Ezomaps

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESOMAPS (ESOMUPS)

Composition:

Active substance: esomeprazole;

1 tablet contains esomeprazole magnesium dihydrate equivalent to 20 mg or 40 mg of esomeprazole;

Excipients: glycerol monostearate 40-55, hydroxypropylcellulose, hypromellose, magnesium stearate, methacrylic acid copolymer (type A), macrogol 6000, microcrystalline cellulose silicified, sugar spheres, meglumine, poloxamer 188, sodium lauryl sulfate, triethyl citrate, talc, sodium hydroxide, Starlac (lactose monohydrate, corn starch), crospovidone, colloidal anhydrous silicon dioxide;

tablets 20 mg: Opadry pink13G84576 (hypromellose, titanium dioxide (E 171), macrogol, talc, paraffin, polysorbate 80, iron oxide red (E 172), iron oxide yellow (E 172));

tablets 40 mg: Opadry pink13G84577 (hypromellose, titanium dioxide (E 171), macrogol, talc, paraffin, polysorbate 80, iron oxide red (E 172), iron oxide yellow (E 172)).

Pharmaceutical form. Gastric-resistant tablets.

Main physicochemical properties:

tablets 20 mg: light pink, oval, beveled-edge tablets with engraving «H» on one side and «186» on the other;

tablets 40 mg: pink, oval, beveled-edge tablets with engraving «H» on one side and «187» on the other.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion through a specific, targeted mechanism of action. It is a specific inhibitor of the proton pump (PPI) in parietal cells. Both the R- and S-isomers of omeprazole exhibit similar pharmacodynamic activity.

Mechanism of Action

Esomeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the secretory canaliculi of parietal cells, where it inhibits the H⁺K⁺-ATPase enzyme—the proton pump—and suppresses both basal and stimulated acid secretion.

Pharmacodynamic Effects

After oral administration of 20 mg and 40 mg esomeprazole, onset of action occurs within one hour.

After repeated administration of 20 mg esomeprazole once daily for 5 days, on day 5 the mean maximal acid secretion stimulated by pentagastrin is reduced by 90% when measured 6–7 hours after dosing.

After 5 days of treatment with 20 mg and 40 mg esomeprazole orally in patients with symptomatic gastroesophageal reflux disease (GERD), intragastric pH remained above 4 for a mean of 13 and 17 hours, respectively, over a 24-hour period. The proportion of patients in whom gastric pH remained above 4 for 8, 12, and 16 hours after administration of 20 mg esomeprazole was 76%, 54%, and 24%, respectively. Corresponding values with 40 mg esomeprazole were 97%, 92%, and 56%.

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

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

After one week of treatment with 20 mg esomeprazole twice daily in combination with appropriate antibiotics, successful eradication of Helicobacter pylori is observed in approximately 90% of patients.

After eradication, no further monotherapy with acid-suppressive agents is required during the following week to effectively treat ulcers and relieve symptoms in patients with uncomplicated duodenal ulcers.

During acid-suppressive therapy, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also rise due to decreased gastric juice acidity. Elevated CgA levels may affect laboratory test results for neuroendocrine tumors. According to published data, PPI therapy should be discontinued at least 5 days before measuring CgA levels. If CgA and gastrin levels have not normalized 5 days after stopping esomeprazole, repeat measurements should be performed 14 days after discontinuation.

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

During prolonged treatment with acid-suppressive agents, a slight increase in the incidence of gastric glandular cysts has been noted. These changes are a physiological consequence of pronounced suppression of gastric juice secretion, are benign in nature, and resolve after completion of therapy.

Reduced gastric acidity from any cause, including PPI use, leads to increased numbers of bacteria normally present in the gastrointestinal tract. PPI therapy may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Clinical Efficacy

In two studies with ranitidine as the active comparator, esomeprazole demonstrated superior efficacy in treating gastric ulcers in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

In two placebo-controlled studies, esomeprazole showed superior efficacy in preventing gastric and duodenal ulcers in patients (aged >60 years and/or with a history of ulcer) taking NSAIDs, including selective COX-2 inhibitors.

