Instructions for Ezonex lyophilized powder for solution for infusions and injections 40 mg vial No. 1
Composition
active ingredient: esomeprazole;
1 vial contains 42.5 mg of esomeprazole sodium, equivalent to 40 mg of esomeprazole;
excipients: disodium edetate, sodium hydroxide.
Dosage form
Lyophilisate for solution for injection and infusion.
Main physicochemical properties: porous lyophilized powder of white or almost white color.
Pharmacotherapeutic group
Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. ATC code A02B C05.
Pharmacological properties
Pharmacodynamics
Esomeprazole is the S-isomer of omeprazole, which inhibits gastric acid secretion by a specific, targeted mechanism of action. It is a specific inhibitor of the parietal cell acid pump. Both the R- and S-isomers of omeprazole have similar pharmacological activities.
Site and mechanism of action
Esomeprazole is a weak base that concentrates and converts to the active form in the highly acidic environment of the secretory tubules of parietal cells, where it inhibits the enzyme H+K+-ATPase – the acid pump – and suppresses both basal and stimulated acid secretion.
Effect on gastric juice secretion
After 5 days of oral administration of 20 mg and 40 mg esomeprazole, gastric pH above 4 was maintained for an average of 13 hours and 17 hours over a 24-hour period, respectively, in patients with symptomatic GERD (gastroesophageal reflux disease). The effect was similar for both oral and intravenous administration.
Using AUC as a proxy for plasma drug concentration, a relationship between acid suppression and exposure following oral administration of esomeprazole has been demonstrated.
When esomeprazole was administered intravenously to healthy volunteers at a dose of 80 mg as a bolus infusion over 30 minutes followed by a continuous intravenous infusion at a rate of 8 mg/hour for 23.5 hours, gastric pH levels above 4 and above 6 were maintained for an average of 21 hours and 11–13 hours, respectively, over a 24-hour period.
Therapeutic effect of acid secretion inhibition
With oral administration of esomeprazole at a dose of 40 mg, approximately 78% of patients with reflux esophagitis recover after 4 weeks, and 93% after 8 weeks of treatment.
Other effects related to inhibition of acid secretion
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. Chromogranin A (CgA) levels also increase due to decreased gastric acidity.
An increase in the number of enterochromaffin-like cells, possibly related to increased gastrin levels, has been observed in some patients during long-term treatment with oral esomeprazole.
A slight increase in the frequency of gastric glandular cyst formation has been observed against the background of long-term treatment with oral antisecretory drugs. These changes are a physiological consequence of pronounced inhibition of gastric juice secretion, are benign and reversible in nature.
Decreased gastric acidity from any cause, including proton pump inhibitors, leads to an increase in the number of bacteria normally present in the gastrointestinal tract in the stomach. Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and in hospitalized patients, possibly also Clostridium difficile.
Children
Results from studies in pediatric patients show that doses of esomeprazole 0.5 mg/kg and 1.0 mg/kg in infants < 1 month and 1-11 months of age, respectively, reduce the mean percentage of time that intraesophageal pH is < 4.
The safety profile of the drug was similar to that observed in adults.
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 excretion
Esomeprazole is completely metabolised by the cytochrome P450 (CYP) system. The main part of the metabolism of esomeprazole depends on the polymorphic CYP2C19, which is responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining metabolism is carried out by another specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in plasma.
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 is approximately 1.3 hours after repeated once daily administration. 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 administration. This time- and dose-dependence is due to a decrease in first-pass metabolism and systemic clearance, probably due to inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.
Esomeprazole is completely eliminated from plasma between doses, and there is no tendency for its accumulation in the body when administered once daily.
After repeated intravenous administration of 40 mg, 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 with oral administration. A linear dose-dependent increase in exposure was observed when esomeprazole was administered as an intravenous infusion over 30 minutes (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) for 23.5 hours.
The main metabolites of esomeprazole do not affect gastric secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the rest in the feces. Less than 1% of the parent compound is excreted in the urine.
Patients of special groups
Approximately 2.9 ± 1.5% of the population lack a functional CYP2C19 enzyme and are referred to as poor metabolisers. In these individuals, the metabolism of esomeprazole is likely to be predominantly catalysed by CYP3A4. After multiple oral doses of esomeprazole 40 mg once daily, the mean total exposure was approximately 100% higher in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). The mean maximum plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These findings do not require any changes in the dosage of esomeprazole.
