Nexium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEXIUM (NEXIUM®)

Composition:

Active substance: esomeprazole;

One vial contains 42.5 mg of sodium esomeprazole, equivalent to 40 mg of esomeprazole;

Excipients: edetate disodium, sodium hydroxide.

Pharmaceutical form.

Powder for solution for injection and infusion.

Main physicochemical properties: porous mass or white or almost white powder.

Pharmacotherapeutic group.

Medicinal products used in acid-related disorders. Proton pump inhibitors. ATC code A02BC05.

Pharmacological properties.

Pharmacodynamics.

Esomeprazole is the S-isomer of omeprazole that inhibits gastric acid secretion through a specific and targeted mechanism of action. It is a specific inhibitor of the acid pump in parietal cells. Both the R- and S-isomers of omeprazole have similar pharmacological activity.

Site and 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 enzyme H⁺K⁺-ATPase (the proton pump), thereby suppressing both basal and stimulated acid secretion.

Effect on gastric acid secretion

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

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

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

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

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

During treatment with acid-suppressing medicinal products, serum gastrin levels increase in response to reduced acid secretion. Chromogranin A (CgA) levels also increase due to reduced gastric acidity. Because of elevated CgA levels, test results for neuroendocrine tumors may be affected. Published data indicate that treatment with proton pump inhibitors (PPIs) should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels to allow normalization, as CgA levels may be falsely elevated after PPI therapy.

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

During prolonged treatment with oral acid-suppressing medicinal products, a slight increase in the incidence of gastric glandular cysts has been observed. These changes are a physiological consequence of pronounced inhibition of gastric acid secretion, are benign, and resolve after discontinuation of treatment.

Reduced gastric acidity for any reason, including the use of proton pump inhibitors, leads to increased bacterial load in the stomach, normally present in the gastrointestinal tract. PPI treatment may slightly increase the risk of gastrointestinal infections caused by, for example, Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients.

Children

In a placebo-controlled study (98 patients aged 1 to 11 months), the efficacy and safety of the medicinal product were evaluated in patients with signs and symptoms of GERD. Esomeprazole 1 mg/kg once daily was administered orally for 2 weeks (open phase), and 80 patients continued for an additional 4 weeks (double-blind, treatment withdrawal phase). No significant difference was observed between esomeprazole and placebo regarding achievement of the primary endpoint or treatment discontinuation due to symptom worsening.

In another placebo-controlled study (52 patients aged <1 month), the efficacy and safety of the medicinal product were evaluated in patients with GERD symptoms. Esomeprazole 0.5 mg/kg once daily was administered orally for at least 10 days. There was no significant difference between esomeprazole and placebo regarding the primary endpoint of change in the number of GERD symptom episodes compared to baseline.

Results from studies in pediatric patients show that esomeprazole doses of 0.5 mg/kg and 1.0 mg/kg in infants aged <1 month and 1–11 months, respectively, reduce the mean percentage of time with intragastric pH < 4.0. The safety profile of the medicinal product was similar to that in adults.

In a study involving pediatric patients 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.

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 by the cytochrome P450 (CYP) system. The majority of esomeprazole metabolism is dependent on the polymorphic CYP2C19, responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remainder of metabolism is mediated by another specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in plasma.

Elimination

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

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

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

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

Linearity/Non-linearity

Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear relationship between dose and AUC after repeated dosing. This time- and dose-dependency is due to reduced presystemic metabolism and systemic clearance, likely caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite.

After repeated administration of 40 mg esomeprazole as intravenous injections, the mean maximum plasma concentration is approximately 13.6 µmol/L. The mean maximum plasma concentration after corresponding oral doses is approximately 4.6 µmol/L. A smaller increase (approximately 30%) in total exposure is observed with intravenous administration compared to oral administration. A linear dose-dependent increase in exposure was observed after 30-minute intravenous infusions of esomeprazole (40 mg, 80 mg, or 120 mg), followed by continuous infusion (at 4 mg/h or 8 mg/h) for 23.5 hours.

Special patient groups

Slow metabolizers

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

Gender

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

Liver 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 total esomeprazole exposure. Therefore, patients with GERD and severe hepatic impairment should not exceed the maximum dose of 20 mg. In cases of bleeding ulcer and severe hepatic impairment, after an initial 80 mg bolus dose, continuous intravenous infusion at a maximum rate of 4 mg/hour for 71.5 hours may be sufficient. Esomeprazole or its main metabolites do not show a tendency to accumulate with once-daily administration.