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

Pharmacokinetics

Absorption

Esomeprazole is acid-labile; therefore, enteric-coated granules are used for oral administration. In vivo, only a negligible portion of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: peak plasma concentration (C_max) is reached within 1–2 hours after administration. Absolute bioavailability of esomeprazole after a single 40 mg dose is 64% and increases to 89% with daily administration once daily. For a 20 mg dose, these values are 50% and 68%, respectively. Food intake slows and reduces esomeprazole absorption, but this does not significantly affect esomeprazole's action on intragastric acidity.

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.

Biological Transformation

Esomeprazole is completely metabolized via the cytochrome P450 (CYP) system. The main part of esomeprazole metabolism is dependent on the polymorphic isoenzyme CYP2C19, responsible for formation of hydroxy- and desmethyl-metabolites of esomeprazole. In addition, metabolism is mediated by another specific isoenzyme, CYP3A4, responsible for formation of esomeprazole sulfone, the main metabolite detected in plasma.

Elimination

The parameters below primarily reflect the pharmacokinetic profile in patients with active CYP2C19 enzyme (extensive metabolizers).

Total plasma clearance is approximately 17 L/h after single-dose administration and approximately 9 L/h after multiple dosing. Elimination half-life from plasma is approximately 1.3 hours with once-daily dosing. Esomeprazole is completely cleared from plasma between doses, and no tendency toward accumulation is observed with once-daily administration.

The main metabolites of esomeprazole do not affect gastric acid secretion. After oral administration, up to 80% of the dose is excreted as metabolites in urine, the remainder in feces. Less than 1% of unchanged esomeprazole is excreted in urine.

Linearity/Non-linearity

Esomeprazole pharmacokinetics have been studied at doses up to 40 mg twice daily. AUC increases with repeated dosing. This increase is dose-dependent and results in non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is attributed to reduced first-pass metabolism and systemic clearance, possibly related to inhibition of CYP2C19 by esomeprazole and/or its sulfone metabolite.

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 repeated administration of 40 mg esomeprazole once daily, mean AUC was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). Mean peak plasma concentration was increased by approximately 60%. These data do not require dosage adjustments for esomeprazole.

Gender

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

Hepatic Impairment

Metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of esomeprazole AUC. Therefore, the maximum daily dose of esomeprazole in patients with severe hepatic impairment should not exceed 20 mg. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.

Renal Impairment

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

Elderly Patients

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

Children aged 12–18 years

After repeated administration of 20 mg and 40 mg esomeprazole, AUC and time to peak plasma concentration (t_max) in children aged 12–18 years were similar to AUC and t_max values in adults for both esomeprazole doses.

Clinical characteristics.

Indications.

Adults

Gastroesophageal reflux disease (GERD):

• Treatment of erosive reflux esophagitis;
• Long-term treatment of patients with healed esophagitis to prevent relapse;
• Symptomatic treatment of GERD.

In combination with appropriate antibacterial therapy for eradication of Helicobacter pylori:

• Treatment of Helicobacter pylori-associated duodenal ulcer;
• Prevention of recurrence of peptic ulcers in patients with ulcers associated with Helicobacter pylori.

Patients requiring long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs):

• Healing of NSAID-induced gastric ulcers;
• Prevention of NSAID-induced gastric and duodenal ulcers in patients at risk.

Long-term treatment following intravenous administration of the drug to prevent recurrence of bleeding from peptic ulcers.

Treatment of Zollinger–Ellison syndrome.

Children aged 12 years and older:

GERD:

• Treatment of erosive reflux esophagitis;
• Long-term treatment of patients with healed esophagitis to prevent relapse;
• Symptomatic treatment of GERD.

In combination with antibiotics for treatment of Helicobacter pylori-associated duodenal ulcer.

Contraindications.

