Nexpro-20

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEXPRO-20, NEXPRO-40 (NEXPRO-20, NEXPRO-40)

Composition:

Active substance: esomeprazole;

1 tablet contains esomeprazole (as enteric-coated esomeprazole magnesium pellets) 20 mg or 40 mg;

Excipients: spherical sugar, ethylcellulose, magnesium stearate, povidone, light magnesium oxide, methacrylic acid copolymer dispersion, diethyl phthalate, talc, microcrystalline cellulose, lactose monohydrate, corn starch, copovidone, polyethylene glycol 8000, crospovidone, colloidal anhydrous silicon dioxide, hypromellose, titanium dioxide (E 171), iron oxide red (E 172), black printing ink OPACODE S-1-1-17823: shellac, iron oxide black (E 172), propylene glycol, ammonium hydroxide.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties:

20 mg tablets: round, biconvex, enteric-coated tablets of reddish-brown color, marked with black "20" on one side and smooth on the other;

40 mg tablets: round, biconvex, enteric-coated tablets of reddish-brown color, marked with black "40" on one side and smooth on the other.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease (GERD). Proton pump inhibitors. ATC code A02BC05.

Pharmacological Properties

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole that reduces gastric acid secretion via a specific mechanism of action. It is a specific inhibitor of the proton pump (H⁺K⁺-ATPase) in the parietal cell. The R- and S-isomers of omeprazole have equivalent pharmacodynamic activity.

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

Effect on Gastric Acid Secretion

After oral administration of 20 mg and 40 mg of esomeprazole, the effect begins within one hour. After repeated administration of 20 mg esomeprazole once daily for 5 days, the mean peak acid output following pentagastrin stimulation is reduced by 90%, measured 6–7 hours after dosing on day 5.

After 5 days of treatment with 20 mg and 40 mg of esomeprazole orally, intragastric pH remained above 4 for a mean of 13 and 17 hours, respectively, and for more than 24 hours in patients with symptomatic reflux esophagitis. The proportion of patients with intragastric pH above 4 for 8, 12, and 16 hours after a 20 mg dose of esomeprazole was 76%, 54%, and 24%, respectively. Corresponding proportions for 40 mg esomeprazole were 97%, 92%, and 56%.

Using AUC as an indirect measure of plasma concentration, a relationship between acid secretion inhibition and drug exposure has been demonstrated.

Therapeutic Effects of Acid Secretion Inhibition

Treatment of reflux esophagitis with 40 mg esomeprazole was successful in approximately 70% of patients after 4 weeks of treatment and in 93% after 8 weeks of treatment.

Administration of 20 mg esomeprazole twice daily for one week in combination with appropriate antibiotics resulted in successful eradication of Helicobacter pylori in approximately 90% of patients. After this one-week treatment, no further monotherapy with acid-suppressing agents was required for successful healing of ulcers and relief of symptoms in uncomplicated duodenal ulcer.

Other Effects Related to Acid Secretion Inhibition

During treatment with acid-suppressing agents, plasma gastrin concentrations increase in response to reduced acid secretion.

An increase in the number of ECL cells may be associated with elevated plasma gastrin levels, which has been observed in some patients during long-term treatment with esomeprazole.

There have been reports of several cases of increased incidence of gastric foveolar hyperplasia with prolonged use of acid-suppressing agents. These changes are physiological consequences of prolonged acid suppression and are benign and reversible.

Reduced gastric acid secretion due to any proton pump inhibitor increases the number of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections caused by, for example, Salmonella or Campylobacter.

Pharmacokinetics

Esomeprazole is acid-labile and is administered orally in an enteric-coated formulation. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma concentrations reached approximately 1–2 hours after administration. Absolute bioavailability is 64% after a single 40 mg dose and increases to 89% after repeated once-daily administration. The values for 20 mg esomeprazole are 50% and 68%, respectively. The steady-state volume of distribution in healthy volunteers is 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Food intake slows and reduces esomeprazole absorption, but this does not affect gastric acid secretion.

Metabolism and Elimination

Esomeprazole is completely metabolized via the cytochrome P450 (CYP) system. The main part of esomeprazole metabolism depends on the polymorphic CYP2C19, responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. Another part depends on a second specific isoenzyme, CYP3A4, which is responsible for the formation of esomeprazole sulfone—the main metabolite in plasma.

