Despazol

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

Composition:

Active substance: esomeprazole;

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

Excipients: mannite (E 421), anhydrous sodium carbonate.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized mass of white to almost white color, without visible inclusions.

Pharmacotherapeutic group.

Agents for treatment of peptic ulcer and gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs). 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 transformed into its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the H⁺K⁺-ATPase enzyme—the proton pump—and suppresses both basal and stimulated acid secretion.

Pharmacodynamic effects

Effect on gastric juice secretion

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

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

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

Therapeutic effect of acid secretion inhibition

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

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

Other effects related to acid secretion inhibition

During treatment with acid-suppressing agents, 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) cell numbers, possibly related to elevated gastrin levels, has been observed in some patients during long-term treatment with oral esomeprazole.

During prolonged treatment with oral acid-suppressing agents, a slight increase in the frequency of gastric glandular cysts has been noted. These changes are a physiological consequence of pronounced inhibition of gastric acid secretion and are benign and reversible in nature.

Reduced gastric acidity from any cause, including use of proton pump inhibitors (PPIs), leads to increased bacterial load in the stomach, normally present in the gastrointestinal tract. PPI treatment 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 doses of esomeprazole 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intraluminal esophageal pH < 4.

The safety profile of the drug was similar to that observed in adults.

In a study involving pediatric patients with GERD (aged <1 to 17 years) receiving long-term PPI treatment, 61% of children showed mild ECL cell hyperplasia of unknown clinical significance; no cases of atrophic gastritis or carcinoid tumors were observed.

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 mediated by the polymorphic CYP2C19, responsible for formation of hydroxy- and desmethyl-metabolites of esomeprazole. The remainder of metabolism is mediated by another specific isoenzyme, CYP3A4, which forms esomeprazole sulphone, the main metabolite in plasma.

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

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

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

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

Linearity/non-linearity

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 sulphone metabolite.

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. Linear, dose-dependent increases in exposure have been observed with 30-minute intravenous infusions of esomeprazole (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

Poor metabolizers

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

Elderly patients

Metabolism of esomeprazole is only slightly altered in elderly patients (71–80 years).

Gender

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

Hepatic impairment

Metabolism of esomeprazole may be impaired in patients with mild 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 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.

Renal impairment

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

Clinical characteristics.

Indications.

Adults

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

• gastroesophageal reflux disease (GERD) in patients with esophagitis and/or severe reflux symptoms;

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

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

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

Children aged 1–18 years

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

• gastroesophageal reflux disease (GERD) in patients with erosive reflux esophagitis and/or severe reflux symptoms.

Contraindications.

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

The medicinal product Despazol must not be used concomitantly with atazanavir or nelfinavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

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

Reduced serum levels of atazanavir and nelfinavir have been observed when omeprazole was 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, maximum concentration (Cmax), and minimum concentration (Cmin) by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%. Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole and atazanavir is not recommended, and concomitant use of esomeprazole and nelfinavir is contraindicated.

Increased serum concentrations of saquinavir (co-administered with ritonavir) (80–100%) were observed with concomitant omeprazole (40 mg daily). Omeprazole 20 mg daily did not affect darunavir exposure (co-administered with ritonavir) or amprenavir exposure (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).

Methotrexate

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

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 drugs whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of digoxin may be increased during esomeprazole therapy. Concomitant administration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in two of ten participants). Digoxin toxicity has been reported rarely. However, caution should be exercised when high doses of esomeprazole are administered to elderly patients. Monitoring of serum digoxin concentrations is recommended.

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, and phenytoin, plasma concentrations of these drugs may increase, and dose reduction may be required.

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; therefore, patients should be closely monitored for adverse reactions during the three-day intravenous treatment period.

Diazepam

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

Phenytoin

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

Cisapride

Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers increased AUC by 32% and elimination half-life (t1/2) by 31%, but no significant increase in plasma Cmax of cisapride was observed. The slight QTc interval prolongation seen with cisapride alone was not increased when cisapride was administered with esomeprazole.

Warfarin

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

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

In a study in healthy volunteers receiving clopidogrel together with esomeprazole and acetylsalicylic acid (ASA) in fixed combination (20 mg + 81 mg, respectively) compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by nearly 40%. 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 has been shown not to have a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

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

Effect of other medicinal products on the pharmacokinetics of esomeprazole

MEDICINAL PRODUCTS THAT ARE INHIBITORS OF 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 the AUC of esomeprazole. Concomitant administration of esomeprazole with combined inhibitors of CYP2C19 and CYP3A4 may increase esomeprazole exposure by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always required in such cases. However, it may be necessary in patients with severe hepatic impairment or when long-term therapy is indicated.

MEDICINAL PRODUCTS THAT ARE INDUCERS OF CYP2C19 AND/OR CYP3A4

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

Children

Interaction studies have only been conducted in adults.

Special precautions for use.

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

Gastrointestinal infections

PPI therapy may slightly increase the risk of gastrointestinal infections such as those caused by Salmonella and Campylobacter (see section "Pharmacodynamics").

Absorption of vitamin B12

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

Hypomagnesemia

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

Patients who are expected to undergo long-term treatment or who are taking PPIs with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before starting PPI therapy and periodically during treatment.

