Esomeprazole ananta

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOMEPRAZOLE ANANTA (ESOMEPRAZOLEANANTA)

Composition:

Active substance: esomeprazole;

1 vial contains esomeprazole sodium equivalent to esomeprazole 40 mg;

Excipient: edetate disodium.

Pharmaceutical form. Lyophilisate for solution for injection and infusion.

Main physicochemical properties: lyophilized mass of white to almost white color.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease.

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 to its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the enzyme H⁺K⁺-ATPase – the proton pump – thereby suppressing both basal and stimulated acid secretion.

Effect on gastric acid secretion

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

Using AUC as an indirect parameter of plasma concentration, a correlation has been demonstrated between acid secretion inhibition and exposure following oral administration of esomeprazole.

Over 24 hours, intravenous administration of 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, maintained gastric pH above 4 and above 6 for a mean duration of 21 hours and 11–13 hours, respectively, during a 24-hour period in healthy volunteers.

Therapeutic effect of acid secretion inhibition

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

Other effects related to acid secretion inhibition

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric acidity. An increase in enterochromaffin-like (ECL) cells, possibly related to elevated gastrin levels, has been observed in some patients during long-term oral esomeprazole therapy.

During prolonged treatment with oral antisecretory 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 and are benign and reversible in nature.

Reduced gastric acidity from any cause, including the use of proton pump inhibitors, leads to increased numbers of bacteria normally present in 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

Results from studies in pediatric patients show that esomeprazole doses of 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intragastric pH <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 elimination

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.

The parameters listed 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 elimination half-life in plasma is approximately 1.3 hours with repeated once-daily dosing. 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-dependence is due to reduced presystemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

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

With repeated administration of 40 mg esomeprazole as intravenous injections, the mean peak plasma concentration is approximately 13.6 µmol/L. The mean peak plasma concentration after corresponding oral doses is approximately 4.6 µmol/L. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared to oral dosing. A linear, dose-dependent increase in exposure has been observed with intravenous infusion of esomeprazole over 30 minutes (at doses of 40 mg, 80 mg, or 120 mg), followed by continuous infusion (at 4 mg/h or 8 mg/h) for 23.5 hours.

The main metabolites of esomeprazole do not affect gastric acid secretion. Approximately 80% of an oral dose of esomeprazole is excreted in urine as metabolites, the remainder in feces. Less than 1% of the parent compound is excreted in urine.

Special patient populations

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 oral doses of 40 mg esomeprazole once daily, mean total exposure was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (rapid metabolizers). The mean peak plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dose adjustment of esomeprazole.

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

After a single oral dose of 40 mg esomeprazole, mean total exposure is approximately 30% higher in women than in men. No sex-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.

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 with 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.

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

Clinical characteristics.

Indications.

Adults

• Antisecretory therapy when oral administration is not possible, for example:
  • gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe reflux symptoms;
  • treatment of gastric ulcers associated with nonsteroidal anti-inflammatory drug (NSAID) therapy;
  • prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk.
• Short-term maintenance of hemostasis and prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers.

Children aged 1 to 18 years

• Antisecretory therapy when oral administration is not possible, for example:
  • gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

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

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.

Interaction studies have been conducted only in adults.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption depends on pH

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

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible via inhibition of CYP2C19.

Reduced 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 (decrease 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%.

Increased serum concentrations of saquinavir (administered concomitantly with ritonavir) by 80–100% were observed with concomitant omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect exposure to darunavir (administered with ritonavir) or amprenavir (in combination with ritonavir). 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). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Methotrexate

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

Tacrolimus

Elevated serum levels of tacrolimus have been reported with concomitant use of esomeprazole. Enhanced monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required; dose adjustment of tacrolimus may be necessary.

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 required.

In vivo interaction studies using 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 events during the three-day intravenous treatment period.

Diazepam

Concomitant oral administration of 30 mg esomeprazole reduced the clearance of diazepam (a CYP2C19 substrate) by 45%.

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased minimum plasma concentrations of phenytoin in epileptic patients by 13%. Monitoring of plasma phenytoin concentrations is recommended at the beginning and upon discontinuation 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 an inhibitor of CYP2C19. In a crossover study in healthy volunteers, administration of omeprazole 40 mg increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.