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

Esomeprazole should not be used concomitantly with 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 mechanism of such interactions are not always known. Increased gastric pH during omeprazole therapy may alter the absorption of protease inhibitors. Another possible mechanism of interaction involves inhibition of CYP2C19 activity.

Reduced serum levels of atazanavir and nelfinavir have been reported when co-administered with omeprazole; therefore, their concomitant use is not recommended. When omeprazole (40 mg once daily) was co-administered with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers, exposure to atazanavir was significantly reduced (AUC, Cmax, and Cmin values decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. When omeprazole (20 mg daily) was co-administered with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers, atazanavir exposure decreased by approximately 30% compared to exposure observed with daily administration of 300 mg atazanavir/100 mg ritonavir without omeprazole 20 mg daily. Concomitant administration of omeprazole (40 mg daily) resulted in a reduction of mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 decreased by 75–92%. Due to the similarity in pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of esomeprazole with atazanavir is not recommended (see section "Special precautions for use"); concomitant use of esomeprazole with nelfinavir is contraindicated (see section "Contraindications").

During concomitant therapy with omeprazole (40 mg daily), increased serum levels of saquinavir (in combination with ritonavir) have been reported (80–100% increase). Treatment with omeprazole at a dose of 20 mg daily did not affect exposure to darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir). Treatment with esomeprazole at a dose of 20 mg daily did not affect exposure to amprenavir (with or without ritonavir). Treatment with omeprazole at a dose of 40 mg daily did not affect exposure to lopinavir (in combination with ritonavir).

Methotrexate

In some patients, increased methotrexate levels have been observed during concomitant use with PPIs.

When administering high-dose methotrexate, consider temporary discontinuation of esomeprazole.

Tacrolimus

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

Medicinal products whose absorption is pH-dependent

Suppression of gastric acidity during treatment with esomeprazole and other PPIs may reduce or increase absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, whereas absorption of drugs such as 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 out of ten subjects). Cases of digoxin toxicity have been rarely reported. However, caution should be exercised when prescribing high doses of esomeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Medicinal products metabolized by CYP2C9

Esomeprazole is an inhibitor of CYP2C19, the main enzyme metabolizing esomeprazole. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, their plasma concentrations may increase, and dose reduction may be required. This should be particularly considered when esomeprazole is prescribed for on-demand use.

Diazepam

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

Phenytoin

During concomitant administration of esomeprazole 40 mg in patients with epilepsy, Cmin of phenytoin in plasma increased by 13%. Monitoring of plasma phenytoin levels is recommended at the start of esomeprazole therapy or upon its discontinuation.

Voriconazole

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

Cilostazol

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

Cisapride

In healthy volunteers, concomitant administration of esomeprazole (40 mg) increased AUC of cisapride in plasma by 32% and its elimination half-life (t½) by 31%, but no significant increase in maximum plasma concentration of cisapride was observed. No significant prolongation of the QTc interval, which was observed during cisapride monotherapy, was seen during concomitant administration of cisapride with esomeprazole (see also section "Special precautions for use").

Warfarin

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

Clopidogrel

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

In a study involving healthy volunteers, when clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in a fixed-dose combination (20 mg + 81 mg, respectively) compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel decreased by nearly 40%.

However, maximum levels of inhibition (ADP-induced) of platelet aggregation in these subjects were similar between the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA.

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

Investigated medicinal products without clinically significant interaction

Amoxicillin and quinidine

It has been demonstrated that esomeprazole has no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

During short-term studies of concomitant administration of esomeprazole with naproxen or rofecoxib, no pharmacokinetic interaction was observed.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products that inhibit CYP2C19 and/or CYP3A4 activity

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

Medicinal products that induce CYP2C19 and/or CYP3A4 activity

Agents known to induce CYP2C19 or CYP3A4 activity, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased serum levels of esomeprazole due to accelerated metabolism.

Children. Drug interaction studies have been conducted only in adults.

Special precautions for use.