The metabolism of esomeprazole is slightly altered in the elderly (71–80 years)
After a single oral dose of 40 mg esomeprazole, the mean total exposure in women is approximately 30% higher than in men. No gender differences were observed with repeated once daily dosing. Similar differences were observed with intravenous administration of esomeprazole. These findings do not impact the posology of esomeprazole.
The metabolism of esomeprazole in patients with mild or moderate hepatic impairment may be altered. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of the total exposure to esomeprazole. Therefore, in patients with GERD and severe hepatic impairment, the maximum dose of 20 mg should not be exceeded. In the case of bleeding ulcers and severe hepatic impairment, after an initial bolus dose of 80 mg, a continuous intravenous infusion at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show a tendency to accumulate when administered once daily.
No studies have been conducted in patients with reduced renal function. Since the kidneys are responsible for the excretion of esomeprazole metabolites, but not the parent compound, no changes in metabolism are expected in patients with renal impairment.
Indication
Adults
Antisecretory therapy when oral administration is not possible, e.g.: gastroesophageal reflux disease in patients with oesophagitis and/or severe reflux symptoms; treatment of gastric ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs); prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk. Short-term maintenance of haemostasis and prevention of rebleeding 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 possible, e.g. gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.
Contraindication
Hypersensitivity to the active substance esomeprazole, other substituted benzimidazoles or any of the excipients of this medicinal product.
Esomeprazole should not be used concomitantly with atazanavir, nelfinavir (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Interaction studies were conducted only in adults.
Effect of esomeprazole on the pharmacokinetics of other drugs
Suppression of gastric secretion during therapy with esomeprazole and other PPIs (proton pump inhibitors) may lead to a decrease or increase in the absorption of drugs whose absorption depends on the pH of the gastric juice. As with other drugs that reduce the acidity of gastric juice, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced and the absorption of digoxin may be increased during the period of use of esomeprazole. With the simultaneous use of omeprazole (20 mg per day) and digoxin in healthy volunteers, the bioavailability of digoxin increased by 10% (up to 30% in two out of ten participants). Toxic effects of digoxin have been observed rarely. However, caution should be exercised when using high doses of esomeprazole in elderly patients. Monitoring of the concentration of digoxin in the patient's blood should be intensified.
Omeprazole has been reported to interact with some protease inhibitors. The clinical significance and mechanisms of these interactions are not always known. The increase in gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other possible mechanisms of interaction include inhibition of CYP2C19. Decreased serum levels of atazanavir and nelfinavir have been observed with concomitant use of omeprazole, and concomitant use of these drugs is therefore not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers decreased atazanavir exposure by approximately 30% compared to the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Co-administration of omeprazole (40 mg daily) decreased the mean AUC, Cmax, and Cmin of nelfinavir by 36-39% and the mean AUC, Cmax, and Cmin of the pharmacologically active metabolite M8 by 75-92%.
Increased serum concentrations of saquinavir (co-administered with ritonavir) (80-100%) were observed with concomitant use of omeprazole (40 mg daily). Omeprazole 20 mg daily had no effect on the exposure of darunavir (co-administered with ritonavir) and amprenavir (in combination with ritonavir). Esomeprazole 20 mg daily had no effect on the exposure of amprenavir (in combination with ritonavir or alone). Omeprazole 40 mg/day did not alter the exposure of lopinavir (in combination with ritonavir). Due to the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.
Drugs metabolized by CYP2C19
Esomeprazole inhibits CYP2C19, the main enzyme that metabolizes esomeprazole. Therefore, when esomeprazole is combined with drugs that are metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., the plasma concentrations of these drugs may increase and a reduction in their doses may be necessary. Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in the clearance of the CYP2C19 substrate diazepam. Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in the trough plasma concentration of phenytoin in epileptic patients. It is recommended to monitor the plasma concentration of phenytoin at the beginning of therapy with esomeprazole and upon its discontinuation. Omeprazole (40 mg once daily) increased the Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively.