Cisapride

Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers increased the area under the plasma concentration-time curve (AUC) by 32% and half-life (t1/2) by 31%, but no significant increase in maximum plasma concentration of cisapride was observed. The slight QTc prolongation observed with cisapride alone was not increased when cisapride was administered in combination with esomeprazole.

Warfarin

In a clinical study, co-administration of 40 mg esomeprazole with warfarin did not alter blood coagulation time beyond 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

A pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg followed by 75 mg/day) and esomeprazole (40 mg daily orally) was observed in healthy volunteers, resulting in a 40% reduction in exposure to the active metabolite of clopidogrel and a 14% reduction in maximum inhibitory activity (ADP-induced) against platelet aggregation.

In a study in healthy volunteers evaluating clopidogrel with a combination of 20 mg esomeprazole and 81 mg acetylsalicylic acid versus clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. However, maximum inhibitory activity (ATP-induced) against platelet aggregation was similar in groups receiving clopidogrel alone and clopidogrel plus combination (esomeprazole + acetylsalicylic acid), likely due to the concomitant administration of low-dose acetylsalicylic acid.

Observational and clinical studies have yielded conflicting data regarding the clinical implications of this PK/PD interaction in terms of major cardiovascular events.

Therefore, concomitant use of esomeprazole and clopidogrel should be avoided.

Medicinal products without clinically significant interaction

It has been shown that esomeprazole does not have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Studies conducted with concomitant administration of esomeprazole and 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 that inhibit 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 a combined inhibitor of CYP2C19 and CYP3A4 may increase esomeprazole exposure by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always necessary in such cases. However, it may be required in patients with severe hepatic impairment or when long-term treatment is indicated.

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

Special precautions for use

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

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").

Concomitant use of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If co-administration of atazanavir with proton pump inhibitors is considered essential, close monitoring of the patient is recommended and the dose of atazanavir should be increased to 400 mg in combination with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.

Esomeprazole, like all drugs that inhibit acid secretion, may reduce 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.

Esomeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19 should be considered at the beginning and end of esomeprazole therapy. An interaction between clopidogrel and omeprazole has been reported (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction has not been fully established. As a precautionary measure, concomitant use of esomeprazole and clopidogrel is not recommended.

Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least three months, and in most cases, for over a year. Hypomagnesemia may present with serious manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its development may be insidious and go unnoticed. In most patients with hypomagnesemia, symptoms improved after magnesium replacement and discontinuation of PPI therapy. For patients requiring long-term treatment or those taking PPIs together with digoxin or medications that can cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels before initiating PPI therapy and periodically during treatment.

Subacute cutaneous lupus erythematosus (SCLE)

The use of PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus (SCLE). If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of the drug should be considered. Previous occurrence of SCLE during prior PPI therapy may increase the risk of recurrence with other PPIs.

Proton pump inhibitors, especially when used at high doses and for prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, predominantly in elderly patients or those with other risk factors. Observational studies indicate that proton pump inhibitors may increase the overall risk of fractures by 10–40%. This increased risk may partly be attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should receive adequate intake of vitamin D and calcium.

Effect on laboratory test results

Elevated levels of chromogranin A (CgA) may interfere with the diagnosis of neuroendocrine tumors. To avoid this, esomeprazole therapy should be discontinued at least 5 days before measuring CgA levels. If CgA and gastrin levels do not normalize after initial measurement, repeat testing should be performed 14 days after discontinuation of PPI treatment.

Each vial contains less than 1 mmol of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

Data on the use of esomeprazole during pregnancy are limited. Animal studies do not indicate any direct or indirect harmful effects of esomeprazole on embryonal/fetal development. Animal studies using the racemic mixture do not indicate any direct or indirect harmful effects on pregnancy, delivery, or postnatal development. Esomeprazole should be used during pregnancy only with caution.

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

Ability to influence reaction speed while driving or operating machinery

Esomeprazole has minimal influence on the ability to drive vehicles or operate machinery. However, there have been reports of adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) (see section "Adverse reactions"). If such symptoms occur, patients should refrain from driving vehicles or operating machinery.

Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients who cannot take the medicinal product orally, the drug may be administered parenterally at a dose of 20–40 mg once daily. The dose for patients with reflux esophagitis is 40 mg once daily. The dose for patients receiving symptomatic treatment of gastroesophageal reflux disease is 20 mg once daily.

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

Short-term maintenance of hemostasis and prevention of recurrent bleeding in patients after endoscopic treatment of acute bleeding from gastric or duodenal ulcers

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

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

Administration method

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

Injections

Dose 40 mg

5 mL of reconstituted solution (8 mg/mL) should be 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) should be administered as an intravenous injection over at least 3 minutes. Any unused solution should be discarded.

Infusions

Dose 40 mg

The reconstituted solution should be administered as an intravenous infusion over 10–30 minutes.

Dose 20 mg

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

Dose 80 mg

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

Dose 8 mg/hour

The reconstituted solution should be administered as a prolonged intravenous infusion over 71.5 hours (calculated infusion rate of 8 mg/hour; the shelf life of the reconstituted solution is specified in the section «Shelf life»).

Renal impairment

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

Hepatic impairment

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

Bleeding ulcers: dose adjustment is not required for patients with mild or moderate hepatic impairment. For patients with severe hepatic impairment, after the initial 80 mg bolus dose of Esomeprazole Ananta for infusion, continued administration as a prolonged intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section «Pharmacokinetics»).

Elderly patients

Dose adjustment is not required.

Children

Dosage

Children aged 1–18 years

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

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

Treatment with the intravenous medicinal product is usually short-term, and patients should be switched to oral therapy 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 (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.

Dose 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 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 10 mg

Administer one-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 (where applicable)

Before administration, visually inspect the reconstituted solution for particles and discoloration. Only use clear solutions. The solution is 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 the 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 colourless or slightly yellow.

Infusion solution 40 mg

Prepare the 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 the 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 colourless or slightly yellow.

Storage after preparation: Chemical and physical in-use stability has been demonstrated for 12 hours at room temperature not exceeding 30°C. From a microbiological standpoint, the product should be used immediately.

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 very limited. Symptoms observed after oral ingestion of a 280 mg dose included gastrointestinal symptoms and weakness. Single oral doses of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours have not resulted in serious adverse effects. There is no specific antidote. Esomeprazole is highly protein-bound in plasma and therefore not effectively removed by dialysis. As with any overdose, symptomatic treatment and general supportive measures should be employed.

Side effects.

Summary of safety profile

Among the adverse reactions most commonly observed during clinical trials (as well as in the post-marketing period), headache, abdominal pain, diarrhea, and nausea are reported. Furthermore, the safety profile of the drug is consistent across different dosage forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

The adverse reactions listed below have been identified or suspected in clinical trials of esomeprazole administered orally or intravenously.

Blood and lymphatic system disorders: 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 precautions"); severe hypomagnesemia may correlate with hypocalcemia; hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders: insomnia, agitation, confusion, depression, aggression, hallucinations.

Nervous system disorders: headache, dizziness, paresthesia, somnolence, taste disturbances.

Eye disorders: blurred vision.

Ear and labyrinth disorders: vertigo.

Respiratory, thoracic and mediastinal disorders: bronchospasm.

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign), dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

Hepatobiliary disorders: 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, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders: fractures of the femur, wrist, or spine (see section "Special precautions"), 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 primarily observed in a study using high doses administered over 3 days (72 hours). Preclinical studies of intravenous esomeprazole did not show vascular irritation; however, mild inflammatory tissue reaction at the site of subcutaneous (perivenous) injection was noted. Preclinical findings indicated that clinical manifestations of tissue irritation were concentration-dependent.

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

Paediatric population

Data are available from a study administering esomeprazole once daily for 4 days in children aged 1 to 18 years (see section "Pharmacokinetics"). A total of 57 patients were included in the safety assessment (including 8 children aged 1–5 years). The safety profile of the drug was consistent with the known safety profile of esomeprazole, and no new patient safety concerns were identified.

Shelf life. 2 years.

Storage conditions. Store in the original packaging to protect from light at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibilities.

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

Packaging.

1 vial with lyophilisate in a box.

Prescription status. Prescription only.

Manufacturer. Aspiro Pharma Limited.

Manufacturer's address and location of operation.

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.