In the event of any alarming symptoms, particularly such as significant spontaneous weight loss, recurrent vomiting, dysphagia, vomiting with blood, or melena, as well as in case of gastric ulcer or suspected gastric ulcer, malignancy must be ruled out, since treatment with esomeprazole may mask symptoms and delay diagnosis.

Long-term use of the drug

Patients who use the drug for a prolonged period (especially those using it for more than one year) should be under regular medical supervision.

Treatment as needed

Patients taking the medicinal product Esomaps on-demand should be instructed to inform their physician about any changes in symptom pattern.

Eradication of Helicobacter pylori

When prescribing esomeprazole for eradication of Helicobacter pylori, possible drug interactions between all components of triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4; therefore, when prescribing triple therapy to patients who are also taking other drugs metabolized by CYP3A4 (e.g., cisapride), possible contraindications and interactions between clarithromycin and these medicinal products must be taken into account.

Gastrointestinal infections

Use of PPIs may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter (see section "Pharmacodynamics").

Absorption of vitamin B12

Esomeprazole, like all medicinal products that inhibit hydrochloric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered when treating patients long-term, especially those with low body stores of vitamin B12 or those with risk factors for reduced vitamin B12 absorption.

Hypomagnesemia

Severe hypomagnesemia has been reported in patients taking PPIs such as esomeprazole for at least three months, and in most cases, for over one year. Possible serious manifestations of hypomagnesemia include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia; however, these symptoms may develop insidiously and may be overlooked. In most cases, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

Consider measuring magnesium levels before initiating PPI therapy and periodically during treatment in patients expected to be on long-term therapy, or in patients taking PPIs concomitantly with digoxin or with medicinal products that may cause hypomagnesemia (e.g., diuretics).

Risk of fractures

PPIs, particularly when used at high doses and over a prolonged period (>1 year), may modestly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Data from observational studies indicate that PPIs may increase the overall risk of fractures by 10–40%. Some of these increased fracture cases may be associated with other risk factors. Patients at risk of developing osteoporosis should use the medicinal product in accordance with current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

Cases of SCLE with PPIs have been very rare. If skin lesions appear, particularly on exposed skin areas, and are accompanied by arthralgia, the patient should seek immediate medical attention, and the healthcare provider should consider discontinuing Esomaps. Development of SCLE after treatment with one PPI increases the risk of SCLE 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 combination of atazanavir with PPIs cannot be avoided, close monitoring of patients in an inpatient setting is recommended, along with increasing the atazanavir dose to 400 mg with 100 mg ritonavir; the esomeprazole dose should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19; therefore, potential interactions between esomeprazole and medicinal products metabolized by CYP2C19 should be considered at the beginning or end of esomeprazole treatment. An interaction has been observed between clopidogrel and esomeprazole (see section "Interaction with other medicinal products and other forms of interaction"). The clinical significance of this interaction remains uncertain. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

When prescribing esomeprazole for on-demand use, potential consequences of drug interactions with other medicinal products should be considered due to fluctuations in esomeprazole plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Sucrose; lactose

This medicinal product contains sucrose (spherical sugar) and lactose monohydrate.

In case of diagnosed intolerance to certain sugars, consult a physician before taking this medicinal product.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may affect laboratory test results for detecting neuroendocrine tumors. To avoid such interference, esomeprazole treatment should be discontinued at least 5 days before measuring CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to the reference range after the first measurement, the test should be repeated 14 days after completion of PPI treatment.

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data on the use of the medicinal product Esomaps during pregnancy. A somewhat larger amount of epidemiological data on the use of racemic omeprazole during pregnancy suggests no congenital malformations or fetotoxic effects. Animal studies with esomeprazole did not reveal any direct or indirect harmful effects on embryonal/fetal development. Studies in animals with the racemic mixture did not show any direct or indirect effects on pregnancy, delivery, or postnatal development. The drug should be prescribed to pregnant women with caution.

A moderate amount of data in pregnant women (from 300 to 1000 pregnancy cases) indicates no teratogenic effects or toxic effects of esomeprazole on the fetus/newborn child's health.

