Pemozar

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEMOZAR (PEMOZAR)

Composition:

Active substance: esomeprazole;

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

Excipients: disodium edetate, sodium hydroxide (for pH adjustment).

Pharmaceutical form. Lyophilized powder for solution for injection and infusion.

Main physico-chemical characteristics: lyophilisate mass from white to almost white.

Pharmacotherapeutic group.

Medicinal products used in acid-related disorders. Proton pump inhibitors. Esomeprazole. ATC code A02BC05.

Pharmacological properties.

Pharmacodynamics.

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

Site and mechanism of action

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

Effect on gastric acid secretion

After 5 days of oral administration of esomeprazole at doses of 20 mg and 40 mg in patients with symptoms of gastroesophageal reflux disease (GERD), intragastric pH remained above 4 for an average of 13 hours and 17 hours per 24-hour period, respectively. This effect is consistent regardless of the route of esomeprazole administration—oral or intravenous.

Using the area under the concentration–time curve (AUC) as a surrogate parameter for plasma concentration, a relationship between acid secretion inhibition and exposure after oral administration of esomeprazole has been demonstrated.

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

Therapeutic effects of acid secretion inhibition

Treatment of reflux esophagitis with esomeprazole 40 mg was successful in approximately 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.

During antisecretory therapy, serum gastrin levels rise in response to decreased acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity. Elevated CgA levels may affect laboratory test results for neuroendocrine tumors. Published data indicate that treatment with proton pump inhibitors (PPIs) should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels to allow normalization, as this marker may be elevated after PPI therapy.

In some patients, long-term oral esomeprazole treatment has been associated with an increase in enterochromaffin-like (ECL) cells, possibly related to elevated serum gastrin levels.

There are reports of a slightly increased incidence of gastric glandular cysts during prolonged treatment with oral antisecretory agents. These changes are a physiological consequence of pronounced acid secretion suppression. They are benign and likely reversible.

Reduced gastric acidity from any cause, including use of proton pump inhibitors, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors increases the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Children

Results from studies involving 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 average percentage of time with intraesophageal pH <4.

The safety profile observed was similar to that 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 via the cytochrome P450 (CYP) system. The major part of esomeprazole metabolism depends on the polymorphic isoenzyme CYP2C19, responsible for formation of hydroxy- and desmethyl-metabolites of esomeprazole. Another part depends on a different specific isoenzyme, CYP3A4, which is responsible for the formation of 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/h after a single dose and approximately 9 L/h after repeated administration. The plasma half-life is approximately 1.3 hours with repeated once-daily dosing.

Esomeprazole is completely eliminated from plasma between doses and does not tend to accumulate with once-daily administration.

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

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-dependency 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 administration of 40 mg 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 is observed when esomeprazole is administered as a 30-minute intravenous infusion (40 mg, 80 mg, or 120 mg) followed by continuous infusion (at 4 mg/h or 8 mg/h) for 23.5 hours.

Special patient groups

Slow metabolizers

Approximately 2.9 ± 1.5% of the population lacks functional CYP2C19 enzyme and is referred to as poor metabolizers. In these individuals, esomeprazole metabolism is likely catalyzed predominantly by CYP3A4. After multiple oral doses of 40 mg once daily, mean total exposure was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (rapid metabolizers). Mean peak plasma concentration was increased by approximately 60%. Similar differences were observed with intravenous administration of esomeprazole. These data do not require dose adjustment for esomeprazole.

Gender

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

Hepatic impairment

Metabolism of esomeprazole may be impaired in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of total esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed the maximum dose of 20 mg. In cases of bleeding ulcer and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a maximum rate of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.

Renal impairment

Studies in patients with reduced renal function have not been conducted. Since the kidneys are responsible for the elimination of esomeprazole metabolites, but not the parent compound, no changes in metabolism are expected in patients with renal impairment.

Elderly patients

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

Clinical characteristics.

Indications.

Adults

• Antisecretory therapy in cases where 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 following endoscopic treatment of acute bleeding from gastric or duodenal ulcers.

Children and adolescents aged 1 to 18 years

• Antisecretory therapy in cases where 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, other substituted benzimidazoles, or any of the excipients of this medicinal product. Esomeprazole must not be used concomitantly with nelfinavir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Other interaction mechanisms are possible via inhibition of CYP2C19. Reduced serum 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 Cmin by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%. Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended (see section "Special precautions for use"), and concomitant use of esomeprazole and nelfinavir is contraindicated (see section "Contraindications").

