4.1. Therapeutic indications

Esomeprazole 40 mg powder for solution for injection/infusion is indicated in adults for:

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

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

- healing of gastric ulcers associated with NSAID 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 40 mg powder for solution for injection/infusion 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.).

Patients with impaired hepatic function

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 for infusion, a continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient (see section 5.2).

Elderly

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.

4.3. Contraindications

Hypersensitivity to the active substance or to other 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).

4.4. Special warnings and precautions for use

In the presence of any alarm symptom (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 modestly increase the risk of hip, wrist and spine fracture, 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 health care 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 drugs 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 and 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.

This medicinal product contains 0.74 mmol sodium (or 17 mg) per maximum daily dose of esomeprazole, that is to say essentially 'sodium- free'.

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

Effects 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 the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the 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, Cmax and Cmin). 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 the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36–39% and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%. Due to similar pharmacodynamic 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-metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed. No in vivo interaction studies have been performed with the 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) Cmax and AUC 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 Cmax 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 halflife(t1/2) 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 + the 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 effects 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 CYP3A4

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 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 CYP3A4

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.

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/fetal 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 esomeprazole to pregnant women.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicated 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 program 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, <1/10; uncommon ≥1/1000, <1/100; rare ≥1/10,000, <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

Metabolism 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 been 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.

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, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 to 18 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.

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.