4.1. Therapeutic indications

Esomeprazole is indicated in adults for:

• Gastric antisecretory treatment when the oral route is not possible, such as:

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

- healing of gastric ulcers associated with Nonsteroidal Anti-inflammatory drug (NSAIDs) therapy.

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

• prevention of rebleeding following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Esomeprazole is indicated in children and adolescents aged 1-18 years for:

• Gastric antisecretory treatment when the oral route is not possible, such as:

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

4.2. Posology and method of administration

Posology Adults Gastric antisecretory treatment when the oral route is not possible Patients who cannot take oral medication may be treated parenterally with 20-40 mg once daily. Patients with reflux oesophagitis should be treated with 40 mg once daily. Patients treated symptomatically for reflux disease should be treated with 20 mg once daily. For healing of gastric ulcers associated with NSAID therapy, the usual dose is 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy, patients at risk should be treated with 20 mg once daily. Usually the intravenous treatment duration is short and transfer to oral treatment should be made as soon as possible. Prevention of rebleeding of gastric and duodenal ulcers Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers, 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous intravenous infusion of 8 mg/h given over 3 days (72 hours). The parenteral treatment period should be followed by oral acid suppression therapy. Method of administration For instructions on reconstitution of the medicinal product before administration, see section 6.6. Injection 40 mg dose 5 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. 20 mg dose 2.5 ml or half of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. Any unused solution should be discarded. Infusion 40 mg dose The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes 20 mg dose Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded. 80 mg bolus dose The reconstituted solution should be given as a continuous intravenous infusion over 30 minutes. 8 mg/h dose The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours (calculated rate of infusion of 8 mg/h. See section 6.3 for shelf-life of the reconstituted solution). Special populations Renal impairment Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section 5.2). Hepatic impairment GERD: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg esomeprazole should not be exceeded (see section 5.2). Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, following an initial bolus dose of 80 mg esomeprazole, a continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient (see section 5.2). Elderly patients Dose adjustment is not required in the elderly. Paediatric population Posology Children and adolescents aged 1-18 years Gastric antisecretory treatment when the oral route is not possible Patients who cannot take oral medication may be treated parenterally once daily, as a part of a full treatment period for GERD (see doses in table below). Usually the intravenous treatment duration should be short and transfer to oral treatment should be made as soon as possible. Recommended intravenous doses of esomeprazole Age group Treatment of erosive reflux esophagitis Symptomatic treatment of GERD 1-11 years Weight <20 kg: 10 mg once daily Weight ≥ 20 kg: 10 mg or 20 mg once daily 10 mg once daily 12-18 years 40 mg once daily 20 mg once daily Method of Administration For instructions on reconstitution of the medicinal product before administration, see section 6.6. Injection 40 mg dose 5 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. 20 mg dose 2.5 ml or half of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. Any unused solution should be discarded. 10 mg dose 1.25 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. Any unused solution should be discarded. Infusion 40 mg dose The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. 20 mg dose Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded. 10 mg dose A quarter of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded. <summary id="CONTRAINDICATIONS" data-evt="smpcSectionOpen"

4.3. Contraindications

Hypersensitivity to the active substance, to substituted benzimidazoles or to any of the excipients listed in section 6.1. Esomeprazole should not be used concomitantly with nelfinavir (see section 4.5). <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

4.4. Special warnings and precautions for use

In the presence of any alarming symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole may alleviate symptoms and delay diagnosis. Gastrointestinal infections Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1). Absorption of vitamin B12 Esomeprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy. Hypomagnesaemia Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole, for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. Risk of Fracture Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may moderately increase the risk of hip, wrist and spine fractures, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium. Subacute cutaneous lupus erythematosus (SCLE) Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping esomeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors. Combination with other medicines Co-administration of esomeprazole with atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded. Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole with clopidogrel should be discouraged. Serious cutaneous adverse reactions (SCARs) Serious 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), which can be life-threatening or fatal, have been reported very rarely in association with esomeprazole treatment. Patients should be advised of the signs and symptoms of the severe skin reaction EM/SJS/TEN/DRESS and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. Esomeprazole should be discontinued immediately upon signs and symptoms of severe skin reactions and additional medical care/close monitoring should be provided as needed. Re-challenge should not be undertaken in patients with EM/SJS/TEN/DRESS. Interference with laboratory tests Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment. <summary id="INTERACTIONS" data-evt="smpcSectionOpen"