Risk of fractures

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

Subacute cutaneous lupus erythematosus

PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of the drug should be considered. Development of subacute cutaneous lupus erythematosus during previous PPI therapy may increase 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 esomeprazole dose should not exceed 20 mg.

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

Serious skin reactions

Very rare, potentially life-threatening serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with esomeprazole treatment.

Patients should be informed about the signs and symptoms of serious skin reactions and advised to seek immediate medical attention if any such signs or symptoms occur.

Esomeprazole should be discontinued immediately at the first appearance of signs or symptoms of serious skin reactions, and medical assistance/monitoring should be provided as needed.

Re-administration of the drug is not recommended in patients who have experienced erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS).

Effect on laboratory test results

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

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of esomeprazole during pregnancy are limited. Epidemiological studies on the use of the racemic mixture omeprazole during pregnancy show no increased risk of congenital malformations or fetal toxicity. Animal studies have not revealed any direct or indirect harmful effects on embryofetal development. Studies in animals with the racemic mixture do not indicate any direct or indirect adverse effects on pregnancy, delivery, or postnatal development. Esomeprazole should be used during pregnancy only if clearly needed and with caution.

A moderate amount of data from pregnant women (between 300 and 1000 pregnancy outcomes) indicates no teratogenic effects or toxic influence of esomeprazole on the fetus or newborn health.

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

Breastfeeding

It is not known whether esomeprazole passes into human breast milk. Studies in breastfeeding women have not been conducted. Therefore, esomeprazole 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.

The medicinal product Despazol has minimal influence on the ability to drive vehicles or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section "Adverse reactions"). If such disorders occur, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible

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

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

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

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

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).

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

Method of Administration

Instructions for preparing the reconstituted solution are provided in the 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. Any unused solution must be discarded.

Infusions

Dose of 40 mg

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

Dose of 20 mg

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

Dose of 80 mg

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

Dose of 8 mg/hour

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

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, these 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 the initial 80 mg intravenous bolus dose of esomeprazole for infusion, subsequent continuous intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly Patients

No dose adjustment is required.

Children

Dosage

Children aged 1–18 years

As an agent for gastric acid suppression when oral administration is not feasible

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

Treatment with intravenous formulation is generally short-term; 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 of 40 mg

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

Dose of 20 mg

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

Dose of 10 mg

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

Infusions

Dose of 40 mg

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

Dose of 20 mg

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

Dose of 10 mg

Administer one-quarter of the reconstituted solution as an intravenous infusion over 10–30 minutes. Any unused portion of the 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, the unused portion must 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 yellow.

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 yellow.

Children

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

Overdose

Experience with intentional overdose is very limited to date. Symptoms observed following an oral dose of 280 mg included gastrointestinal effects and weakness. No adverse effects were observed after a single oral dose of 80 mg esomeprazole or intravenous administration of 308 mg esomeprazole over 24 hours. There is no specific antidote. Esomeprazole is highly plasma protein-bound and therefore not effectively removed by dialysis. As with any overdose, symptomatic treatment and general supportive measures should be employed.

Adverse Reactions.

Summary of safety profile

The most commonly observed adverse reactions during clinical trials (as well as in the post-marketing period) include headache, abdominal pain, diarrhea, and nausea. Furthermore, the safety profile of esomeprazole 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 with esomeprazole following oral or intravenous administration, as well as during post-marketing surveillance following oral administration of the drug. Reactions are categorized by system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Rare: leukopenia, thrombocytopenia.

Very rare: agranulocytosis, pancytopenia.

Immune system disorders

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

Metabolism and nutrition disorders

Uncommon: peripheral edema.

Rare: hyponatremia.

Frequency not known: hypomagnesemia (see section "Special warnings and 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: reactions at the injection site*.

Uncommon: dermatitis, pruritus, rash, urticaria.

Rare: alopecia, photosensitivity.

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

Frequency not known: subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders

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

Rare: arthralgia, myalgia.

Very rare: muscle weakness.

Renal and urinary disorders

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

Reproductive system and breast disorders

Very rare: gynecomastia.

General disorders and administration site conditions

Rare: malaise, increased sweating.

*Reactions at the injection site were predominantly observed in a study using high doses over 3 days (72 hours).

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

Reporting of suspected 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 are required to report any suspected adverse reactions.

Paediatric population

A randomized, open-label, international study was conducted to evaluate the pharmacokinetics of multiple intravenous doses of esomeprazole administered once daily for 4 days in children aged 0 to 18 years (see section "Pharmacokinetics"). A total of 57 patients (including 8 children aged 1–5 years) were included in the safety assessment. Safety data were consistent with the known safety profile of esomeprazole, and no new safety concerns were identified.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

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

Packaging.

1 vial made of glass, stoppered with a rubber plug and sealed with an aluminum crimp cap fitted with a flip-off cap providing a tamper-evident seal, in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

Naprod Life Sciences Pvt. Ltd.

Manufacturer's address.

G-17/1, M.I.D.C., Tarapur, Boisar, Dist. Thane 401506, Maharashtra, India.

Marketing Authorization Holder.

M. Biotech Ltd.

Address of Marketing Authorization Holder.

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