeprazole.

Patients with 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 esomeprazole AUC. Therefore, patients with GERD and severe hepatic impairment should not exceed a maximum dose of 20 mg. For patients with bleeding ulcers and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion of esomeprazole at a maximum rate of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.

Patients with renal impairment. No studies have been conducted in patients with impaired renal function. Since the kidneys are responsible for excretion of esomeprazole metabolites but not the parent compound, changes in esomeprazole metabolism are not expected in patients with renal impairment.

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

Gender differences. After a single 40 mg dose of esomeprazole, the mean AUC in women is approximately 30% higher than in men. No gender-related differences are observed with repeated once-daily administration of esomeprazole. Similar differences were observed with intravenous administration of esomeprazole. These differences do not require dose adjustments.

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 systemic exposure results of esomeprazole after 3-minute intravenous injection in pediatric patients and healthy adult volunteers. Values in Table 1 are presented as geometric means (range). The 20 mg dose in adults was administered as a 30-minute infusion. Maximum steady-state plasma concentration (C_{ss, max}) was estimated at 5 minutes after dosing in all pediatric age groups, and at 7 minutes after dosing in adults receiving 40 mg and at the end of the 20 mg infusion.

Table 1

* The age group from 0 to 1 month included patients with postmenstrual age (sum of gestational age and postnatal age in completed weeks) ≥ 32 completed weeks and < 44 completed weeks. The age group from 1 to 11 months included patients with postmenstrual age ≥ 44 completed weeks.

** Two patients were excluded: one most likely due to reduced CYP2C19 isoenzyme activity, 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 would decrease by 37–49%, 54–66%, and 61–72%, respectively, on average across all age groups and dosing groups, compared to Css,max after a 3-minute injection.

Clinical Characteristics

Indications

Adults

• For antisecretory therapy when oral administration is not feasible, for example:

• in GERD patients with esophagitis and/or severe reflux symptoms;

• for treatment of gastric ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) therapy;

• for prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.

• For prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding due to gastric or duodenal ulcer.

Children aged 1 to 18 years

• For antisecretory therapy when oral administration is not feasible, for example:

• in GERD patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications

• Hypersensitivity to the active substance, to other substituted benzimidazoles, or to any of the excipients.
• Concomitant use with nelfinavir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

Interaction studies have been conducted only in adults.

Effect of esomeprazole on the pharmacokinetics of other drugs

Protease inhibitors

An interaction between omeprazole and certain protease inhibitors has been observed. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible due to inhibition of CYP2C19.

Reduced plasma levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole; therefore, co-administration of these agents is not recommended.

Concomitant administration of omeprazole 40 mg once daily with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (reduction in AUC, Cmax, and minimum plasma 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 AUC by approximately 30% compared to atazanavir 300 mg/ritonavir 100 mg without omeprazole (20 mg daily).

Concomitant administration of omeprazole 40 mg daily reduced mean AUC, Cmax, and Cmin of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 by 75–92%.

Due to the similarity in pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended (see section "Special precautions for use"). Concomitant use of esomeprazole and nelfinavir is contraindicated (see section "Contraindications").

Increased plasma levels (80–100%) of saquinavir (in combination with ritonavir) were observed with concomitant use of omeprazole (40 mg daily).

Omeprazole (20 mg daily) did not affect the AUC of darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir).

Esomeprazole (20 mg daily) did not affect the AUC of amprenavir (in combination with ritonavir or alone).

Administration of omeprazole (40 mg daily) did not alter the AUC of lopinavir (in combination with ritonavir).

Methotrexate

In some patients, increased plasma levels of methotrexate have been observed with concomitant use of PPIs. When using high-dose methotrexate, consider temporary discontinuation of esomeprazole.

Tacrolimus

Increased plasma levels of tacrolimus have been observed with concomitant use of esomeprazole. With concomitant use, intensified monitoring of plasma tacrolimus levels and renal function (creatinine clearance) is recommended, and the tacrolimus dose should be adjusted as needed.

Drugs with pH-dependent absorption

Suppression of gastric acidity during treatment with esomeprazole and other PPIs may reduce or increase the absorption of drugs whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, whereas absorption of drugs such as digoxin may be increased during esomeprazole treatment. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in 2 out of 10 subjects). Rare cases of digoxin toxicity have been reported. However, caution should be exercised when administering high doses of esomeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Drugs metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, and phenytoin, their plasma concentrations 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 effects during the 3-day intravenous esomeprazole administration period.

Diazepam

Concomitant oral administration of esomeprazole (30 mg) resulted in a 45% reduction in the clearance of diazepam, a CYP2C19 substrate.

Phenytoin

Concomitant oral administration of esomeprazole (40 mg) in patients with epilepsy resulted in a 13% increase in phenytoin plasma Cmin. Monitoring of plasma phenytoin levels is recommended at the beginning and after discontinuation of esomeprazole therapy.

