Nexipraz Iv 40 mg powder for solution for injection and infusion

NEXIPRAZ IV is indicated for gastro-oesophageal reflux disease (GORD) as an alternative to oral therapy in patients when oral therapy is not appropriate and for the shortest possible time. Gastro-oesophageal reflux disease (GORD):

• Treatment of erosive reflux oesophagitis
• Long-term management of patients with healed oesophagitis to prevent relapse
• Treatment of severe symptoms of reflux disease.

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

Posology

Adults: When oral therapy is possible or appropriate, intravenous therapy with NEXIPRAZ IV should be discontinued and the therapy should be continued orally.

Gastro-oesophageal reflux disease (GORD): Treatment with NEXIPRAZ IV can be given for up to 7 days as part of a full treatment period for the specified indications.

• 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 IV infusion of 8 mg/hour given over 3 days. The parenteral treatment period should be followed by acid-suppression therapy with 40 mg esomeprazole orally once daily for 4 weeks.

Special populations

• Elderly: Dose adjustment is not required in the elderly.
• 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.
• Hepatic impairment: Gastro-oesophageal reflux disease (GORD): Dose adjustment is not required in patients with mild to moderate liver impairment. Severe liver impairment (Child-Pugh class C): Maximum daily dose of 20 mg of NEXIPRAZ IV should not be exceeded. 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 of NEXIPRAZ IV, a continuous IV dose of 4 mg/hour may be sufficient to maintain adequate acid control.
• Paediatric population: NEXIPRAZ IV should not be used in children since no data are available.

Method of administration

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

Infusion: A solution for infusion is prepared by dissolving the content of 1 vial in up to 100 ml of 0,9 % sodium chloride for IV use. 40 mg dose: The reconstituted solution should be given as an IV infusion over a period of 10 u2013 30 minutes. 20 mg dose: Half of the reconstituted solution should be given as an IV 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 40 mg esomeprazole in up to 100 ml of 0,9 % sodium chloride for IV use. 80 mg bolus dose: The reconstituted solution containing 80 mg esomeprazole should be given as a continuous IV infusion over 30 minutes. 8 mg/hour dose: The reconstituted solution should be given as a continuous IV infusion over a period of 71.5 hours (calculated rate of infusion of 8 mg/hour). The degradation of the reconstituted solution is highly pH dependent and NEXIPRAZ IV must therefore only be reconstituted with 0,9 % sodium chloride for intravenous use according to the instructions above. The reconstituted solution should not be mixed or co-administered in the same infusion set with any other medicine.

• Hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of NEXIPRAZ IV (see section 2).
• Concomitant use with nelfinavir and atazanavir (see section 4.5)

In the presence of any alarming 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 NEXIPRAZ IV may alleviate symptoms and thereby delay diagnosis.

Concomitant administration of NEXIPRAZ IV with medicines such as atazanavir and nelfinavir is contraindicated (see section 4.5 and 4.3).

Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin.

During treatment with NEXIPRAZ IV serum gastrin increases, in response to the decreased acid secretion.

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

Absorption of vitamin B12: NEXIPRAZ IV 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: There have been reports of severe hypomagnesaemia in patients treated with proton pump inhibitors (PPIs) like NEXIPRAZ IV 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 NEXIPRAZ IV. If patients are expected to be on prolonged NEXIPRAZ IV treatment, or given NEXIPRAZ IV with digoxin or medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting NEXIPRAZ IV treatment and periodically during treatment.

Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors, such as NEXIPRAZ IV, are associated with rare cases of subacute cutaneous lupus erythematosus (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 discontinuation of NEXIPRAZ IV treatment should be considered. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Risk of fracture: NEXIPRAZ IV, especially if used in high doses and over long durations (> 1 year), increases the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors increase the overall risk of fracture by 10 u2013 40 %. Patients at risk of developing osteoporosis should be appropriately managed and they should have an adequate intake of vitamin D and calcium.

Clopidogrel: NEXIPRAZ IV is a CYP2C19 inhibitor. When starting or ending treatment with NEXIPRAZ IV, the potential for interactions with medicines metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and NEXIPRAZ IV. Concomitant use of NEXIPRAZ IV and clopidogrel should be discouraged, since the clinical relevance of this interaction is uncertain (see section 4.5).

Chromogranin A (CgA) measurements: NEXIPRAZ IV treatment may lead to an increased CgA level and interfere with investigations for neuroendocrine tumours. NEXIPRAZ IV treatment should be discontinued for at least 5 days before CgA measurements, in order to avoid this interaction. If CgA and gastrin levels have not returned to reference range after the initial measurement, measurements should be repeated 14 days after NEXIPRAZ IV treatment has been discontinued.

Renal Failure: Interstitial nephritis may progress to renal failure as it is not necessarily reversed when treatment is discontinued.

Paediatric population: NEXIPRAZ IV should not be used in children, since no data are available.

Effects of NEXIPRAZ IV on the pharmacokinetics of other medicines:

Protease inhibitors: Omeprazole has been reported to interact with some antiretroviral medicines. 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 antiretroviral medicine. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral medicines, e.g. atazanavir and nelfinavir, decreased serum levels have been reported when given together with esomeprazole and concomitant administration is not recommended. For other antiretroviral medicines, e.g. saquinavir, increased serum levels have been reported. There are also some antiretroviral medicines for which unchanged serum levels have been reported when given with omeprazole. Due to similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with NEXIPRAZ IV and antiretroviral medicines, e.g. atazanavir and nelfinavir is contraindicated (see section 4.3).

Methotrexate: There have been reports of increased methotrexate levels in some patients when NEXIPRAZ IV was co-administered with methotrexate. In high-dose methotrexate administration, a temporary withdrawal of NEXIPRAZ IV may need to be considered.

Tacrolimus: Concomitant administration of NEXIPRAZ IV with tacrolimus 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 it may be necessary to adjust the dosage of tacrolimus.

Medicines with pH dependent absorption: The absorption of ketoconazole, erlotinib and itraconazole can decrease, and the absorption of digoxin can increase during treatment with NEXIPRAZ IV.

Medicines metabolised by CYP2C19: NEXIPRAZ IV inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when NEXIPRAZ IV is combined with medicines metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicines may be increased and a dose reduction could be needed.

Diazepam: Concomitant 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.

Phenytoin: Concomitant 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 plasma concentrations of phenytoin when treatment with NEXIPRAZ IV is introduced or withdrawn.

Cilostazol: NEXIPRAZ IV acts as a CYP2C19 inhibitor and may increase AUC for cilostazol and one of its active metabolites.

Warfarin: Concomitant 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 is recommended when initiating and ending concomitant NEXIPRAZ IV treatment with warfarin or other coumarin derivatives.

Clopidogrel: Clopidogrel given concomitantly with NEXIPRAZ IV has shown a pharmacokinetic (PK)/ pharmacodynamic (PD) interaction between clopidogrel and NEXIPRAZ IV. Concomitant use of NEXIPRAZ IV with clopidogrel should be discouraged, as inconsistent data is available with regards to the clinical implications of this PK/PD interaction on cardiovascular events (see section 4.4).

Effects of other medicines on the pharmacokinetics of NEXIPRAZ IV:

Medicines which inhibit CYP2C19 and/or CYP3A4: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of NEXIPRAZ IV and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of NEXIPRAZ IV and a combined inhibitor of CYP2C19 and CYP3A4, e.g. voriconazole, may result in more than doubling of esomeprazole exposure. However, dose adjustment of NEXIPRAZ IV is not required in either of these situations. In patients with severe hepatic impairment, and if long-term treatment is indicated, dose adjustment should be considered.

Medicines which induce CYP2C19 and/or CYP3A4: Medicines known to induce CYP2C19 or CYP3A4 or both, such as St Johnu2019s wort and rifampicin, may lead to decreased serum levels of NEXIPRAZ IV by increasing the metabolism of NEXIPRAZ IV.

Investigated medicines with no clinically relevant interaction: Amoxicillin or quinidine: NEXIPRAZ IV has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine. Naproxen or rofecoxib: Studies evaluating concomitant administration of NEXIPRAZ IV and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Pregnancy: Limited clinical data on exposed pregnancies are available. A moderate amount of data on pregnant women (between 300 u2013 1 000 pregnancy outcomes) indicated no malformative or foeto/neonatal toxicity of NEXIPRAZ IV. However, caution should be exercised when prescribing NEXIPRAZ IV to pregnant women.

Breastfeeding: It is not known whether NEXIPRAZ IV is excreted in human breast milk. No studies in lactating women have been performed. Therefore, NEXIPRAZ IV should not be used during breastfeeding.

NEXIPRAZ IV may cause dizziness and blurred vision. Caution is advised before driving a vehicle or operating machinery until the effects of NEXIPRAZ IV are known.

b) Tabulated summary of adverse reactions

System organ class

Frequency

Adverse reactions

Blood and the lymphatic system disorders

Less frequent

Leucopenia, thrombocytopenia, agranulocytosis, pancytopenia

Immune system disorders

Less frequent

Hypersensitivity reactions e.g. angioedema and anaphylactic reaction/shock

Metabolism and nutrition disorders

Less frequent

Frequency unknown

Peripheral oedema, hyponatraemia

Hypomagnesaemia (Severe hypomagnesaemia can correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.)

Psychiatric disorders

Less frequent

Insomnia, agitation, confusion, depression, aggression, hallucinations

Nervous system disorders

Frequent

Less frequent

Headache

Dizziness, paraesthesia, somnolence, taste disturbance

Eye disorders

Less frequent

Blurred vision, eye disorders

Ear and labyrinth disorders

Less frequent

Vertigo, tinnitus

Cardiac disorders:

Frequency unknown

Angina, tachycardia, bradycardia

Respiratory, thoracic and mediastinal disorders

Less frequent

Bronchospasm, coughing

Gastrointestinal disorders

Frequent

Less frequent

Frequency unknown

Abdominal pain, diarrhoea, flatulence, nausea, vomiting, constipation

Dry mouth, stomatitis, gastrointestinal candidiasis, pancreatitis

Microscopic colitis

Hepato-biliary disorders

Less frequent

Increased liver enzymes, hepatitis with or without jaundice, hepatic failure, hepatic encephalopathy

Skin and subcutaneous tissue disorders:

Less frequent

Frequency unknown

Dermatitis, pruritus, urticaria, rash, alopecia, photosensitivity, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, bullous eruption

Subacute cutaneous lupus erythematosus

Musculoskeletal, connective tissue and bone disorders:

Less frequent

Arthralgia, myalgia, muscular weakness, fractures of the hip, wrist or spine, back pain

Renal and urinary disorders

Less frequent

Interstitial nephritis, urinary disorders, renal failure

Reproductive system and breast disorders

Less frequent

Gynaecomastia, impotence

General disorders and administrative site conditions

Frequent

Less frequent

Frequency unknown: Administration site reactions

Fatigue

Malaise, hyperhidrosis

Symptoms of overdosage may be an exaggeration and/or exacerbation of side effects. No specific antidote is known. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.