4.5. Interaction with other medicinal products and other forms of interaction

Effect of esomeprazole on the pharmacokinetics of other medicinal products Protease inhibitors Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers, resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, C max and C min ). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg qd) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/100 mg ritonavir qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, C max and C min by 36-39% and mean AUC, C max and C min for the pharmacologically active metabolite M8 was reduced by 75-92%. Due to the similar pharmacodynamics effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended (see section 4.4) and concomitant administration with esomeprazole and nelfinavir is contraindicated (see section 4.3). For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir). Methotrexate When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high dose methotrexate administration, a temporary withdrawal of esomeprazole may need to be considered. Tacrolimus Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed and dosage of tacrolimus adjusted if needed. Medicinal products with pH dependent absorption Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic medicinal product monitoring of digoxin should then be reinforced. Medicinal products metabolised by CYP2C19 Esomeprazole inhibits CYP2C19, the major esomeprazole metabolizing enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentration of these medicinal products may be increased and a dose reduction could be needed. No in-vivo interaction studies have been performed with high-dose intravenous regimen (80 mg + 8 mg/h). The effect of esomeprazole on medicinal products metabolised by CYP2C19 may be more pronounced during this regimen and patients should be monitored closely for adverse effects during the 3-day intravenous treatment period. Diazepam Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Phenytoin Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn. Voriconazole Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C max and AUC of by 15% and 41% respectively. Cilostazol Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C max and AUC for cilostazol by 18% and 26% respectively and one of its active metabolites by 29% and 69%, respectively. Cisapride In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t 1/2 ), but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole. Warfarin Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing of oral esomeprazole, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives. Clopidogrel Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP-induced) platelet aggregation by an average of 14%. When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP-induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + combined (esomeprazole + ASA) product groups. Inconsistent data on the clinical implications of a PK / PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged. Investigated medicinal products with no clinically relevant interaction Amoxicillin or quinidine Esomeprazole has been shown to have no clinically relevant effect on the pharmacokinetics of amoxicillin or quinidine. Naproxen or rofecoxib Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies. Effects of other medicinal products on the pharmacokinetics of esomeprazole Medicinal products which inhibit CYP2C19 and/or CPY3A4 Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC of by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated. Medicinal products which induce CYP2C19 and/or CPY3A4 Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism. Paediatric population Interaction studies have only been performed in adults. <summary id="PREGNANCY" data-evt="smpcSectionOpen"

4.6. Fertility, pregnancy and lactation

Pregnancy

Clinical data on exposed pregnancies with esomeprazole are insufficient.

With the racemic mixture, omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of esomeprazole.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Breast-feeding

It is not known whether esomeprazole is excreted in human breast milk. There is insufficient information on the effects of esomeprazole in newborns/infants. Esomeprazole should not be used during breast-feeding.

Fertility

Animal studies with the racemic mixture omeprazole, given by oral administration, do not indicate effects with respect to fertility.

4.7. Effects on ability to drive and use machines

Esomeprazole has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (uncommon) have been reported (see section 4.8). If affected, patients should not drive or use machines.

4.8. Undesirable effects

Summary of the safety profile Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose-related adverse reactions have been identified. Tabulated list of adverse reactions The following adverse medicinal product reactions have been identified or suspected in the clinical trials programme for esomeprazole administered orally or intravenously and post-marketing when administered orally. The reactions are classified according to 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), not known (cannot be estimated from the available data) System Organ Class Frequency Undesirable effect Blood and lymphatic system disorders Rare Leukopenia, thrombocytopenia Very rare Agranulocytosis, pancytopenia Immune system disorders Rare Hypersensitivity reactions, e.g. fever, angioedema and anaphylactic reaction/shock Metabolic and Nutrition disorders Uncommon Peripheral oedema Rare Hyponatraemia Not known Hypomagnesaemia (see section 4.4); Severe hypomagnesaemia can correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia. Psychiatric disorders Uncommon Insomnia Rare Agitation, confusion, depression Very rare Aggression, hallucinations Nervous system disorders Common Headache Uncommon Dizziness, paraesthesia, somnolence Rare Taste disturbance Eye disorders Uncommon Blurred vision Ear and labyrinth disorders Uncommon Vertigo Respiratory, thoracic and mediastinal disorders Rare Bronchospasm Gastrointestinal disorders Common Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign) Uncommon Dry mouth Rare Stomatitis, gastrointestinal candidiasis Not known Microscopic colitis Hepatobiliary disorders Uncommon increased liver enzymes Rare Hepatitis with or without jaundice Very rare Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Common Administration site reactions* Uncommon Dermatitis, pruritus, rash, urticaria Rare Alopecia, photosensitivity Very rare Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) Not known Subacute cutaneous lupus erythematosus (see section 4.4) Musculoskeletal and connective tissue disorders Uncommon Fracture of the hip, wrist or spine (see section 4.4) Rare Arthralgia, myalgia Very rare muscular weakness Renal and urinary disorders Very rare Interstitial nephritis: in some patients, renal failure has been reported concomitantly. Reproductive system and breast disorders Very rare Gynaecomastia General disorders and administration site conditions Rare Malaise, increased sweating * Administration site reactions have mainly observed in a study with high-dose exposure over 3 days (72 hours) (see section 5.3). Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole (the racemate) intravenous injection, especially at high doses, but no causal relationship has been established. Paediatric population A randomized, open-label multi-national study was conducted to evaluate the pharmacokinetics of repeated intravenous doses for 4 days of once daily esomeprazole in paediatric patients 0 to18 years old (see section 5.2). A total of 57 patients (8 children in the age group 1-5 years) were included for safety evaluation. The safety results are consistent with the known safety profile of esomeprazole and no new safety signals were identified. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. <summary id="OVERDOSE" data-evt="smpcSectionOpen"

4.9. Overdose

There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280 mg were gastrointestinal symptoms and weakness. Single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg esomeprazole over 24 hours were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.