Zercym

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZERZIM

Composition:

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

Excipients: microcrystalline cellulose, Starlac (lactose monohydrate, corn starch), hydroxypropylcellulose, macrogol, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

tablets 20 mg: Opadry pink 13G84576 (hypromellose, titanium dioxide (E 171), macrogol, talc, paraffin, polysorbate 80, iron oxide red (E 172), iron oxide yellow (E 172));

tablets 40 mg: Opadry pink 13G84577 (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:

20 mg tablets: light pink, oval-shaped tablets with beveled edges, marked with "H" on one side and "186" on the other;

40 mg tablets: light pink, oval-shaped tablets with beveled edges, marked with "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 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.

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

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

After five days of treatment with 20 mg and 40 mg oral esomeprazole 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 proportions for patients receiving 40 mg esomeprazole were 97%, 92%, and 56%.

Using the area under the plasma concentration-time curve (AUC) as an indirect parameter of drug concentration in blood plasma, a correlation between acid secretion inhibition and drug exposure after administration has been demonstrated.

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

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.

Following one week of eradication therapy, no further monotherapy with acid-suppressive agents is required for effective ulcer treatment and symptom relief 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, proton pump inhibitor (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 therapy, 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 cells (ECL cells) has been observed, possibly due to elevated serum gastrin levels. These findings are considered clinically insignificant.

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

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial load in the stomach, 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, the medicinal product Zerzim demonstrated superior efficacy in treating gastric ulcers in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) selective NSAIDs.

In two placebo-controlled studies, the medicinal product demonstrated superior efficacy in the prevention of gastric and duodenal ulcers in patients (aged >60 years and/or with a history of ulcer) taking NSAIDs, including COX-2 selective NSAIDs.

Pediatric Population

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

Pharmacokinetics

Absorption

Esomeprazole is unstable in acidic environments; therefore, enteric-coated granules must be 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 the 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 majority of esomeprazole metabolism is dependent on the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remaining portion of metabolism is mediated by another specific isoenzyme, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite detected in plasma.

Elimination

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

Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after multiple doses. The elimination half-life (t_1/2) 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 of esomeprazole, up to 80% of the dose is excreted in urine as metabolites, with the remainder excreted in feces. Less than 1% of unchanged esomeprazole is found in urine.

Linearity/Non-linearity

The pharmacokinetics of esomeprazole were studied following 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-dependence is attributed to reduced first-pass metabolism and systemic clearance, possibly related to inhibition of the CYP2C19 enzyme 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 C_max was increased by approximately 60%. These data do not require dosage adjustments for esomeprazole.

Elderly Patients

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

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 or moderate hepatic impairment. In patients with severe hepatic impairment, the rate of metabolism is reduced, resulting in a doubling of AUC. Therefore, the maximum 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, significant changes in esomeprazole metabolism are not expected in patients with renal impairment.

Pediatric Population

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 those observed in adults receiving the same 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 NSAIDs:

• healing of NSAID-induced gastric ulcers;
• prevention of gastric and duodenal ulcers induced by NSAIDs in patients at risk.

Long-term treatment following intravenous administration of the drug for prevention of 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.

Esomprazole should 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 esomprazole on the pharmacokinetics of other drugs

Protease inhibitors

Interactions between omeprazole and certain protease inhibitors have been reported. The clinical significance and mechanisms 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 is inhibition of CYP2C19 activity.

It has been reported that co-administration of omeprazole reduces serum levels of atazanavir and nelfinavir; therefore, concomitant use of these medicinal products 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 decreased by approximately 75%). Increasing the dose of atazanavir 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 of nelfinavir by 36–39%, and mean values of AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 decreased by 75–92%. Due to the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomprazole, concomitant use of esomprazole with atazanavir is not recommended (see section "Special precautions for use"); concomitant use of esomprazole 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). Omeprazole treatment at a dose of 20 mg daily did not affect exposure to darunavir (in combination with ritonavir) or to amprenavir (in combination with ritonavir). Treatment with esomprazole at a dose of 20 mg daily did not affect exposure to amprenavir (with or without ritonavir). Omeprazole treatment 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 high-dose methotrexate is prescribed, temporary discontinuation of esomprazole should be considered.