Voriconazole

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

Cilostazol

Omeprazole, as well as esomeprazole, acts as an inhibitor of CYP2C19. In a crossover study, administration of omeprazole (40 mg) to healthy volunteers increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Cisapride

In healthy volunteers, concomitant oral administration with esomeprazole (40 mg) increased AUC by 32% and t½ by 31%, but no significant increase in cisapride Cmax was observed. The slight QTc prolongation observed with cisapride monotherapy was not observed with concomitant administration of cisapride and esomeprazole.

Warfarin

A clinical study showed that co-administration of oral esomeprazole 40 mg in patients on warfarin therapy kept coagulation time within acceptable limits. However, during the post-marketing period, several cases of clinically significant increase in the international normalized ratio (INR) were reported with concomitant oral administration of these agents. Monitoring of INR is recommended at the beginning and after discontinuation of concomitant esomeprazole use in patients on warfarin or other coumarin derivatives.

Clopidogrel

Pharmacokinetic (PK)/pharmacodynamic (PD) interaction studies between clopidogrel (loading dose 300 mg / maintenance dose 75 mg daily) and esomeprazole (oral 40 mg daily) in healthy volunteers showed a mean reduction in AUC of clopidogrel's active metabolite by 40% and a mean reduction in maximum inhibition of (ADP-induced) platelet aggregation by 14%.

In a study in healthy volunteers where clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in a fixed-dose combination (20 mg + 81 mg, respectively) compared to clopidogrel monotherapy, a reduction in AUC of clopidogrel's active metabolite by nearly 40% was observed. However, maximum levels of inhibition (ADP-induced) of platelet aggregation were similar in the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA.

Observational and clinical studies have provided conflicting data on the clinical aspects of PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Drugs that inhibit CYP2C19 and/or CYP3A4 activity

Esomeprazole is metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubles the AUC of esomeprazole. Concomitant administration of esomeprazole with a combined CYP2C19 and CYP3A4 inhibitor may increase esomeprazole AUC by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCτ by 280%. Dose adjustment of esomeprazole is generally not required in any of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases requiring long-term treatment.

Drugs that induce CYP2C19 and/or CYP3A4 activity

Agents that induce CYP2C19 or CYP3A4 activity, or both enzymes (such as rifampicin and St. John's wort), may reduce esomeprazole plasma levels by accelerating its metabolism.

Drugs with no clinically significant interaction

Amoxicillin and quinidine

In interaction studies, esomeprazole did not have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

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

Special precautions for use

In the presence of any alarming symptoms (such as significant unexplained weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be ruled out, since esomeprazole may mask symptoms and delay diagnosis.

Gastrointestinal infections

Use of PPIs slightly increases the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Absorption of vitamin B12

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

Hypomagnesaemia

Cases of severe hypomagnesaemia have been reported in patients taking PPIs, such as esomeprazole, for at least three months, mostly after a year of therapy. Hypomagnesaemia may present with serious manifestations such as fatigue, tetany, delirium, seizures, dizziness and ventricular arrhythmias, and its onset may be gradual and remain unnoticed. In most patients with hypomagnesaemia, condition improved after magnesium replacement therapy and discontinuation of PPIs. For patients expected to require long-term treatment or those taking PPIs with digoxin or other agents that may cause hypomagnesaemia (e.g. diuretics), measurement of magnesium levels before starting PPI therapy and periodically during treatment may be appropriate.

Fracture risk

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

Subacute cutaneous lupus erythematosus

PPI use 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 medicinal product should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous PPI therapy increases the risk of its recurrence when using 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 concomitant use of atazanavir with a PPI 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 esomeprazole dose should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19. Potential interactions with medicinal products 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. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Severe cutaneous adverse reactions

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

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

If a patient develops symptoms and signs suggestive of severe cutaneous reactions, esomeprazole should be discontinued immediately, and appropriate medical treatment and/or close monitoring should be provided as needed.

The medicinal product should not be re-administered to patients who previously experienced severe cutaneous adverse reactions (EM/SJS/TEN/DRESS) following esomeprazole intake.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with investigations for diagnosing neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal ranges after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI therapy.

Each vial of the medicinal product Pompezo contains less than 1 mmol sodium (23 mg) per 40 mg, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy. There are insufficient data on the use of esomeprazole during pregnancy. Epidemiological studies on the use of the racemic mixture omeprazole during pregnancy do not indicate an increased risk of congenital malformations or fetal toxicity. Studies in animals with esomeprazole have not shown direct or indirect adverse effects on embryonal/foetal development. Animal studies with the racemic mixture have not shown direct or indirect effects on pregnancy, delivery or postnatal development. Esomeprazole should be used during pregnancy only if clearly needed and with caution.

Available data from a limited number of pregnancies (from 300 to 1000 exposed pregnancies) indicate no malformative effects or toxic effects of esomeprazole on the fetus or neonatal health.

Animal studies indicate no direct or indirect adverse effects of esomeprazole on fertility due to its toxicological profile.

Breastfeeding period. It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the effects of esomeprazole on newborns or breastfed infants. In view of this, the medicinal product should not be used in women who are breastfeeding.