When concomitant oral esomeprazole 40 mg was administered to patients taking warfarin in a clinical trial, the bleeding time remained within the acceptable range. However, in the post-marketing period, a few isolated cases of clinically significant increases in MCH have been reported with oral esomeprazole when these drugs were used concomitantly. Monitoring is recommended at the beginning and end of concomitant use of esomeprazole and warfarin or other coumarin derivatives.
Increased serum levels of tacrolimus have been reported with concomitant use of esomeprazole.
Omeprazole, like esomeprazole, is an inhibitor of CYP2C19. In a cross-over study in healthy volunteers, the use of omeprazole at a dose of 40 mg resulted in an increase in Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%.
Concomitant oral administration of 40 mg esomeprazole and cisapride to healthy volunteers resulted in a 32% increase in the area under the concentration-time curve (AUC) and a 31% increase in the elimination half-life (t1/2), but no significant increase in the maximum plasma concentration of cisapride was observed. The slight prolongation of the QTc interval observed with cisapride alone was not increased when cisapride was given in combination with esomeprazole.
In vivo interaction studies with the high-dose intravenous formulation (80 mg + 8 mg/hour) have not been performed. The effect of esomeprazole on drugs metabolized by CYP2C19 may be more pronounced with this regimen, and patients should be closely monitored for adverse events during the 3-day intravenous period.
In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) was administered alone and in combination with omeprazole (80 mg concomitantly with clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was reduced by 46% (day 1) and 42% (day 5) when clopidogrel and omeprazole were co-administered. The mean inhibition of platelet aggregation was reduced by 47% (24 hours) and 30% (day 5) when clopidogrel and omeprazole were co-administered. Another study demonstrated that co-administration of clopidogrel and omeprazole at different times did not eliminate their interaction, which is likely due to the inhibitory effect of omeprazole on CYP2C19. Observational and clinical studies have yielded conflicting data on the clinical manifestations of this PK/PD interaction in terms of major cardiovascular events.
Unknown mechanism
Methotrexate levels have been increased in some patients when used with PPIs. Temporary discontinuation of esomeprazole may be necessary when high doses of methotrexate are used.
Effect of other medicinal products on the pharmacokinetics of esomeprazole
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) resulted in a doubling of esomeprazole exposure (AUC). Concomitant administration of esomeprazole and a combined CYP2C19 and CYP3A4 inhibitor may result in a more than two-fold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always necessary in these situations. However, it may be necessary in patients with severe hepatic impairment and in cases where long-term treatment is indicated.
Drugs that can induce CYP2C19 or CYP3A4 or both of these enzymes (such as rifampicin and St. John's wort) may reduce serum concentrations of esomeprazole due to increased metabolism.
Application features
In the presence of any alarming symptoms (such as significant unexpected weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and in the presence or suspicion of gastric ulcer, malignancy should be excluded, as Ezonexa® may mask symptoms and delay diagnosis.
Proton pump inhibitor therapy may slightly increase the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section 5.1).
The use of esomeprazole concomitantly with atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is considered necessary, close monitoring of the patient is recommended and the dose of atazanavir should be increased to 400 mg with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.
Esomeprazole, like all acid-blocking drugs, may inhibit the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with reduced body stores or risk factors for impaired vitamin B12 absorption during long-term therapy.
Esomeprazole is a CYP2C19 inhibitor. When initiating and ending therapy with esomeprazole, the possibility of interactions with drugs metabolized by CYP2C19 should be considered. An interaction between clopidogrel and omeprazole has been reported (see section 4.5). The clinical significance of this interaction is not fully understood. As a precautionary measure, concomitant use of esomeprazole and clopidogrel is not recommended.
Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors (PPIs) such as esomeprazole for at least three months, and in most cases for a year. Hypomagnesemia can have serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, but its development may be gradual and go unnoticed. In most patients with hypomagnesemia, the condition improved after magnesium replacement therapy and discontinuation of the PPI.
Proton pump inhibitors, especially when used at high doses and for long periods (>1 year), may slightly increase the risk of hip, wrist, and spine fractures, mainly in elderly patients or those with other risk factors. Results of review studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. This increase may be partly due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines; they should also receive adequate vitamin D and calcium.
Impact on laboratory test results
Elevated CgA levels may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole should be temporarily discontinued for at least five days before CgA measurement.