Tacrolimus

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

Drugs whose absorption is pH-dependent

Suppression of gastric acid secretion during treatment with esomprazole and other PPIs may decrease or increase absorption of drugs whose absorption is pH-dependent. As with other drugs 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 esomprazole treatment. 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). Rare cases of digoxin toxicity have been reported. However, caution should be exercised when prescribing high doses of esomprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Drugs metabolized by CYP2C19

Esomprazole is an inhibitor of CYP2C19, the main enzyme responsible for esomprazole metabolism. Therefore, when esomprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, or phenytoin, plasma concentrations of these drugs may increase, and dose reduction may be necessary. This should be particularly considered when prescribing esomprazole for on-demand use.

Diazepam

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

Phenytoin

During concomitant administration of esomeptrazole 40 mg in patients with epilepsy, a 13% increase in the minimum plasma concentration of phenytoin was observed. Monitoring of phenytoin plasma levels is recommended at the beginning of esomprazole 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 esomprazole act as inhibitors of CYP2C19. In a cross-over study in healthy volunteers, administration of omeprazole 40 mg increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and for one of its active metabolites by 29% and 69%, respectively.

• Cisapride *

In healthy volunteers, co-administration with esomprazole (40 mg) increased AUC by 32% and t1/2 by 31%, but no significant increase in maximum plasma levels of cisapride was observed. No significant prolongation of the QTc interval, which was observed during monotherapy with cisapride, was noted during concomitant administration of cisapride with esomprazole (see also section "Special precautions for use").

Warfarin

A clinical study showed that co-administration of esomprazole 40 mg in patients on warfarin therapy kept coagulation time within acceptable limits. However, in the post-marketing period, several isolated cases of clinically significant increases in the international normalized ratio (INR) have been reported during concomitant use of these drugs. Monitoring is recommended at the beginning and after discontinuation of concomitant use of esomprazole with 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 esomprazole (oral 40 mg daily) in healthy volunteers showed a mean reduction in exposure to the active metabolite of clopidogrel by 40% and a mean reduction in maximum inhibition (ADP-induced) of platelet aggregation by 14%.

In a study in healthy volunteers where clopidogrel was administered together with esomprazole and acetylsalicylic acid (ASA) in fixed combination doses (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 were similar in the clopidogrel monotherapy group and in the group receiving clopidogrel with esomprazole and ASA.

Observational and clinical studies have yielded conflicting data on the clinical aspects of PK/PD interaction between esomprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin and quinidine

It has been observed that esomprazole does not 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 esomprazole with naproxen or rofecoxib.

Effect of other medicinal products on the pharmacokinetics of esomprazole

Medicinal products that inhibit CYP2C19 and/or CYP3A4 activity

Esomprazole is metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant administration of esomprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubles the AUC of esomprazole. Concomitant administration of esomprazole and a combined inhibitor of CYP2C19 and CYP3A4 may increase the AUC of esomprazole by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomprazole is usually not required in any 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

Drugs 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 esomprazole by accelerating its metabolism.

Paediatric population

Drug interaction studies have been conducted only in adults.

Special precautions for use

In the presence of any alarming symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena), as well as in the presence of gastric ulcer or suspicion thereof, malignancy must be ruled out, since treatment with Zercym may mask symptoms and delay diagnosis.

Long-term use

Patients receiving long-term treatment (particularly those treated for more than one year) should be under regular medical supervision.

Treatment on-demand

Patients using Zercym on-demand should be instructed to contact their physician if there is a change in symptom pattern.