The parameters below primarily reflect the pharmacokinetics in individuals with functional CYP2C19 enzyme (extensive metabolizers).

Total plasma clearance is approximately 17 L/hour after a single dose and about 9 L/hour after repeated administration. The elimination half-life in plasma is approximately 1.3 hours after repeated once-daily dosing. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. The area under the plasma concentration-time curve (AUC) increases with repeated dosing. This increase is dose-dependent and results in more than dose-proportional increases in AUC after repeated administration. This time- and dose-dependency is explained by reduced first-pass metabolism and systemic clearance due to inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite. Esomeprazole is completely cleared from plasma between doses, with no tendency for accumulation when administered once daily.

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

Special Patient Populations

Approximately 2.9±1.5% of patients have deficiency of the CYP2C19 enzyme (referred to as poor metabolizers). In these individuals, esomeprazole metabolism is primarily mediated by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean AUC in poor metabolizers is approximately 100% higher than in individuals with normal CYP2C19 function (extensive metabolizers). The mean peak plasma concentration is increased by approximately 60%. These findings have no impact on esomeprazole dosing.

Esomeprazole metabolism is not significantly altered in elderly patients (aged 71–80 years).

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

Patients with Hepatic or Renal Impairment

Metabolism of esomeprazole may be impaired in patients with mild to moderate liver dysfunction. Metabolism is reduced in patients with severe hepatic impairment, resulting in a doubling of the AUC. Therefore, the maximum recommended dose in patients with severe hepatic impairment is 20 mg. Esomeprazole and its metabolites do not accumulate during once-daily administration. Studies in patients with renal impairment have not been conducted. Since the kidneys are responsible for the excretion of esomeprazole metabolites, not the parent compound, changes in metabolism are not expected in patients with renal impairment.

Use in Pediatrics

Children aged 12–18 years: after multiple doses of 20 mg and 40 mg esomeprazole, the overall exposure and time to peak plasma concentration were similar to those observed in adults.

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 gastroesophageal reflux disease (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 Helicobacter pylori-associated ulcers.

Patients requiring long-term use of nonsteroidal anti-inflammatory drugs (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 to prevent recurrence of bleeding from peptic ulcers.

Treatment of Zollinger-Ellison syndrome.

Children aged 12 years and older:

Gastroesophageal reflux disease (GERD):

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

Esomeprazole 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 esomeprazole 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 observed 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.

Decreased serum levels of atazanavir and nelfinavir have been reported when co-administered with omeprazole, and therefore their concomitant use is not recommended. Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers significantly reduced atazanavir exposure (AUC, Cmax, and Cmin decreased 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 resulted in approximately 30% reduction in atazanavir exposure compared to daily administration of 300 mg atazanavir/100 mg ritonavir without omeprazole 20 mg daily. Concomitant use of omeprazole (40 mg daily) reduced average AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and average 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 between 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) were reported (80–100%). Omeprazole treatment at a dose of 20 mg daily did not affect darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir) exposure. Esomeprazole treatment at a dose of 20 mg daily did not affect amprenavir exposure (with or without ritonavir). Omeprazole treatment at a dose of 40 mg daily did not affect lopinavir (in combination with ritonavir) exposure.

Methotrexate

In some patients, increased methotrexate levels have been observed during concomitant use with proton pump inhibitors.

When prescribing high-dose methotrexate, temporary discontinuation of esomeprazole should be considered.

Tacrolimus

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

Drugs whose absorption is pH-dependent

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

Drugs metabolized by CYP2C19

Esomeprazole is an inhibitor of CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., plasma concentrations of these drugs may increase, and dose reduction may be required. This should be particularly considered if 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

Concomitant administration of esomeprazole 40 mg in patients with epilepsy resulted in a 13% increase in the minimum plasma concentration of phenytoin. Monitoring of plasma phenytoin levels is recommended at the beginning 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 one of its active metabolites by 29% and 69%, respectively.

Cisapride

In healthy volunteers, concomitant administration with esomeprazole (40 mg) increased the area under the plasma concentration-time curve (AUC) of cisapride 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 noted 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 on warfarin therapy did not alter coagulation time beyond 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 concomitant esomeprazole use in patients receiving 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) conducted 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 involving healthy volunteers, when clopidogrel was administered together with esomeprazole and acetylsalicylic acid (ASA) in a fixed-dose combination (20 mg + 81 mg, respectively), exposure to the active metabolite of clopidogrel was reduced by nearly 40% compared to clopidogrel monotherapy.