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

Methotrexate

When methotrexate is used concomitantly with PPIs (proton pump inhibitors), its levels may increase in some patients. Temporary discontinuation of esomeprazole may be required when administering high-dose methotrexate.

Tacrolimus

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

Medicinal products whose absorption is pH-dependent

Suppression of gastric acid secretion during therapy with esomeprazole and other PPIs may lead to reduced or enhanced absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of digoxin may be increased during esomeprazole therapy. In healthy volunteers, concomitant administration of omeprazole (20 mg daily) and digoxin increased digoxin bioavailability 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 serum digoxin concentrations should be intensified.

Medicinal products metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is used concomitantly with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., their plasma concentrations may increase, necessitating dose reduction.

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 during such treatment regimens may be more pronounced, and patients should be closely monitored for adverse reactions during the 3-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 the minimum plasma concentrations of phenytoin in patients with epilepsy by 13%. Monitoring of plasma phenytoin concentrations is recommended at the start 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, acts as an inhibitor of CYP2C19. Administration of omeprazole 40 mg to healthy volunteers in a study resulted in increases in Cmax and area under the concentration-time curve (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 of 40 mg esomeprazole and cisapride resulted in a 32% increase in AUC and a 31% increase in elimination half-life, but no significant increase in peak plasma levels of cisapride was observed. A slight prolongation of the QTc interval was observed with cisapride alone, which did not further increase when cisapride was administered in combination with esomeprazole.

Warfarin

In a clinical study, co-administration of 40 mg esomeprazole orally with warfarin did not alter blood coagulation time beyond acceptable limits. However, during the post-marketing period, several isolated cases of clinically significant increases in INR (International Normalized Ratio) have been reported with concomitant use of these agents. Monitoring is recommended at the initiation and upon discontinuation of concomitant therapy with esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

Results from pharmacokinetic (PK)/pharmacodynamic (PD) interaction studies in healthy volunteers evaluating clopidogrel (loading dose 300 mg/maintenance dose 75 mg daily) and esomeprazole (40 mg orally daily) showed a mean 40% reduction in exposure to the active metabolite of clopidogrel and a mean 14% reduction in maximum inhibition of adenosine diphosphate (ADP)-induced platelet aggregation.

In a study in healthy volunteers, when clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in fixed combination doses (20 mg + 81 mg, respectively), exposure to the active metabolite of clopidogrel was reduced by nearly 40% compared to clopidogrel monotherapy. However, maximum levels of inhibition (ADP-induced) of platelet aggregation were similar between the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA. Observational and clinical studies have yielded conflicting data on the clinical implications of the PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin or quinidine

Esomeprazole did not show 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.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

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

Medicinal products inducing CYP2C19 and CYP3A4 activity

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

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use.

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

Gastrointestinal infections

PPI therapy is associated with a slight increase in the risk of gastrointestinal infections, such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Vitamin B12 absorption

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

Hypomagnesemia

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

For patients requiring long-term PPI treatment or those taking PPIs together with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics), it may be advisable to measure magnesium levels prior to initiating PPI therapy and periodically during treatment.

Risk of fracture

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

Subacute cutaneous lupus erythematosus

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 esomeprazole should be considered. Development of subacute cutaneous lupus erythematosus during prior PPI therapy increases the risk of recurrence with other PPIs.

Combination with other medicinal products

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

Esomeprazole is 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.

Serious cutaneous adverse reactions (SCARs)

Very rare cases of serious cutaneous adverse reactions (SCARs), such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening, have been reported with esomeprazole treatment.

Patients should be informed about the signs and symptoms of severe skin reactions (EM/SJS/TEN/DRESS) and advised to seek immediate medical attention if any such signs or symptoms occur.

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

Re-challenge with esomeprazole should not be attempted in patients who have experienced EM/SJS/TEN/DRESS.

Effect on laboratory test results

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

One vial of the medicinal product contains less than 1 mmol of sodium, i.e., the product is essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of esomeprazole during pregnancy are limited. Epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy, involving a somewhat larger number of cases, indicate no risk of congenital malformations or fetotoxic effects. Animal studies do not indicate a direct or indirect harmful effect of esomeprazole on embryonic/fetal development. Animal studies using the racemic mixture do not indicate a direct or indirect harmful effect on pregnancy, delivery, or postnatal development. Esomeprazole should be used during pregnancy only with caution.

Available data from a limited number of pregnant women (between 300 and 1000 pregnancy outcomes) indicate no malformative or toxic effects of esomeprazole on the fetus or neonatal health.

