Nexium

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

Composition:

Active substance: esomeprazole;

1 film-coated tablet contains magnesium esomeprazole trihydrate equivalent to 40 mg of esomeprazole;

Excipients: glycerol monostearate, hydroxypropylcellulose, hypromellose, magnesium stearate, methacrylic acid copolymer (type A), microcrystalline cellulose, synthetic paraffin, macrogol, polysorbate 80, crospovidone, sodium stearyl fumarate, spherical sugar, talc, titanium dioxide (E 171), triethyl citrate;

Colourants: iron oxide red-brown (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

pink, oval, biconvex, film-coated tablet with the imprint "40 mG" on one side and on the other side.

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 (H+/K+-ATPase) in parietal cells. 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 and 40 mg esomeprazole, onset of action occurs within one hour. After repeated administration of 20 mg esomeprazole once daily for five days, on day 5, the mean maximal acid secretion stimulated by pentagastrin is reduced by 90%, measured 6–7 hours after the last dose.

After five days of treatment with 20 mg and 40 mg esomeprazole orally in patients with symptomatic gastroesophageal reflux disease (GERD), intragastric pH above 4 was maintained on average for 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 with 40 mg esomeprazole were 97%, 92%, and 56%.

Using AUC as an indirect parameter of drug concentration in plasma, a correlation has been demonstrated between acid secretion inhibition and esomeprazole plasma levels.

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

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

After one week of eradication therapy, no further monotherapy with acid-suppressing agents is required for effective ulcer treatment and symptom relief in patients with uncomplicated duodenal ulcers.

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

During treatment with acid-suppressing agents, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity. Elevated CgA levels may interfere with laboratory tests for neuroendocrine tumors. According to published data, proton pump inhibitors (PPIs) should be discontinued at least 5–14 days before measuring CgA levels to allow levels, which may be falsely elevated during PPI therapy, to return to normal ranges.

During long-term esomeprazole therapy in both 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 long-term treatment with acid-suppressing agents, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are a physiological consequence of pronounced suppression of gastric juice secretion; they are benign in nature and resolve after treatment discontinuation.

Reduced gastric acidity from any cause, including PPI use, leads to increased bacterial colonization 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, Nexium 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, Nexium demonstrated superior efficacy in preventing gastric and duodenal ulcers in patients (aged >60 years and/or with pre-existing ulcers) taking NSAIDs, including selective COX-2 inhibitors.

Children

In a study involving children with GERD (aged <1 to 17 years) receiving long-term PPI therapy, ECL cell hyperplasia of minor 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 are used for oral administration. In vivo, only a minor portion of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: peak plasma concentration 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 once-daily dosing. 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.

Biotransformation

Esomeprazole is completely metabolized via the cytochrome P450 (CYP) system. The majority of esomeprazole metabolism depends on the polymorphic isoenzyme CYP2C19, responsible for forming hydroxy- and desmethyl-metabolites of esomeprazole. The remaining portion is metabolized by another specific isoenzyme, CYP3A4, which forms esomeprazole sulfone, the main metabolite detected in plasma.

Elimination

The parameters below primarily reflect pharmacokinetic characteristics in patients with functional CYP2C19 enzyme (rapid metabolizers).

Total plasma clearance is approximately 17 L/h after single-dose administration and approximately 9 L/h after multiple dosing. The plasma half-life is approximately 1.3 hours with once-daily dosing. Esomeprazole is completely cleared from plasma between doses, and no tendency for 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 in urine as metabolites, and the remainder is excreted in feces. Less than 1% of unchanged esomeprazole is found in urine.

Linearity/Non-linearity

The pharmacokinetics of esomeprazole have been studied after doses up to 40 mg twice daily. The area under the plasma concentration-time curve (AUC) increases with repeated esomeprazole administration. This increase is dose-dependent and results in non-linear dose-AUC relationships after repeated dosing. This time- and dose-dependence is due 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, the mean AUC was approximately 100% higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). The mean peak plasma concentration was approximately 60% higher. These data do not require dose adjustments for esomeprazole.