Results of animal studies indicate no direct or indirect harmful effect of the drug on reproductive function due to its toxic influence.

Breastfeeding period

It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the consequences of esomeprazole exposure in newborns/infants. Esomeprazole should not be used during breastfeeding.

Fertility

Results of 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 Esomaps has minimal effect on the ability to drive or operate machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) have been reported (see section "Adverse reactions"). If such disorders occur, patients should not drive or operate machinery.

Administration and Dosage

Adults

Gastroesophageal reflux disease (GERD)

• Treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

An additional 4-week course of treatment is recommended for patients with unresolved esophagitis or persistent symptoms.

• Long-term treatment of patients with healed esophagitis to prevent relapse:

20 mg once daily.

• Symptomatic treatment of GERD

The dose for patients without esophagitis is 20 mg once daily. If symptom control has not been achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, ongoing symptom control may be maintained with 20 mg once daily. If necessary, treatment may be switched to an on-demand regimen, i.e., 20 mg once daily as needed. This dosing regimen is not recommended for ongoing symptom control in patients at risk of developing gastric and duodenal ulcers who are taking NSAIDs.

In combination with appropriate antibacterial medicinal products for eradication of Helicobacter pylori, and for

• treatment of Helicobacter pylori-associated duodenal ulcer, and
• prevention of recurrence of peptic ulcers in patients with ulcers associated with Helicobacter pylori:

20 mg of the medicinal product Ezoomaps with 1 g of amoxicillin and 500 mg of clarithromycin twice daily for 7 days.

Patients requiring long-term NSAID therapy

• Treatment of NSAID-associated gastric ulcers:

The usual dose is 20 mg once daily. The duration of treatment is 4–8 weeks.

• Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk:

20 mg once daily.

Long-term treatment following intravenous administration of the drug for prevention of recurrent bleeding from peptic ulcers:

40 mg once daily for 4 weeks following intravenous administration of the drug for prevention of recurrent bleeding from peptic ulcers.

Zollinger-Ellison syndrome

The recommended initial dose of the medicinal product Ezoomaps is 40 mg twice daily. The dose should then be individually adjusted; treatment continues as long as clinical indications require. Based on available clinical data, most patients can be controlled with doses of 80 mg to 160 mg of esomeprazole per day. If the daily dose exceeds 80 mg, it should be divided and administered twice daily.

Special patient groups

Patients with renal impairment

Dose adjustment is not required in patients with renal impairment. Due to limited experience with the use of the drug, caution should be exercised when treating patients with severe renal impairment (see section "Pharmacokinetics").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. The maximum dose of the medicinal product Ezoomaps in patients with severe hepatic impairment should not exceed 20 mg (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required in elderly patients.

Children

Children aged 12 years and older

GERD

• Treatment of erosive reflux esophagitis:

40 mg once daily for 4 weeks.

An additional 4-week course of treatment is recommended for patients with unresolved esophagitis or persistent symptoms.

• Long-term treatment of patients with healed esophagitis to prevent relapse:

20 mg once daily.

• Symptomatic treatment of GERD

The dose for patients without esophagitis is 20 mg once daily. If symptom control has not been achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, ongoing symptom control may be maintained with 20 mg once daily.

Treatment of Helicobacter pylori-associated duodenal ulcer

When selecting an appropriate combination therapy, official national, regional, and local recommendations regarding bacterial resistance, duration of treatment (usually 7 days, but sometimes up to 14 days), and proper use of antibacterial agents should be taken into account. Treatment should be conducted under the supervision of a specialist.

Dosage recommendations for the medicinal product

Body weight	Dosage
30-40 kg	In combination with two antibiotics: esomeprazole 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight – all medications are taken simultaneously twice daily for one week.
> 40 kg	In combination with two antibiotics: esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg – all medications are taken simultaneously twice daily for one week.