Eradication of Helicobacter pylori

When prescribing esomeprazole for Helicobacter pylori eradication, potential 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 receiving other medicinal products 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 gastric acid, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered when treating patients with low vitamin B12 stores or patients with risk factors for reduced vitamin B12 absorption over a long period.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs such as esomeprazole for at least three months, and in most cases, for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias may occur; however, these symptoms may develop insidiously and may go unnoticed. In most cases, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients expected to be on long-term treatment, or for patients receiving PPIs concomitantly with digoxin or other medicinal products that may cause hypomagnesaemia (e.g., diuretics), healthcare professionals should consider measuring magnesium levels before initiating PPI treatment and periodically during therapy.

Risk of fractures

PPIs, particularly when used at high doses and over long durations (>1 year), may modestly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other risk factors. Observational study data suggest that PPIs may increase the overall risk of fractures by 10–40%. Some of these increased fracture rates may be associated with 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 (SCLE)

PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, especially in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Zercym should be considered. Development of SCLE during previous treatment with a PPI may increase the risk of recurrence when using 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 a PPI 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 start 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 plasma concentrations of esomeprazole (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

If intolerance to certain sugars has been diagnosed, patients should consult their physician before taking this medicinal product.

Effect on laboratory test results

Due to increased chromogranin A (CgA) levels, PPIs may interfere with laboratory tests for neuroendocrine tumours. To avoid such interference, esomeprazole treatment should be discontinued at least 5 days before measuring CgA levels (see section "Pharmacodynamics").

Serious skin adverse reactions (SSARs)

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

Patients should be informed about the signs and symptoms of serious skin reactions.

If any signs or symptoms of EM/SJS/TEN/DRESS occur, esomeprazole should be discontinued immediately, and immediate medical attention should be sought. Additional medical support and careful monitoring may be required. Esomeprazole should not be re-administered to patients who have experienced EM/SJS/TEN/DRESS.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of Zercym during pregnancy. Epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy, involving a somewhat larger number of cases, suggest no congenital malformations or fetotoxic effects. Animal studies with esomeprazole have not shown direct or indirect harmful effects on embryonal/fetal development. Animal studies with the racemic mixture have not shown direct or indirect effects on pregnancy, delivery, or postnatal development. Zercym 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 cases) indicates no teratogenic effects or toxic influence of esomeprazole on the fetus or newborn child.

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

Breastfeeding

It is unknown whether esomeprazole passes into human breast milk. There is insufficient information on the effects of esomeprazole on newborns or breastfed infants. Esomeprazole should not be used during breastfeeding.

Fertility

Animal studies with the racemic mixture of omeprazole indicate no effect 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 (rare) have been reported (see section "Adverse reactions"). If such disorders occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Zerzim tablets should be swallowed whole with sufficient liquid. The tablets must not be chewed or crushed. For patients who have difficulty swallowing, it is recommended to dissolve the tablet in 100 mL of non-carbonated water. No other liquids should be used.

For patients who have difficulty swallowing, the tablet may be administered via a nasogastric tube after dissolving it in half a glass of non-carbonated water. It is very important that the syringe and tube used for this procedure are appropriate.

Administration of the drug through a nasogastric tube:

1. Place the tablet into a suitable syringe and fill it with approximately 25 mL of water and 5 mL of air. For some tubes, 50 mL of water may be required to facilitate passage of the tablet through the tube.
2. Shake the syringe for 2 minutes to allow the tablet to disintegrate.
3. Hold the syringe vertically with the tip facing upward and check the patency of the tip.
4. Attach the syringe to the tube, keeping it vertical.
5. Shake the syringe and turn it with the tip downward. Quickly administer 5–10 mL of the solution. After administration, turn the syringe back, shake it again (the syringe should be held vertically to prevent clogging of the tip).
6. Turn the syringe again and administer another 5–10 mL of solution into the tube. Repeat this procedure until the syringe is empty.
7. To rinse out any remaining residue, fill the syringe with 25 mL of water and 5 mL of air, shake it, turn it with the tip downward, and quickly administer the liquid. For some tubes, 50 mL of water may be required.

Adults

GERD

• Treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

Patients with untreated esophagitis or persistent symptoms should be treated for an additional 4 weeks.