Gender

After a single 40 mg dose, the mean AUC in women is approximately 30% higher than in men. No gender-related differences are observed with repeated once-daily dosing. 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 the 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, 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).

Children aged 12–18 years

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

Clinical characteristics.

Indications.

Nexium, enteric-coated tablets, are indicated in adult patients for the following conditions:

Gastroesophageal reflux disease (GERD):

• Treatment of erosive reflux esophagitis.

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

Treatment of Zollinger–Ellison syndrome.

Nexium, enteric-coated tablets, are indicated in children aged 12 years and older for the following conditions:

Gastroesophageal reflux disease (GERD):

• Treatment of erosive reflux esophagitis.

Contraindications.

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in the section "Composition".

Esomeprazole must 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 mechanisms of such observed interactions are not always known. Increased gastric pH during omeprazole treatment may alter the absorption of protease inhibitors. Other possible mechanisms of interaction include inhibition of CYP2C19 activity.

Decreased 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, atazanavir exposure 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 reductions in mean AUC, Cmax, and Cmin of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin of its pharmacologically active metabolite M8 decreased by 75–92%. Due to the similarity of 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) and saquinavir (in combination with ritonavir), increased serum levels of saquinavir (80–100%) have been reported. Treatment with omeprazole 20 mg daily did not affect the exposure of darunavir (in combination with ritonavir) or amprenavir (in combination with ritonavir). Treatment with esomeprazole 20 mg daily did not affect the exposure of amprenavir (with or without ritonavir). Treatment with omeprazole 40 mg daily did not affect the exposure of lopinavir (in combination with ritonavir).

• Methotrexate *

Elevated methotrexate levels have been observed in some patients receiving concomitant treatment with proton pump inhibitors. When administering high-dose methotrexate, temporary discontinuation of esomeprazole should be considered.

• 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; dose adjustment of tacrolimus may be necessary.

• Medicinal products whose absorption is pH-dependent *

Reduced gastric acidity during treatment with esomeprazole and other PPIs may decrease or increase the 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 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 esomeprazole to elderly patients. Close clinical and laboratory monitoring of digoxin is necessary.

• Medicinal products metabolized by CYP2C19 *

Esomeprazole is an inhibitor of CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., their plasma concentrations may increase, and dose reduction may be required. This should be particularly considered when esomeprazole is prescribed on an "as-needed" basis.

• 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 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 one of its active metabolites by 29% and 69%, respectively.

• Cisapride *

In healthy volunteers, co-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. The slight prolongation of the QTc interval observed during cisapride monotherapy was not observed 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 maintained 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 medicinal products. Monitoring is recommended at the beginning and after discontinuation of concomitant esomeprazole use 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) 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 fixed combination doses (20 mg + 81 mg, respectively), compared to clopidogrel monotherapy, exposure to the active metabolite of clopidogrel was reduced by almost 40%. However, maximum levels of inhibition of ADP-induced platelet aggregation were similar between the clopidogrel monotherapy group and the group receiving clopidogrel with esomeprazole and ASA.

Observational and clinical studies have yielded conflicting data regarding 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 noted that esomeprazole does not have a 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 the CYP3A4 inhibitor clarithromycin (500 mg twice daily) results in a doubling of esomeprazole exposure (AUC). Concomitant administration of esomeprazole with combined inhibitors of CYP2C19 and CYP3A4 may lead to more than a two-fold increase in esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCτ by 280%. Dose adjustment of esomeprazole is generally not required in any of these situations. However, dose adjustment should be considered for patients with severe hepatic impairment and when long-term treatment is indicated.

Medicinal products that induce CYP2C19 and/or CYP3A4 activity

Medicinal products that induce CYP2C19 or CYP3A4 activity (such as rifampicin and St. John's wort) may lead to decreased serum levels of esomeprazole by accelerating its metabolism.

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use.

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

Long-term use of the medicinal product

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

Treatment "on demand"

Patients taking Nexium on an "as-needed" basis should be instructed to contact their physician if there is a change in the nature of their symptoms.