One vial of the drug contains less than 1 mmol sodium, i.e. the drug is practically sodium-free.
Ability to influence reaction speed when driving vehicles or other mechanisms
Ezonexa® is unlikely to affect the ability to drive or operate machinery. During treatment with the drug, adverse reactions from the nervous system or the organs of vision may occur.
Use during pregnancy or breastfeeding
Data on the use of esomeprazole during pregnancy are limited. Animal studies do not indicate direct or indirect harmful effects with respect to embryofoetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development, therefore Ezonex® should be administered with caution to pregnant women.
It is not known whether esomeprazole passes into breast milk. Studies in breastfeeding women have not been conducted, therefore Ezonex® should not be used during breastfeeding.
Method of administration and doses
Dosage
Adults
Antisecretory therapy if oral administration is not possible.
Patients who cannot take the drug orally may be given the drug 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 for reflux disease is 20 mg once daily.
In the treatment of gastric ulcers caused by NSAIDs, the usual dose is 20 mg once a day. To prevent gastric and duodenal ulcers caused by NSAIDs, patients at risk are prescribed the drug at a dose of 20 mg once a day.
Treatment with intravenous medication is usually short-term, and patients should be switched to oral medication as soon as possible.
Short-term maintenance of hemostasis and prevention of rebleeding in patients after endoscopic treatment of acute bleeding due to gastric or duodenal ulcer
After therapeutic endoscopy of acute bleeding gastric or duodenal ulcers, 80 mg of the drug is administered as a bolus infusion lasting 30 minutes, after which the drug is continued by continuous intravenous infusion at a rate of 8 mg/hour for 3 days (72 hours).
After parenteral treatment, therapy should be continued with oral agents that suppress acid secretion.
Method of application
Instructions for preparing the reconstituted solution are provided in this section below (“Instructions for use, handling and disposal (where applicable)”).
Injections
Dose 40 mg
5 ml of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes.
Dose 20 mg
2.5 ml or half of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes. Any unused solution is discarded.
Infusions
Dose 40 mg
The reconstituted solution is administered as an intravenous infusion over 10 to 30 minutes.
Dose 20 mg
Half of the reconstituted solution is administered as an intravenous infusion over 10 to 30 minutes. Any unused solution is discarded.
Dose 80 mg
The reconstituted solution is administered as a continuous intravenous infusion over 30 minutes.
Dose 8 mg/h
The reconstituted solution is administered as a continuous intravenous infusion over 71.5 hours (calculated infusion rate 8 mg/hour; the shelf life of the reconstituted solution is indicated in the “Expiration Date” section).
Kidney dysfunction
No dose adjustment is necessary for patients with renal impairment. Since experience in patients with severe renal impairment is limited, the drug should be administered with caution to such patients (see section 5.2).
Liver dysfunction
Bleeding ulcers: No dose adjustment is required in patients with mild or moderate hepatic impairment; in patients with severe hepatic impairment, after an initial bolus dose of 80 mg Ezonex for infusion, a continuous intravenous infusion of 4 mg/hour for 71.5 hours may be sufficient (see section 5.2).
Elderly patients
No dose adjustment is required.
Children
Dosage
Children aged 1-18 years
As a means of suppressing gastric secretion when oral administration of the drug is not possible
For patients who cannot take the drug orally, the drug can be administered parenterally once daily (doses are listed in the table below) as part of the complete treatment period for GERD.
Treatment with an intravenous drug should usually be short-term, and patients should be switched to oral medication as soon as possible.
Recommended doses of esomeprazole for intravenous administration
| 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 old | 40 mg once daily | 20 mg once daily |
Method of application
Instructions for preparing the reconstituted solution are provided in this section below (“Instructions for use, handling and disposal (where applicable)”).
Injections
Dose 40 mg
5 ml of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes.
Dose 20 mg
2.5 ml or half of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes. Any unused solution is discarded.
Dose 10 mg
1.25 ml of the reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes. Any unused solution is discarded.
Infusions
Dose 40 mg
The reconstituted solution is administered as an intravenous infusion over 10 to 30 minutes.
Dose 20 mg
Half of the reconstituted solution is administered as an intravenous infusion over 10 to 30 minutes. Any unused solution is discarded.