However, maximum levels of inhibition of (ADP-induced) platelet aggregation were similar in the group receiving clopidogrel monotherapy 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 and quinidine

It has been observed that esomeprazole 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 esomeprazole with naproxen or rofecoxib.

Effect of other medicinal products on the pharmacokinetics of esomeprazole

Meds that inhibit CYP2C19 and/or CYP3A4 activity

Esomeprazole is metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubles esomeprazole exposure (AUC). Concomitant administration of esomeprazole with a combined inhibitor of CYP2C19 and CYP3A4 may lead to more than a twofold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCτ by 280%. Dose adjustment of esomeprazole is generally 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.

Meds that induce CYP2C19 and/or CYP3A4 activity

Medicinal products known to induce CYP2C19 or CYP3A4 activity, or both (such as rifampicin and St. John's wort), may reduce esomeprazole serum levels by accelerating its metabolism.

Paediatric population

Drug interaction studies have only been conducted in adults.

Special precautions for use.

In the presence of any alarming symptoms (e.g., significant spontaneous weight loss, recurrent vomiting, dysphagia, hematemesis, or melena), as well as in the presence of gastric ulcer or suspected gastric ulcer, malignancy must be excluded, since treatment with esomeprazole may mask symptoms and delay diagnosis.

Long-term use

Patients receiving the drug for a prolonged period (especially those treated for more than one year) should be under regular medical supervision.

Treatment on demand

Patients taking esomeprazole on an "as-needed" basis should be instructed to contact their physician if there is a change in symptom pattern.

Helicobacter pylori eradication

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

Vitamin B12 absorption

Esomeprazole, like all medicinal products that inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered when administering long-term treatment to patients 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 treated with proton pump inhibitors (PPIs), such as esomeprazole, for at least three months, and in most cases, for over a year. Serious manifestations of hypomagnesemia may include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias; however, these symptoms may develop insidiously and may be overlooked. In most cases, the condition improved after magnesium supplementation and discontinuation of PPI therapy.

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

Fracture risk

Proton pump inhibitors, 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 those with other risk factors. Observational study data suggest that PPIs may increase the overall risk of fractures by 10–40%. Some of this increased fracture incidence may be related to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions (SCARs)

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

Patients should be informed about the signs and symptoms of severe skin reactions (EM/SJS/TEN/DRESS) and advised to seek immediate medical attention if such symptoms occur. If symptoms suggestive of these reactions develop, esomeprazole should be discontinued immediately, and additional medical care and close monitoring should be provided as needed. Esomeprazole should not be re-administered to patients who have experienced EM/SJS/TEN/DRESS.

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 proton pump inhibitor cannot be avoided, close monitoring of patients in an inpatient setting is recommended, and the dose of atazanavir should be increased to 400 mg with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.

Esomeprazole is an inhibitor of CYP2C19. Therefore, when initiating or discontinuing esomeprazole therapy, potential interactions between esomeprazole and other drugs metabolized by CYP2C19 should be considered. 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 due to fluctuations in plasma concentrations of esomeprazole should be considered (see section "Interaction with other medicinal products and other forms of interaction").

If a patient has known intolerance to certain sugars, consultation with a physician is advised before taking this medicinal product.

Effect on laboratory test results

Due to increased levels of chromogranin A (CgA), esomeprazole may affect laboratory test results for detection of neuroendocrine tumors. To avoid this effect, esomeprazole treatment should be discontinued at least 5 days before measuring CgA levels (see section "Pharmacodynamics").

Use during pregnancy or breastfeeding.

Pregnancy

Currently, there is insufficient data on the use of esomeprazole during pregnancy. A somewhat larger number of epidemiological studies on the use of racemic omeprazole during pregnancy suggest no congenital malformations or fetotoxic effects. Animal studies with esomeprazole have not shown direct or indirect harmful effects on embryonic/fetal development. Studies in animals with the racemic mixture have not shown direct or indirect adverse effects on pregnancy, delivery, or postnatal development. Esomeprazole should be used with caution in pregnant women.

A moderate amount of data from pregnant women (between 300 and 1000 pregnancy cases) indicates no malformative effects or toxic effects of esomeprazole on the fetus or newborn infant.

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

Breastfeeding

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

Fertility

Results of animal studies with racemic omeprazole indicate no effect of omeprazole on fertility following oral administration.

Ability to affect reaction speed when driving or operating machinery.

Esomeprazole 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 refrain from driving or operating machinery.

Method of Administration and Dosage

Adults

Gastroesophageal reflux disease (GERD)

• Treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

For patients with untreated esophagitis or persistent symptoms, an additional 4 weeks of treatment is recommended.

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

20 mg once daily.

• Symptomatic treatment of gastroesophageal reflux disease (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, ongoing control may be maintained with 20 mg once daily. If necessary, treatment may be switched to an "on-demand" regimen, i.e., taking 20 mg once daily as needed. However, "on-demand" use 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 agents for eradication of Helicobacter pylori, and for

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

20 mg of esomeprazole together with 1 g of amoxicillin and 500 mg of clarithromycin twice daily for 7 days.

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

• Treatment of gastric ulcers associated with NSAID use:

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

• Prevention of gastric and duodenal ulcers associated with 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 peptic ulcer bleeding.

Treatment of Zollinger-Ellison syndrome

The recommended initial dose of esomeprazole is 40 mg twice daily. The dose should then be individually adjusted; treatment should continue as long as clinically indicated. Based on available clinical data, most patients can be controlled with doses ranging from 80 to 160 mg of esomeprazole per day. If the daily dose exceeds 80 mg, the dose should be divided and administered twice daily.

Special patient populations

Patients with impaired renal function

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 impaired hepatic function

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

Elderly patients

Dose adjustment is not required in elderly patients.

Pediatric population

Children aged 12 years and older

Gastroesophageal reflux disease (GERD)

• Treatment of erosive reflux esophagitis:

40 mg once daily for 4 weeks.

For patients with untreated esophagitis or persistent symptoms, an additional 4 weeks of treatment is recommended.

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

20 mg once daily.

• Symptomatic treatment of gastroesophageal reflux disease (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, ongoing control may be maintained with 20 mg once daily.

Treatment of duodenal ulcer caused by Helicobacter pylori

When selecting an appropriate combination therapy, official national, regional, and local guidelines 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.

Table 1

Dosage recommendations

Children under 12 years of age

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

Method of administration

The tablet should be swallowed whole with liquid. Tablets must 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. Other liquids should not be used, as they may dissolve the enteric coating. Stir until the tablets disintegrate, and the suspension should then be taken immediately or within 30 minutes. The glass should be refilled with water, stirred, and the remaining contents consumed. The pellets must 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 a tube are provided below.

Administration of the drug via gastric tube

1. Place the tablet in a suitable syringe and draw into the syringe approximately 25 mL of water and about 5 mL of air. For some tubes, dilution of the medication in 50 mL of water may be required to prevent clogging of the tube by tablet granules.
2. Immediately shake the syringe for approximately 2 minutes to dissolve the tablet.
3. Hold the syringe with the tip upward and ensure that the tip is not clogged.
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 medication into the tube. After administration, return the syringe to its original position and shake it (the syringe must be held with the tip upward to prevent clogging of the tip).
6. Turn the syringe with the tip downward and administer another 5–10 mL of medication 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 necessary.

Children.

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

Use 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 gastroesophageal reflux disease (GERD).

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

Overdose.

Data regarding overdose are limited. Gastrointestinal symptoms and weakness have been reported following ingestion of 280 mg of esomeprazole. A single dose of esomeprazole 80 mg does not cause severe adverse effects. No specific antidote is known.

Esomeprazole is highly bound to plasma proteins and therefore is not dialyzable. As with any overdose, symptomatic and general supportive treatment should be provided.

Adverse reactions.

Summary of safety profile

Among the adverse reactions most commonly observed during clinical trials (as well as in the post-marketing period), headache, abdominal pain, diarrhea, and nausea have been reported. 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.

List of adverse reactions presented in tabular form

The following adverse reactions to esomeprazole have been reported or suspected during clinical trials and in the post-marketing period. 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 (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Table 2

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

7 tablets in a blister pack; 2 blisters in a cardboard box.

10 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and location of business activity.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana, Gujarat 382721, India.