Renal impairment

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

Elderly patients

Esomeprazole metabolism is only slightly altered in elderly individuals (71–80 years).

Children

In a randomized, open-label, international multiple-dose study, esomeprazole was administered as a 3-minute injection once daily for 4 days. A total of 59 children aged 0 to 18 years were enrolled, of whom 50 (including 7 children aged 1 to 5 years) completed the study and were included in the pharmacokinetic evaluation of esomeprazole.

Table 1 presents the systemic exposure results of esomeprazole after intravenous administration as a 3-minute injection in pediatric patients and healthy adult volunteers. Values in Table 1 are presented as geometric means (range). The 20 mg dose in adults was administered as a 30-minute infusion. The maximum steady-state plasma concentration (Css,max) was measured 5 minutes after dosing in all pediatric age groups, and 7 minutes after dosing in adults receiving 40 mg and at the end of the 20 mg infusion.

Table 1

Age group	Dose group	AUC (μmol*h/L)	Css,max (μmol/L)
0–1 month*	0.5 mg/kg (n = 6)	7.5 (4.5–20.5)	3.7 (2.7–5.8)
1–11 months*	1.0 mg/kg (n = 6)	10.5 (4.5–22.5)	8.7 (4.5–14.0)
1–5 years	10 mg (n = 7)	7.9 (2.9–16.6)	9.4 (4.4–17.2)
6–11 years	10 mg (n = 8)	6.9 (3.5–10.9)	5.6 (3.1–13.2)
	20 mg (n = 8)	14.4 (7.2–42.3)	8.8 (3.4–29.4)
	20 mg (n = 6)**	10.1 (7.2–13.7)	8.1 (3.4–29.4)
12–17 years	20 mg (n = 6)	8.1 (4.7–15.9)	7.1 (4.8–9.0)
	40 mg (n = 8)	17.6 (13.1–19.8)	10.5 (7.8–14.2)
Adults	20 mg (n = 22)	5.1 (1.5–11.8)	3.9 (1.5–6.7)
	40 mg (n = 41)	12.6 (4.8–21.7)	8.5 (5.4–17.9)

* The age group from 0 to 1 month included patients with corrected age (sum of gestational age and postnatal age in completed weeks) ≥ 32 completed weeks and < 44 completed weeks. The age group from 1 to 11 months included patients with corrected age ≥ 44 completed weeks.

** Two patients were excluded: one most likely due to reduced CYP2C19 isoenzyme activity, the other due to concomitant use of a CYP3A4 isoenzyme inhibitor.

According to the developed model, Css,max after intravenous administration of esomeprazole via 10-minute, 20-minute, and 30-minute infusions will decrease on average by 37–49%, 54–66%, and 61–72%, respectively, across all age groups and dosing groups, compared to the Css,max value after a 3-minute injection.

Clinical characteristics.

Indications.

Adults

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

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

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

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

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

Children aged 1 to 18 years

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

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

Contraindications.

Hypersensitivity to the active substance, other 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 forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

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

It has been reported that concomitant use of omeprazole reduces serum levels of atazanavir and nelfinavir; therefore, their concomitant use is not recommended. Coadministration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant reduction in atazanavir exposure (decrease in AUC, Cmax, and Cmin by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Coadministration of omeprazole (20 mg daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers reduced atazanavir exposure by approximately 30% compared to exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg daily. Coadministration of omeprazole (40 mg daily) reduced mean AUC, Cmax, and Cmin values of nelfinavir by 36–39%, and mean AUC, Cmax, and Cmin values of its pharmacologically active metabolite M8 by 75–92%.

Due to the similarity in pharmacodynamic effects and pharmacokinetic properties between omeprazole and esomeprazole, concomitant use of esomeprazole with atazanavir is not recommended (see section "Special warnings and precautions for use"); concomitant use of esomeprazole with nelfinavir is contraindicated (see section "Contraindications").

Increased serum concentrations of saquinavir (coadministered with ritonavir) by 80–100% were observed with concomitant use of omeprazole (40 mg daily). Omeprazole at a dose of 20 mg daily did not affect the exposure of darunavir (coadministered with ritonavir) or amprenavir (in combination with ritonavir). Esomeprazole at a dose of 20 mg daily did not affect the exposure of amprenavir (with or without ritonavir). Administration of omeprazole at 40 mg/day did not alter the exposure of lopinavir (in combination with ritonavir).

Methotrexate

During concomitant use of methotrexate with PPIs, elevated methotrexate levels have been observed in some patients. When administering 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 blood 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 (proton pump inhibitors) may decrease or increase the absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of digoxin may be increased during esomeprazole therapy. Coadministration of omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (up to 30% in two out of ten participants). Toxic effects of digoxin were rarely observed. However, caution should be exercised when using high doses of esomeprazole in elderly patients. Monitoring of digoxin blood concentrations should be intensified.

Medicinal products metabolized by CYP2C19

Esomeprazole inhibits CYP2C19, the main enzyme responsible for esomeprazole metabolism. Therefore, when esomeprazole is combined with medicinal products metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., plasma concentrations of these drugs may increase, and dose reduction may be required. In vivo interaction studies using intravenous formulations at high doses (80 mg + 8 mg/hour) have not been conducted. The effect of esomeprazole on drugs metabolized by CYP2C19 under such treatment regimens may be more pronounced, and patients should be closely monitored for adverse events during the 3-day intravenous treatment period.

Diazepam

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

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin increased the minimum plasma concentrations of phenytoin in epileptic patients by 13%. Monitoring of phenytoin plasma concentrations is recommended at the beginning and upon discontinuation of esomeprazole therapy.

Voriconazole

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

Cilostazol

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

Cisapride

Concomitant oral administration of 40 mg esomeprazole and cisapride in healthy volunteers increased the area under the concentration-time curve (AUC) by 32% and the elimination half-life (t1/2) 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 when cisapride was administered in combination with esomeprazole.

Warfarin

A clinical study showed that coagulation time remained within acceptable limits when esomeprazole 40 mg was administered orally concomitantly with warfarin. However, during the post-marketing period, several isolated cases of clinically significant increases in INR (International Normalized Ratio) were reported with concomitant use of these medicinal products. Monitoring is recommended at the initiation and termination of concomitant esomeprazole and warfarin or other coumarin derivatives.

Clopidogrel

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

In a study in healthy volunteers receiving clopidogrel together with esomeprazole and acetylsalicylic acid (ASA) in a fixed-dose combination (20 mg + 81 mg, respectively), compared to clopidogrel monotherapy, exposure to clopidogrel's active metabolite was reduced by nearly 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 on the clinical implications of the PK/PD interaction between esomeprazole and major cardiovascular events. As a precautionary measure, concomitant use of esomeprazole and clopidogrel should be avoided.

Investigated medicinal products without clinically significant interaction

Amoxicillin or quinidine

It has been shown 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

MEDICINAL PRODUCTS THAT INDUCE CYP2C19 AND/OR CYP3A4 ACTIVITY

Esomeprazole is metabolized by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubled esomeprazole exposure (AUC). Concomitant use of esomeprazole with combined CYP2C19 and CYP3A4 inhibitors may increase esomeprazole exposure by more than two-fold. The CYP2C19 and CYP3A4 inhibitor voriconazole increased AUCτ of omeprazole by 280%. Dose adjustment of esomeprazole is not always necessary in such cases. However, it may be required in patients with severe hepatic impairment or when long-term treatment is indicated.

MEDICINAL PRODUCTS THAT INDUCE CYP2C19 AND/OR CYP3A4 ACTIVITY

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

Children

Drug interaction studies have been conducted only in adults.

Special precautions for use

In the presence of any alarming symptoms (such as, for example, significant unexplained weight loss, recurrent vomiting, dysphagia, hematemesis or melena) or suspicion of, or existing, gastric ulcer, malignancy should be excluded, since the medicinal product Nexium may mask symptoms and delay diagnosis.

Gastrointestinal infections

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

Vitamin B12 absorption

Esomeprazole, like all medicinal products that inhibit acid secretion, may impair vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered in patients with reduced vitamin stores or risk factors for impaired vitamin B12 absorption during long-term therapy.

Hypomagnesaemia

Cases of severe hypomagnesaemia have 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. Hypomagnesaemia may present with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, and its onset may be insidious and remain unnoticed. In most patients with hypomagnesaemia, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients requiring long-term treatment or those receiving PPIs concomitantly with digoxin or medicinal products capable of causing hypomagnesaemia (e.g., diuretics), it may be advisable to measure magnesium levels before initiating PPI therapy and periodically during treatment.

Risk of fractures

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

Subacute cutaneous lupus erythematosus

The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of Nexium should be considered. Development of subacute cutaneous lupus erythematosus during previous treatment with proton pump inhibitors may increase the risk of recurrence when using 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 forms of interaction"). If combination 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 in combination with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.

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

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), 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 appear.

If signs or symptoms of severe skin reactions occur, esomeprazole should be discontinued immediately, and additional medical care or close monitoring should be provided.

Re-administration of the medicinal product should not be undertaken in patients with EM/SJS/TEN/DRESS.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with laboratory tests for neuroendocrine tumours. To avoid this, esomeprazole treatment should be temporarily discontinued at least five days before measuring CgA levels. If CgA and gastrin levels have not normalized after the initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Each vial of the medicinal product Nexium contains less than 1 mmol sodium (23 mg) per 40 mg, i.e., it is considered essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of the medicinal product Nexium during pregnancy are limited. A somewhat larger amount of epidemiological data on the use of the racemic mixture of omeprazole during pregnancy suggests no risk of congenital malformations or toxic effects of the drug on the fetus. Animal studies with esomeprazole did not reveal any direct or indirect harmful effects of the drug on embryonic/fetal development.

Animal studies with the racemic mixture did not reveal any direct or indirect harmful effects on pregnancy, delivery, or postnatal development. Nexium should be prescribed to pregnant women with caution.

A moderate amount of data on the use of the drug in pregnant women (from 300 to 1000 pregnancy cases) indicates no risk of congenital malformations or toxic effects of esomeprazole on fetal/neonatal health.

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

Breastfeeding

It is unknown whether esomeprazole passes into breast milk. Information on the effects of esomeprazole on neonates/infants is insufficient. 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 of the drug.

Ability to influence the ability to drive and use machines

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

Method of Administration and Dosage

Dosage

Adults

Antisecretory therapy when oral administration is not possible
For patients unable to take the medicinal product orally, the drug may be administered parenterally at a dose of 20–40 mg once daily. The dose for patients with reflux esophagitis is 40 mg once daily. The dose for patients receiving symptomatic treatment of gastroesophageal reflux disease (GERD) is 20 mg once daily.

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

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

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

Following therapeutic endoscopy for acute bleeding from gastric or duodenal ulcer, administer 80 mg of the medicinal product as a bolus infusion over 30 minutes, followed by continuous intravenous infusion of the drug at a rate of 8 mg/hour for 3 days (72 hours).

After parenteral treatment, therapy should be continued using oral agents that suppress acid secretion.

Method of Administration

Instructions for preparation of the reconstituted solution are provided in this section below; see section "Special precautions for disposal and handling of unused medicinal product".

Injections

Dose of 40 mg

5 mL of reconstituted solution (8 mg/mL) should be administered as an intravenous injection over at least 3 minutes.

Dose of 20 mg

2.5 mL, or half of the reconstituted solution (8 mg/mL), should be administered as an intravenous injection over at least 3 minutes. Any unused solution must be discarded.

Infusions

Dose of 40 mg

The reconstituted solution should be administered as an intravenous infusion over 10–30 minutes.

Dose of 20 mg

Half of the reconstituted solution should be administered as an intravenous infusion over 10–30 minutes. Any unused solution must be discarded.

Bolus dose of 80 mg

The reconstituted solution should be administered as a prolonged intravenous infusion over 30 minutes.

Dose of 8 mg/hour

The reconstituted solution should be administered as a continuous intravenous infusion over 71.5 hours (calculated infusion rate of 8 mg/hour; shelf life of the reconstituted solution is specified in the section "Shelf Life").

Special Patient Populations

Renal Impairment

Dose adjustment is not required in patients with renal impairment. As experience with the use of the drug in patients with severe renal impairment is limited, these patients should be treated with caution (see section "Pharmacokinetics").

Hepatic Impairment

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

Bleeding ulcers: dose adjustment is not required in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, after administration of the initial 80 mg bolus dose of Nexium for infusion, subsequent continuous intravenous infusion at a rate of 4 mg/hour for 71.5 hours may be sufficient (see section "Pharmacokinetics").

Elderly Patients

Dose adjustment is not required.

Children

Dosage

Children aged 1–18 years

Antisecretory therapy when oral administration is not possible

For patients unable to take the medicinal product orally, the drug may be administered parenterally once daily during the full course of treatment for GERD (doses are given in Table 2).

Treatment with the intravenous medicinal product should usually be short-term; patients should be switched to oral therapy as soon as possible.

Table 2

Recommended intravenous doses of esomeprazole

Age group	Treatment of erosive reflux esophagitis	Symptomatic treatment of GERD
1–11 years	Body weight <20 kg: 10 mg once daily Body weight ≥20 kg: 10 or 20 mg once daily	10 mg once daily
12–18 years	40 mg once daily	20 mg once daily

Method of administration

Instructions for preparing the reconstituted solution are provided in this section below; see section "Special precautions for disposal and handling of unused medicinal product".