Dose 10 mg
A quarter of the reconstituted solution is administered as an intravenous infusion over 10 to 30 minutes. Any unused solution is discarded.
Instructions for use, handling and disposal (where applicable)
The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solutions should be used. The solution is for single use only.
If the entire reconstituted vial contents are not required, the unused solution should be disposed of in accordance with local requirements.
Solution for injection 40 mg
Prepare a solution for injection (8 mg/ml) by adding 5 ml of 0.9% sodium chloride for intravenous use to a vial of esomeprazole 40 mg.
The reconstituted solution for injection is clear and colorless to slightly yellowish.
Solution for infusion 40 mg
Prepare a solution for infusion by dissolving the contents of one vial of esomeprazole 40 mg in 100 ml of 0.9% sodium chloride for intravenous use.
Solution for infusion 80 mg
Prepare an infusion solution by dissolving the contents of two 40 mg esomeprazole vials in 100 ml of 0.9% sodium chloride for intravenous use.
The reconstituted solution for infusion is clear and colourless or slightly yellowish.
Children
It is used in children over 1 year of age as an antisecretory therapy when oral administration of the drug is not possible.
Overdose
Experience with intentional overdose is currently very limited. Symptoms following oral administration of 280 mg were gastrointestinal symptoms and weakness. A single oral dose of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours were without sequelae. No specific antidote is known. Esomeprazole is highly bound to plasma proteins and is therefore poorly dialysable. As with any overdose, symptomatic treatment and general supportive measures should be given.
Adverse reactions
The following adverse drug reactions have been identified or suspected in the clinical trial program of esomeprazole with oral or intravenous administration, as well as during post-marketing surveillance with oral administration.
From the blood and lymphatic system: leukopenia, thrombocytopenia; agranulocytosis, pancytopenia.
Immune system disorders: Hypersensitivity reactions, such as fever, angioedema and anaphylactic reactions/shock.
Metabolism and nutrition disorders: peripheral edema, hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"); severe hypomagnesemia may correlate with hypocalcemia.
On the part of the psyche: insomnia, agitation, confusion, depression, aggression, hallucinations.
From the nervous system: headache, dizziness, paresthesia, drowsiness, taste disturbances.
From the organs of vision: blurred vision.
Respiratory, thoracic and mediastinal disorders: bronchospasm.
On the part of the digestive system: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.
Hepatobiliary system: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease.
Skin and subcutaneous tissue disorders: injection site reactions*, dermatitis, pruritus, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: fractures of the hip, wrist or spine (see section "Special warnings and precautions for use"), arthralgia, myalgia, muscle weakness.
Renal and urinary disorders: interstitial nephritis; renal failure has been reported in some patients.
Reproductive system and breast disorders: gynecomastia.
General disorders and administration site conditions: malaise, increased sweating.
*Injection site reactions were observed mainly in the high dose study for 3 days (72 hours). In the preclinical study program of esomeprazole for intravenous use, no vascular irritation was observed, but a slight inflammatory tissue reaction was observed at the site of subcutaneous (subcutaneous) injection. The results of the preclinical study indicated that the clinical manifestation of tissue irritation was concentration-related.
Irreversible visual disturbances have been reported in isolated cases in critically ill patients receiving omeprazole (racemate) as an intravenous injection, especially at high doses, but a causal relationship has not been established.
Pediatric population
A randomised, open-label, international study was conducted to evaluate the pharmacokinetics of multiple intravenous doses of esomeprazole over 4 days when administered once daily in children aged 0 to 18 years (see section 5.2). A total of 57 patients (8 children aged 1 to 5 years) were included in the safety assessment. The safety data were consistent with the known safety profile of esomeprazole and no new safety concerns were identified.
Expiration date
2 years.
Shelf life after reconstitution: Chemical and physical in-use stability has been demonstrated for 12 hours at 30°C. From a microbiological point of view, the product should be used immediately.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature not exceeding 30 ºС.
Vials can be stored without secondary packaging under normal room light for up to 24 hours.
Keep out of reach of children.
Incompatibility
This medicine should not be used with other medicines other than those mentioned in the section “Method of administration and dosage”.
Packaging
10 ml in a bottle. 1 bottle in a pack (production from bulk packaging by the manufacturer Laboratorios Norman S.A., Spain).
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