Eradication of Helicobacter pylori

When prescribing esomeprazole for eradication of Helicobacter pylori, potential drug interactions between all components of triple therapy must 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 proton pump inhibitors (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 secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered when conducting long-term treatment in patients with reduced body stores of vitamin B12 or in patients 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 one year or longer. Serious manifestations of hypomagnesemia 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 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 medicinal products that may cause hypomagnesemia (e.g., diuretics), healthcare professionals should consider monitoring magnesium levels before initiating PPI therapy and periodically during treatment.

Risk of fractures

Proton pump inhibitors, particularly when used at high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist, and spine fractures, 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 these increased fracture rates 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.

Subacute cutaneous lupus erythematosus (SCLE)

Cases of SCLE have been very rare with the use of proton pump inhibitors. If skin lesions appear, particularly on sun-exposed areas of the skin, and are accompanied by arthralgia, the patient should seek immediate medical attention, and the healthcare provider should consider discontinuing treatment with Nexium. Development of SCLE after treatment with one proton pump inhibitor may increase the risk of SCLE upon use of other proton pump inhibitors.

Combination with other medicinal products

Concomitant use of esomeprazole with atazanavir is not recommended (see section "Interaction with other medicinal products and other types of interactions"). If co-administration of atazanavir with a proton pump inhibitor cannot be avoided, close clinical monitoring 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, potential interactions between esomeprazole and other medicinal products metabolized by CYP2C19 should be considered at the initiation or discontinuation of esomeprazole therapy. An interaction has been observed between clopidogrel and esomeprazole (see section "Interaction with other medicinal products and other types of interactions"). 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, due to fluctuations in plasma concentrations of esomeprazole, potential interactions with other medicinal products should be considered; see section "Interaction with other medicinal products and other types of interactions".

Severe cutaneous adverse reactions (SCARs)

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

Patients should be informed about the possible signs and symptoms of severe cutaneous adverse reactions (EM/SJS/TEN/DRESS) and should seek immediate medical advice if any characteristic signs or symptoms occur.

If signs or symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately and further medical evaluation/monitoring should be provided.

Re-administration of the medicinal product should not be attempted in patients who have experienced EM/SJS/TEN/DRESS.

Sucrose

This medicinal product contains sucrose.

One 40 mg film-coated tablet contains 30 mg of sucrose.

Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

Effect on laboratory test results

Due to increased chromogranin A (CgA) levels, there may be an impact on laboratory tests for detecting neuroendocrine tumors. To avoid this effect, 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 proton pump inhibitor therapy.

Sodium content

One tablet of this medicinal product contains less than 1 mmol sodium (23 mg), i.e., it is considered essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are currently insufficient clinical data on the use of Nexium during pregnancy. Epidemiological studies on the use of the racemic mixture of omeprazole during pregnancy indicate no risk of congenital malformations or toxic effects of the drug on the fetus. Animal studies with esomeprazole have not shown direct or indirect harmful effects on embryonic/fetal development. Animal studies with the racemic mixture have not shown direct or indirect harmful effects on pregnancy, delivery, or postnatal development. The medicinal product should be prescribed with caution during pregnancy.

A moderate amount of data from pregnant women (between 300 and 1000 pregnancy cases) indicates no risk of congenital malformations 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 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 the racemic mixture of omeprazole indicate no effect of omeprazole on fertility following oral administration.

Ability to affect reaction speed when driving or operating machinery.

Esomeprazole has a negligible 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

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 following intravenous administration of the drug for prevention of recurrence of bleeding from peptic ulcers:

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

Zollinger–Ellison syndrome

The recommended initial dose of Nexium is 40 mg twice daily. The dose should then be adjusted individually; treatment continues as long as clinical indications require. Based on available clinical data, disease control can be achieved in most patients with doses ranging from 80 to 160 mg of esomeprazole per day. If daily doses exceed 80 mg, the dose should be divided and administered twice daily.