Fertility. Based on animal studies with the racemic mixture of omeprazole, omeprazole does not affect fertility when administered orally.

Ability to influence the speed of reactions while driving or operating machinery

Esomeprazole has minimal influence on the ability to drive 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 or operating machinery.

Dosage and Administration

Adults

Dosage

Antisecretory therapy when oral administration of esomeprazole is not possible

For patients who cannot take esomeprazole orally, the drug may be administered parenterally at a dose of 20–40 mg once daily.

For patients with reflux esophagitis, the recommended dose is 40 mg once daily.

For patients receiving symptomatic treatment of gastroesophageal reflux disease, the dose 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, at-risk patients should receive 20 mg once daily.

Treatment with intravenous esomeprazole is generally short-term; patients should be switched to oral therapy as soon as possible.

Prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers

After endoscopic therapy for acute bleeding from gastric or duodenal ulcers, administer 80 mg of the drug as a 30-minute intravenous bolus infusion, 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.

Administration method

Instructions for preparation of the reconstituted solution are provided below (see "Instructions for preparation, use, and disposal").

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.

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 80 mg:

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

Dose of 8 mg/hour:

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

Special patient groups

Patients with renal impairment

Dose adjustment is not required in patients with renal impairment. As experience with esomeprazole in patients with severe renal impairment is limited, the drug should be used with caution in such patients (see section "Pharmacokinetics").

Patients with 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 administration of an initial 80 mg bolus dose, continuation with a continuous intravenous infusion at 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required.

Children aged 1–18 years

Dosage

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

For patients unable to take the drug orally, the drug may be administered parenterally once daily during the full course of treatment for GERD (doses are specified in the table below).

Treatment with intravenous esomeprazole should generally be brief; patients should be switched to oral esomeprazole as soon as possible.

Recommended intravenous doses of esomeprazole

Method of Administration

Instructions for preparing the reconstituted solution are provided below ("Instructions for preparation, use, and disposal").

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 preparation, use, and disposal

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

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

Injection solution 40 mg

To prepare an injection solution (8 mg/ml), add 5 ml of 0.9% sodium chloride for intravenous use to a vial containing 40 mg of esomeprazole lyophilisate.

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

Infusion solution 40 mg

To prepare an infusion solution, dissolve the content of one vial of esomeprazole 40 mg in 100 ml of 0.9% sodium chloride for intravenous use.

Infusion solution 80 mg

To prepare an infusion solution, dissolve the contents of two vials of esomeprazole 40 mg each in 100 ml of 0.9% sodium chloride for intravenous use.

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

Children. The medicinal product may be used in children aged 1 year and older as an antisecretory therapy when oral administration of esomeprazole is not feasible.

Overdose

Currently, data on intentional overdose are very limited. Symptoms reported following oral administration of esomeprazole at a dose of 280 mg included gastrointestinal disturbances and weakness. A single oral dose of 80 mg of esomeprazole and intravenous administration of 308 mg of esomeprazole over 24 hours did not result in any adverse effects. No specific antidote is known. Esomeprazole is highly protein-bound in plasma, so dialysis is unlikely to be effective. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

Among the adverse reactions most commonly observed in clinical studies and during post-marketing use of esomeprazole, headache, abdominal pain, diarrhea, and nausea are reported. The safety profile of esomeprazole is consistent across different dosage forms, indications, age groups, and other patient populations. No dose-dependent adverse reactions have been identified.

The adverse reactions listed below have been reported or suspected during clinical trials with oral or intravenous administration of esomeprazole, as well as during the post-marketing period with oral administration. The reactions are categorized according to frequency of occurrence: very common (> 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare — leukopenia, thrombocytopenia; very rare — agranulocytosis, pancytopenia.

Immune system disorders:

Rare — hypersensitivity reactions, e.g., fever, angioedema, anaphylactic reaction/shock.

Metabolism and nutrition disorders:

Uncommon — peripheral edema; rare — hyponatremia; frequency not known — hypomagnesemia (see section "Special precautions for use"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders:

Uncommon — insomnia; rare — agitation, confusion, depression; very rare — aggression, hallucinations.

Nervous system disorders:

Common — headache; uncommon — dizziness, paresthesia, 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, diarrhea, 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 — reactions at injection site*; uncommon — dermatitis, pruritus, rash, urticaria; rare — alopecia, photosensitivity; very rare — polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS); frequency not known — subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders:

Uncommon — fracture of the hip, wrist, or spine (see section "Special precautions for use"); rare — arthralgia, myalgia; very rare — muscle weakness.

Renal and urinary disorders:

Very rare — interstitial nephritis (in some patients, renal failure was also observed concurrently).

Reproductive system and breast disorders:

Very rare — gynecomastia.

General disorders and administration site conditions:

Rare — malaise, increased sweating.

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C, protected from light and kept out of reach of children.

Incompatibilities. This medicinal product should not be mixed with other medicinal products except as specified in the section "Dosage and administration".

Packaging. In a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey