Nexiam 40 40 mg Powder for solution for injection and infusion.

NEXIAM 40 mg IV is indicated for Gastro-oesophageal reflux disease as an alternative where oral therapy is not appropriate and for the shortest possible time.

Gastro-oesophageal reflux disease:

• treatment of erosive reflux oesophagitis
• long-term management of patients with healed oesophagitis to prevent relapse
• treatment of severe symptoms of reflux disease

NEXIAM 40 mg IV is indicated for the short-term maintenance of haemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Posology

Adults: Gastro-oesophageal reflux disease (GORD): Treatment with NEXIAM 40 mg IV can be given for up to 7 days as part of a full treatment period for the specified indications. When oral therapy is possible or appropriate, intravenous therapy with NEXIAM 40 mg IV should be discontinued and the therapy should be continued orally.

Treatment of erosive reflux oesophagitis: 40 mg once daily. The duration of treatment should be 4 weeks. An additional 4 weeks treatment is recommended for patients in whom the oesophagitis has not healed or who have persistent symptoms.

Long-term management of patients with healed oesophagitis to prevent relapse and treatment of severe symptoms of reflux disease: 20 mg once daily.

Maintenance of haemostasis and prevention of rebleeding of gastric or duodenal ulcers: 80 mg administered as bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr given over 3 days. The parenteral treatment period should be followed by acid-suppression therapy with NEXIAM 40 mg once daily for 4 weeks.

Method of administration

NEXIAM 40 mg IV should be reconstituted with sodium chloride 0,9 % solution for injection/infusion before use. No other solvent should be used. To reduce contamination the product should be used immediately after reconstitution. If the entire reconstituted content of the vial is not required for a single dose, any unused reconstituted solution should be discarded. NEXIAM 40 mg IV is for single use in one patient only.

Injection (40 mg vial): A solution for injection is prepared by adding 5 mL of 0,9 % sodium chloride for intravenous use to the vial. 40 mg dose: The reconstituted solution should be given as an intravenous injection over a period of at least 3 minutes. 20 mg dose: Half of the reconstituted solution should be given as an intravenous injection over a period of approximately 3 minutes.

Infusion (40 mg vial): A solution for infusion is prepared by dissolving the contents of 1 vial in up to 100 mL 0,9 % sodium chloride for intravenous use. 40 mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10 u2013 30 minutes. 20 mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 u2013 30 minutes.

Continuous infusion (40 mg vial): A solution for infusion is prepared by dissolving the content of 2 vials of esomeprazole 40 mg in up to 100 mL of 0,9 % sodium chloride for intravenous use. 80 mg bolus dose: The reconstituted solution containing 80 mg esomeprazole should be given as an intravenous infusion over a period of 30 minutes. 8 mg/hour 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/hr).

• Known hypersensitivity to esomeprazole, to substituted benzimidazoles or to any of the excipients of NEXIAM 40 mg IV listed in section 6.1.
• Concomitant administration of esomeprazole with atazanavir or nelfinavir (see section 4.5).

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 NEXIAM 40 mg IV may alleviate symptoms and delay diagnosis.

Co-administration of clopidogrel and esomeprazole results in decreased exposure to the active metabolite of clopidogrel by an average of 40 %. The maximum inhibition of (ADP induced) platelet aggregation decreased by an average of 14 %. Based on these data, concomitant use of esomeprazole and clopidogrel should be avoided.

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 dysrhythmia 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 other medicines that may cause hypomagnesaemia (e.g. diuretics), the medical practitioner should consider measuring magnesium serum levels before starting PPI treatment and periodically during treatment.

Clostridium difficile is a bacteria that can cause severe debilitating diarrhoea, that does not improve. Symptoms may include watery stools, abdominal pain, fever, and patients may develop more serious intestinal conditions.

Concomitant administration with NEXIAM 40 mg IV and medicines such as atazanavir and nelfinavir is not recommended (see section 4.5). Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin.

Other effects related to acid inhibition: During treatment with NEXIAM 40 mg IV serum gastrin increases, in response to decreased acid secretion. During long-term oral treatment with NEXIAM 40 mg IV gastric glandular cysts occur. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign, and appear to be reversible.

Decreased gastric acidity due to any means including proton pump inhibitors such as NEXIAM 40 mg IV, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and also Clostridium difficile in hospitalised patients.

Proton pump inhibitor (PPI) therapy has a potential association with an increased risk of osteoporosis-related fractures, particularly with long-term use, potentially impacting the hip, spine, and wrist bones. The risk is more apparent in patients with secondary risk factors of osteoporosis, such as renal dysfunction. Patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.

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, 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 medical practitioner immediately when observing any indicative signs or symptoms. NEXIAM 40 mg IV 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/DRES.

Children: NEXIAM 40 mg IV should not be used in children since no data are available.

Effects of NEXIAM 40 mg IV on the pharmacokinetics of other medicines: The gastric acid suppression during treatment with NEXIAM 40 mg IV may decrease or increase the absorption of medicines with a gastric pH dependent absorption. Like with other medicines that decrease the intragastric acidity, the absorption of medicines such as ketoconazole, itraconazole and erlotinib can decrease while the absorption of medicines such as 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 2 out of 10 subjects). Digoxin toxicity has been reported. Caution should be exercised when NEXIAM 40 mg IV is given at high doses in elderly patients. Therapeutic monitoring of digoxin levels should be done.

The absorption of ketoconazole and itraconazole can decrease during treatment with NEXIAM 40 mg IV. NEXIAM 40 mg IV inhibits CYP2C19, the major esomeprazole metabolising enzyme. Concomitant oral administration of 30 mg esomeprazole resulted in a 45 % decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance. Concomitant oral administration of 40 mg esomeprazole resulted in a 13 % increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this study. It is recommended to monitor the plasma concentrations of phenytoin when treatment with NEXIAM 40 mg IV is introduced or withdrawn.

Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R-isomer of warfarin, the coagulation times were within the accepted range. However, from post-marketed use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring of the INR is recommended when warfarin is coadministered with NEXIAM at initiation of treatment, during the treatment and at ending treatment.

Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. 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 metabolites by 29 % and 69 % respectively.

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole 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. Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. When given together with PPIs, methotrexate levels have been reported to increase in some patients by up to three-fold. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.

Omeprazole has been reported to interact with some antiretroviral medicines. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral medicine. Other possible interaction mechanisms are via inhibition of CYP2C19. For some antiretroviral medicines, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. For other antiretroviral medicines, such as saquinavir, increased serum levels of 80 u2013 100 % have been reported. There are also some antiretroviral medicines for which unchanged serum levels have been reported when given with omeprazole. Close monitoring or dose alteration is recommended. Concomitant administration with NEXIAM 40 mg IV and antiretroviral medicines such as atazanavir and nelfinavir is not recommended. NEXIAM 40 mg IV substantially decreases the concentration of atazanavir and nelfinavir (see section 4.3).

Co-administration of NEXIAM (40 mg once daily) reduced mean nelfinavir exposure by approximately 40 % and the mean exposure of the pharmacologically active metabolite was reduced by approximately 75 u2013 90 %.

Tipranavir may decrease the concentration of NEXIAM 40 mg IV. Co-administration is not recommended. However, if used concurrently, the dose of NEXIAM 40 mg IV should be increased.

NEXIAM 40 mg IV has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

Effects of other medicines on the pharmacokinetics of NEXIAM 40 mg IV: NEXIAM 40 mg IV is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of NEXIAM 40 mg IV and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily) resulted in a doubling of the exposure (AUC) to NEXIAM 40 mg IV. Concomitant administration of NEXIAM 40 mg IV and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the NEXIAM 40 mg IV exposure. However, dose adjustment of NEXIAM 40 mg IV is not required in either of these situations. However, dose adjustment should be considered in patients with severe (Child-Pugh Class C) hepatic impairment and if on long-term treatment.

Voriconazole: Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C max and AUC t by 15 % and 41 %, respectively. Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. Johnu2019s wort (Hypericum perforatum)) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Pregnancy

For esomeprazole limited clinical data on exposed pregnancies are available.

Lactation

It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore, NEXIAM 40 mg IV should not be used during breastfeeding.

NEXIAM 40 mg IV may cause dizziness and blurred vision, thereby affecting the ability to drive or use machinery.

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 summary of adverse reactions

The following adverse reactions have been reported. The following definitions of frequency are used: Common: u2265 1/100; Uncommon: u2265 1/1000 and < 1/100; Rare: u2265 1/10 000 and < 1/1000; Very rare: < 1/10 000

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Rare Leukopenia, thrombocytopenia Very rare Agranulocytosis, pancytopenia

Immune system disorders Rare Hypersensitivity reactions e.g. angioedema and anaphylactic reaction/shock.

Metabolism and nutrition disorders Uncommon Peripheral oedema Rare Hyponatraemia Very rare Hypomagnesaemia (see section 4.4), severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.

Psychiatric disorders Uncommon Insomnia Rare Agitation, confusion, depression Very rare Aggression, hallucination

Nervous system disorders Common Headache Uncommon Dizziness, paraesthesia, somnolence Rare Taste disturbance

Eye disorders Rare Blurred vision

Ear and labyrinth disorders Uncommon Vertigo

Respiratory, thoracic and mediastinal disorders Rare Bronchospasm

Gastrointestinal disorders Common Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation Uncommon Dry mouth Rare Stomatitis, gastrointestinal candidiasis, gastrointestinal infections Very rare Microscopic colitis

Hepatobiliary disorders Uncommon Increased liver enzymes Rare Hepatitis with or without jaundice Very rare Hepatic failure, hepatic encephalopathy

Skin and subcutaneous tissue disorders Common Administration site reactions* Uncommon Dermatitis, pruritus, urticaria, rash Rare Alopecia, photosensitivity Very rare Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS)

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

Reproductive system and breast disorders Very rare Gynaecomastia

General disorders and administration site conditions Rare Malaise, hyperhidrosis

*Administration site reactions have mainly been observed in a study with high-dose exposure over 3 days (72 hours). In the non-clinical programme for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted. The non-clinical findings somewhat indicated that the clinical tissue irritation was concentration related.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of NEXIAM 40 mg IV is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.