• 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 is not achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, continued 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. The "on-demand" use of the drug 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 the eradication of Helicobacter pylori, and also for

• treatment of duodenal ulcer caused by Helicobacter pylori;
• prevention of relapse of peptic ulcers in patients with ulcers associated with Helicobacter pylori:

20 mg of Zerzim, 1 g of amoxicillin, and 500 mg of clarithromycin twice daily for 7 days.

Patients requiring long-term NSAID therapy

• Treatment of gastric ulcers induced by NSAID use:

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

• Prevention of gastric and duodenal ulcers induced by NSAID use 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.

Treatment of Zollinger-Ellison syndrome

The recommended initial dose of Zerzim is 40 mg twice daily. The dose should then be individually adjusted; treatment should continue until clinical indications resolve. Based on available clinical data, most patients can be controlled with daily doses of esomeprazole ranging from 80 mg to 160 mg. 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 drug in patients with severe renal impairment, caution should be exercised when treating such patients (see section "Pharmacokinetics").

Patients with hepatic impairment

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

Elderly patients

Dose adjustment is not required in elderly patients.

Pediatric population

Children aged 12 years and older

GERD

• Treatment of erosive reflux esophagitis:

40 mg once daily for 4 weeks.

Patients with untreated esophagitis or persistent symptoms should be treated for an additional 4 weeks.

• 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 is not achieved after 4 weeks of treatment, the patient should undergo further evaluation. After symptom resolution, continued control may be maintained with 20 mg once daily.

Treatment of duodenal ulcer caused by Helicobacter pylori

When selecting 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 considered. Treatment should be conducted under the supervision of a specialist.

Table 1

Dosage recommendations

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

Children.

Zercym should not be used in children under 12 years of age, as there is lack of data regarding such use.

It may be 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 caused by Helicobacter pylori.

Overdose.

Data regarding intentional overdose are very limited to date. Symptoms reported following intake of the drug at a dose of 280 mg 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 by dialysis is not significant. As with any overdose, symptomatic and supportive treatment should be provided.

Adverse reactions.

Summary of safety profile

The most commonly reported 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 the drug is consistent across different pharmaceutical forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

List of adverse reactions presented in tabular form

The adverse reactions listed below have been reported or suspected during clinical trials and in the post-marketing period with esomeprazole. None of these reactions were found to be dose-dependent. The 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 based on available data).

Table 2

System organ class	Frequency	Adverse effect
Blood and lymphatic system	rare	Leukopenia, thrombocytopenia
	very rare	Agranulocytosis, pancytopenia
Immune system	rare	Hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition	uncommon	Peripheral edema
	rare	Hypotension
	frequency not known	Hypomagnesemia (see section "Special precautions"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
Psychiatric	uncommon	Insomnia
	rare	Agitation, confusion, depression
	very rare	Aggression, hallucinations
Nervous system	common	Headache
	uncommon	Dizziness, paresthesia, 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	Elevated liver enzymes
	rare	Hepatitis, with or without jaundice
	very rare	Hepatic reactions, including liver failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue	uncommon	Dermatitis, pruritus, rash, urticaria
	rare	Alopecia, photosensitivity
	very rare	Severe skin reactions including 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 precautions")
Musculoskeletal and connective tissue	uncommon	Fracture of femur, wrist or spine (see section "Special precautions")
	rare	Arthralgia, myalgia
	very rare	Muscle weakness
Renal and urinary	very rare	Interstitial nephritis (in some patients renal failure has also been reported)
Reproductive system and breast	very rare	Gynecomastia
General disorders	rare	Malaise, increased sweating

Do not use if you are allergic to esomeprazole. Esomeprazole may cause serious skin reactions. Symptoms may include:

• skin redness;
• blisters;
• rash.

If an allergic reaction occurs, discontinue use and seek immediate medical attention.

Shelf life. 2 years.

Storage conditions.

Keep out of reach of children. Store at a temperature not exceeding 25 °C.

Packaging.

7 tablets per blister, 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of business activity.

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