Animal studies indicate no direct or indirect harmful effect of the drug on reproductive function due to its toxicological profile.

Breastfeeding period

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

Fertility

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

Ability to influence reaction speed when 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 vehicles or operating machinery.

Administration and Dosage

Adults

Antisecretory therapy when oral administration is not possible

For patients unable to take the medication orally, parenteral administration of esomeprazole at a dose of 20–40 mg once daily is recommended. Patients with reflux esophagitis should receive a dose of 40 mg once daily. For patients with gastroesophageal reflux disease (GERD) receiving symptomatic treatment, a dose of 20 mg once daily is recommended.

For treatment of gastric and duodenal ulcers associated with NSAID use, the usual dose is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk, a dose of 20 mg once daily is recommended.

Treatment with intravenous medication is generally 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 endoscopic therapy for acute bleeding from gastric or duodenal ulcers, administer 80 mg of the drug 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).

Administration method

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

Injections

Dose of 40 mg: Administer 5 mL of reconstituted solution (8 mg/mL) as an intravenous injection over at least 3 minutes.

Dose of 20 mg: Administer 2.5 mL, or half of the reconstituted solution (8 mg/mL), as an intravenous injection over at least 3 minutes. 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.

Bolus 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).

Special patient groups

Renal impairment

Dose adjustment is not required in patients with renal impairment. However, due to limited experience with the drug in patients with severe renal impairment, such patients should be treated with caution (see section "Pharmacokinetics").

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 of esomeprazole should not exceed 20 mg (see section "Pharmacokinetics").

Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, after administration of an initial 80 mg intravenous bolus dose of esomeprazole, subsequent continuous 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 in elderly patients.

Children aged 1–18 years

Antisecretory therapy when oral administration is not possible

For patients unable to take the medication orally, parenteral administration of the drug once daily may be prescribed as part of a treatment course for GERD (see dosing recommendations in the table below).

Intravenous treatment is generally short-term, and patients should be switched to oral therapy as soon as possible.

Recommended intravenous doses of esomeprazole

Method of Administration

Instructions for preparing the reconstituted solution are provided in this section below ("Instructions for Use, Handling, and Disposal (where applicable)").

Injections

40 mg dose. 5 ml of reconstituted solution (8 mg/ml) is administered as an intravenous injection over at least 3 minutes.

20 mg dose. 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 must be discarded.

10 mg dose

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

Infusions

40 mg dose. The reconstituted solution is administered as an intravenous infusion over 10–30 minutes.

20 mg dose. Half of the reconstituted solution is administered as an intravenous infusion over 10–30 minutes. Any unused solution must be discarded.

10 mg dose

One quarter of the reconstituted solution is administered as an intravenous infusion over 10–30 minutes. Any unused solution must be discarded.

Instructions for Use, Handling, and Disposal (where applicable)

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

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

40 mg Injection Solution

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

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

40 mg Infusion Solution

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

80 mg Infusion Solution

Prepare the 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 infusion solution is clear and colorless or slightly yellowish.

Children

For use 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 following oral ingestion of 280 mg included gastrointestinal effects and weakness. Single oral doses of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any serious consequences. 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 implemented.

Adverse Reactions

Among the adverse reactions most commonly observed during clinical trials (as well as in the post-marketing period), headache, abdominal pain, diarrhea, and nausea 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 were identified or suspected during clinical studies with esomeprazole administered orally or intravenously, as well as during post-marketing surveillance of oral administration. Reactions are categorized by frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); 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, and anaphylactic reactions/shock.

Metabolism and nutrition disorders

Uncommon: peripheral edema.
Rare: hyponatremia.
Frequency not known: hypomagnesemia (see section "Special precautions for use"); severe hypomagnesemia may be associated 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: infusion site reactions*.
Uncommon: dermatitis, pruritus, rash, urticaria.
Rare: alopecia, photosensitivity.
Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).
Frequency not known: Subacute cutaneous lupus erythematosus (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 associated with renal failure).

Reproductive system and breast disorders

Very rare: gynecomastia.

General disorders and administration site conditions

Rare: malaise, increased sweating.

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

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

Reporting of adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Paediatric population

Data are available from studies involving administration of esomeprazole for 4 days once daily in children aged 0 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 observed was consistent with the known safety profile of esomeprazole, and no new patient safety concerns were identified.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.

Packaging.

1 vial of powder in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Ltd.

Manufacturer's address and place of business.

Baroda Highway, Halol, Gujarat, 389350, India.