Special Patient Populations

Renal Impairment

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

Hepatic Impairment

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

Elderly Patients

Dosage adjustment of the drug is not required in elderly patients.

Children

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.

Children under 12 years of age

Nexium, enteric-coated tablets, 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 tablet 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, then the liquid containing the granules should be consumed immediately or within 30 minutes. Fill the glass with water again, stir the residue, and drink. Granules must not be chewed or crushed.

For patients unable to swallow, the tablet should be dissolved in non-carbonated water and administered via a gastric tube. It is important to carefully verify the suitability of the syringe and tube selected. 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 into an appropriate syringe and draw into the syringe approximately 25 mL of water and about 5 mL of air. For some tubes, dilution of the drug in 50 mL of water may be required to prevent clogging of the tube by tablet granules.
2. Immediately begin shaking 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 blocked.
4. Attach the syringe to the tube, continuing to hold the syringe in an upward direction.
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 previous 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 remaining residue from the syringe. For some tubes, 50 mL of water may be required.

Children

Nexium, enteric-coated tablets, should not be used in children under 12 years of age, as data on such use are lacking.

The drug is indicated for children aged 12 years and older for the following indication:

Gastroesophageal reflux disease (GERD)

• Treatment of erosive reflux esophagitis.

Overdose

Data on intentional overdose are very limited to date. Symptoms reported after 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 known specific antidote. Esomeprazole is highly plasma protein-bound, so dialysis is not effective for its elimination. As with any overdose, symptomatic and supportive treatment should be provided.

Adverse reactions.

Summary of safety profile

The most commonly observed adverse reactions during clinical trials (as well as in the post-marketing period) include headache, abdominal pain, diarrhea, and nausea. Furthermore, the safety profile of the medicinal product is consistent across different dosage forms, indications, age groups, and patient populations. No dose-dependent adverse reactions have been identified.

List of adverse reactions in tabular form

Below are listed the adverse reactions associated with esomeprazole, which 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 of occurrence: 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 based on available data).

System Organ Class		Frequency	Adverse Reactions
Blood and lymphatic system disorders		Uncommon	Leukopenia, thrombocytopenia
		Very rare	Agranulocytosis, pancytopenia
Immune system disorders		Uncommon	Hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders		Uncommon	Peripheral oedema
		Uncommon	Hypomagnesemia (see section "Special warnings and precautions for use"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia
		Frequency unknown	Hypomagnesemia (see section "Special warnings and precautions for use"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia
Psychiatric disorders		Uncommon	Insomnia
		Uncommon	Agitation, confusion, depression
		Very rare	Aggression, hallucinations
Nervous system disorders		Common	Headache
		Uncommon	Dizziness, paraesthesia, somnolence
		Uncommon	Taste disturbance
Eye disorders		Uncommon	Blurred vision
Ear and labyrinth disorders		Uncommon	Vertigo
Respiratory, thoracic and mediastinal disorders		Uncommon	Bronchospasm
Gastrointestinal disorders		Common	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign)
		Uncommon	Dry mouth
		Uncommon	Stomatitis, gastrointestinal candidiasis
		Frequency unknown	Microscopic colitis
Hepatobiliary disorders		Uncommon	Elevated liver enzymes
		Uncommon	Hepatitis with or without jaundice
		Very rare	Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders	Uncommon		Dermatitis, pruritus, rash, urticaria
	Uncommon		Alopecia, photosensitivity
	Very rare		Multiform erythema (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)
	Frequency unknown		Subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use")
Musculoskeletal and connective tissue disorders	Uncommon		Fracture of femur, wrist or spine (see section "Special warnings and precautions for use")
	Uncommon		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		Gynaecomastia
General disorders	Uncommon		Malaise, increased sweating

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing use of the medicinal product. This allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are obliged to report any cases of suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Store in the blister pack to protect from moisture.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB / AstraZeneca AB.

Manufacturer's address and place of business.

Gertunavagen, Sodertalje, 152 57, Sweden / Gartunavagen, Sodertalje, 152 57, Sweden.