Injections

Dose 40 mg

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

Dose 20 mg

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

Dose 10 mg

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

Infusions

Dose 40 mg

The reconstituted solution is administered as an intravenous infusion over 10–30 minutes.

Dose 20 mg

Half of the reconstituted solution is administered as an intravenous infusion over 10–30 minutes. Any unused solution must be discarded.

Dose 10 mg

One-quarter of the reconstituted solution is administered as an intravenous infusion over 10–30 minutes. Any unused solution must be discarded.

Special precautions for disposal and handling of unused medicinal product

The reconstituted solution should be inspected visually for particulate matter and discoloration prior to administration. Only clear solution should be used. The solution is for single use only.

If the entire contents of the reconstituted vial are not required, any unused solution should be discarded according to local requirements.

Injection solution 40 mg

Prepare an injection solution (8 mg/ml) by adding 5 ml of 0.9% sodium chloride for intravenous use to a 40 mg esomeprazole vial.

The reconstituted injection solution is clear and colourless or slightly yellowish.

Infusion solution 40 mg

Prepare an infusion solution by dissolving the contents of one 40 mg esomeprazole vial in 100 ml of 0.9% sodium chloride for intravenous use.

Infusion solution 80 mg

Prepare an infusion solution by dissolving the contents of two 40 mg esomeprazole vials in 100 ml of 0.9% sodium chloride for intravenous use.

The reconstituted infusion solution is clear and colourless or slightly yellowish.

Children

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

Overdose

Experience with intentional overdose is currently very limited. Symptoms observed following oral intake of 280 mg included gastrointestinal effects and weakness. A single oral dose of 80 mg esomeprazole and intravenous administration of 308 mg esomeprazole over 24 hours did not result in any adverse effects. There is no specific antidote. Esomeprazole is highly protein-bound and therefore not effectively removed by dialysis. As with any overdose, symptomatic treatment and general supportive measures should be adopted.

Adverse reactions.

Summary of safety profile

Among the adverse reactions most commonly observed during clinical trials (as well as in the post-marketing period of the medicinal product), headache, abdominal pain, diarrhea, and nausea were reported. Furthermore, the safety profile of the medicinal product is consistent across different dosage forms, indications for treatment, age groups, and patient populations. Dose-dependent adverse reactions have not been identified.

List of adverse reactions in tabular form

The adverse reactions listed below were identified or suspected in clinical studies of esomeprazole during its oral or intravenous administration, as well as during post-marketing surveillance of the medicinal product's oral use. Reactions are classified according to their frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Table 3

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 reactions/shock
Metabolism and nutrition disorders	Uncommon	Peripheral edema
	Uncommon	Hypomagnesemia (see section "Special precautions"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
	Frequency unknown	Hypomagnesemia (see section "Special precautions"); severe hypomagnesemia may correlate with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.
Psychiatric disorders	Uncommon	Insomnia
	Uncommon	Excitation, 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	Common	Injection site reactions*
	Uncommon	Dermatitis, pruritus, rash, urticaria
	Uncommon	Alopecia, photosensitivity
	Very rare	Erythema multiforme (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 precautions")
Musculoskeletal and connective tissue disorders	Uncommon	Fracture of femur, wrist or spine (see section "Special precautions")
	Uncommon	Arthralgia, myalgia
	Very rare	Muscle weakness
Renal and urinary disorders	Very rare	Interstitial nephritis (in some patients renal failure was also reported)
Reproductive system and breast disorders	Very rare	Gynaecomastia
General disorders and administration site conditions	Uncommon	Malaise, increased sweating

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

Irreversible vision impairment was reported in isolated cases in critically ill patients receiving omeprazole (racemate) as intravenous injection, particularly at high doses; however, a causal relationship has not been established.

Reporting of Adverse Reactions

It is important to report suspected adverse reactions during the post-marketing period of the medicinal product. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Paediatric Population

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

Shelf Life.

2 years.

Storage period after reconstitution: Chemical and physical in-use stability has been demonstrated for 12 hours at 30 °C. From a microbiological standpoint, the product should be used immediately.

Storage Conditions.

Store in a place inaccessible to children and protected from light, at a temperature not exceeding 30 °C.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and Administration".

Packaging.

10 glass vials with powder in a cardboard box.

Prescription Status.

Prescription only.

Manufacturer.

AstraZeneca AB/AstraZeneca AB

Manufacturer's Address and Place of Business.

Gertunavägen, Södertälje, 152 57, Sweden / Gartunavagen, Sodertalje, 152 57, Sweden