Children under 12 years of age

Esomeprazole should not be used in children under 12 years of age, as data on use in this age group are lacking.

Method of administration

The tablet should be swallowed whole with liquid. Tablets should not be chewed or crushed.

For patients who have difficulty swallowing, the tablets may also be dissolved in half a glass of non-carbonated water. During dissolution, enteric-coated granules are released from the tablet. Other liquids should not be used, as they may dissolve the enteric coating of the granules. Stir until the tablets disintegrate, then the granule suspension should be drunk immediately or within 30 minutes. Refill the glass with water halfway, stir any residue, and drink. Granules should not be chewed or crushed.

For patients unable to swallow, the tablets should be dissolved in non-carbonated water and administered through a gastric tube. It is important to carefully check the compatibility of the selected syringe and tube. Instructions for preparation and administration of the drug via tube are given below.

Administration of the drug via gastric tube

1. Place the tablet into a suitable syringe and draw into the syringe approximately 25 mL of water and approximately 5 mL of air. For some tubes, dilution of the drug in 50 mL of water may be required to avoid blockage of the tube by tablet granules.
2. Shake the syringe immediately for about 2 minutes to dissolve the tablet.
3. Hold the syringe with the tip upward and ensure that the tip is not blocked.
4. Attach the syringe to the tube, continuing to hold the syringe tip upward.
5. Shake the syringe and turn it with the tip downward. Immediately administer 5–10 mL of the dissolved drug into the tube. After administration, return the syringe to its original position and shake it (the syringe should be held with the tip upward to prevent blockage of the tip).
6. Turn the syringe with the tip downward and administer another 5–10 mL of the drug into the tube. Repeat this procedure until the syringe is completely emptied.
7. Draw 25 mL of water and 5 mL of air into the syringe and repeat step 5 if necessary to flush any residue remaining in the syringe. For some tubes, 50 mL of water may be required if needed.

Children.

Esomeprazole should not be used in children under 12 years of age, as data on use in this age group are lacking.

It is used in children aged 12 years and older for the following indications:

Gastroesophageal reflux disease (GERD)

• treatment of erosive reflux esophagitis;
• long-term treatment of patients with healed esophagitis to prevent relapse;
• symptomatic treatment of GERD.

In combination with antibiotics for the treatment of duodenal ulcer associated with Helicobacter pylori.

Overdose.

Data on intentional overdose are very limited to date. Symptoms reported following ingestion of 280 mg of the drug included gastrointestinal symptoms and weakness. A single dose of esomeprazole up to 80 mg did not result in any adverse effects. There is no specific antidote. Esomeprazole is highly bound to plasma proteins, so elimination via dialysis is negligible. As with any overdose, symptomatic and supportive treatment should be provided.

Adverse Reactions

During clinical studies and following the introduction of esomeprazole into widespread medical use, the adverse reactions listed below have been reported. Dose-dependent adverse reactions have not been identified. Adverse reactions are listed according to their 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 such as fever, angioedema, and anaphylactic reaction/shock.

Metabolism and nutrition disorders

Uncommon: peripheral edema.

Rare: hyponatremia.

Very rare: hypomagnesemia; severe hypomagnesemia may lead to hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders

Uncommon: insomnia.

Rare: agitation, depression, confusion.

Very rare: aggression, hallucinations.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, somnolence.

Rare: taste disturbance.

Eye disorders

Rare: 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 reactions, including hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, pruritus, urticaria, rash.

Rare: alopecia, photosensitivity.

Very rare: severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Uncommon: fracture of the hip, wrist, or spine (see section "Special precautions").

Rare: arthralgia, myalgia.

Very rare: muscle weakness.

Renal and urinary disorders

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

Reproductive system and breast disorders

Very rare: gynecomastia.

General disorders

Rare: malaise, increased sweating.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

Tablets 20 mg: 7 tablets in a blister; 2 blisters in a cardboard box.

Tablets 40 mg: 7 tablets in a blister; 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Hetero Labs Limited, India.

Manufacturer's address.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.