Truloc Iv 40 mg Powder for solution for injection/infusion.

TRULOC IV 40 mg is indicated for:

• the treatment of 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
• the short - term maintenance of haemostasis
• the prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Posology

Adults: Gastro - oesophageal Reflux Disease (GORD) Treatment with TRULOC IV 40 mg 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 TRULOC IV 40 mg 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.

Symptomatic gastro - oesophageal reflux disease (GORD) If gastro - oesophageal reflux disease (GORD) symptom control has not been achieved after four weeks of treatment with the prescribed daily dose, especially where differentiation of diagnosis of GORD with angina and congestive heart failure is present, further investigation is recommended.

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

Special populations

Impaired renal function 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.

Impaired hepatic function Gastro - oesophageal reflux disease (GORD) Dose adjustment is not required in patients with mild to moderate liver impairment (Child - Pugh Class A, B). For patients with severe liver impairment (Child - Pugh Class C), a maximum daily dose of 20 mg TRULOC IV 40 mg 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 TRULOC IV 40 mg, a continuous intravenous infusion dose of 4 mg/hour may be sufficient to maintain adequate acid control.

Elderly Dose adjustment is not required in the elderly.

Paediatric population TRULOC IV 40 mg should not be used in children since no data are available.

Method of administration For instructions on reconstitution of the medicine before administration, see section 6.6.

Injection (40 mg 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) 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) 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/hour).

TRULOC IV 40 mg is contraindicated in:

• hypersensitivity to esomeprazole, substituted benzimidazoles or to any of the ingredients of TRULOC IV 40 mg (see section 6.1)
• patients treated concomitantly with nelfinavir or atazanavir (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 TRULOC IV 40 mg may alleviate symptoms and delay diagnosis. TRULOC IV 40 mg should be used with caution in hepatic impairment and dose adjustment may be required (see section 4.2). Concomitant administration with TRULOC IV 40 mg and medicines such as atazanavir and nelfinavir is contraindicated (see sections 4.3 and 4.5). Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin (see section 4.5). Occurrence of acute interstitial nephritis Acute interstitial nephritis has been observed in patients taking PPIs including TRULOC IV 40 mg. Acute interstitial nephritis may occur at any point during therapy, which may progress to acute kidney injury and/or chronic renal failure. Discontinue TRULOC IV 40 mg if acute interstitial nephritis develops.

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

Gastrointestinal infections Decreased gastric acidity due to any means, including proton pump inhibitors such as TRULOC IV 40 mg, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with TRULOC IV 40 mg may lead to increased risk of gastrointestinal infections, such as Salmonella and Campylobacter, Shigella and possibly also Clostridium difficile in hospitalised patients (see section 4.8).

Absorption of vitamin B 12 TRULOC IV 40 mg, as all acid - blocking medicines, may reduce the absorption of vitamin B 12 (cyanocobalamin) due to hypo - or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B 12 absorption on long - term therapy.

Hypomagnesaemia Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like TRULOC IV 40 mg, 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, including TRULOC IV 40 mg, with digoxin or medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting TRULOC IV 40 mg treatment and periodically during treatment.

Risk of fractures Proton pump inhibitors, including TRULOC IV 40 mg, especially if used in high doses and over long duration, 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 u2013 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 sub - acute 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 the healthcare professional should consider stopping TRULOC IV 40 mg. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Combination with other medicines Concomitant administration of clopidogrel and esomeprazole resulted 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 TRULOC IV 40 mg and clopidogrel should be avoided. Co - administration of esomeprazole with atazanavir is not recommended (see section 4.5). Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with medicines 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.

Interference with laboratory tests The increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, the esomeprazole treatment should be temporarily stopped 5 days before CgA measurements. 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 as in TRULOC IV 40 mg.

Paediatric population TRULOC IV 40 mg should not be used in children since no data are available.

Effects of other medicines on the pharmacokinetics of TRULOC IV 40 mg:

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 CYP 2C19.

Antiretroviral medicines 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, 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 have been reported.

There are also some antiretroviral medicines for which unchanged serum levels have been reported when given with omeprazole, including darunavir (with concomitant ritonavir), amprenavir (with concomitant ritonavir) and lopinavir (with concomitant ritonavir). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with TRULOC IV 40 mg and antiretroviral medicines such as atazanavir and nelfinavir is not recommended (see sections 4.3 and 4.4). Tipranavir may decrease the concentration of TRULOC IV 40 mg. Co - administration is not recommended. However, if used concurrently, the dose of TRULOC IV 40 mg should be increased.

Medicines with pH dependent absorption Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicines with a gastric pH dependent absorption. As with other medicines that decrease intragastric acidity, the absorption of medicines such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can increase during treatment with TRULOC IV 40 mg. 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 reported infrequently. However, caution should be exercised when TRULOC IV 40 mg is given at high doses in elderly patients. Therapeutic monitoring of digoxin should then be reinforced.

Medicines metabolised by CYP2C19 Esomeprazole inhibits CYP2C19, the major esomeprazole - metabolising enzyme. Thus, when esomeprazole 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. No in vivo interaction studies have been performed with the high dose intravenous regimen (80 mg+8 mg/h). The effect of esomeprazole on medicines 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 Esomeprazole 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. The interaction is unlikely to be of clinical relevance.

Phenytoin 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 TRULOC IV 40 mg is introduced or withdrawn.

Warfarin Concomitant oral administration of 40 mg esomeprazole to warfarin - treated patients showed that, despite a slight elevation in the trough plasma concentrations of 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 treatment with warfarin or other coumarin derivatives (see section 4.4).

Clopidogrel Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamics interaction between clopidogrel (300 mg loading dose / 75 mg daily maintenance dose) and esomeprazole (40 mg orally 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 %. Inconsistent data on the clinical implications of a pharmacokinetic/pharmacodynamic interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. The use of TRULOC IV 40 mg with clopidogrel should be discouraged.

Methotrexate When given together with proton pump inhibitors, including TRULOC IV 40 mg, methotrexate levels have been reported to increase in some patients. In high - dose methotrexate administration a temporary withdrawal of TRULOC IV 40 mg may need to be considered.

Tacrolimus Concomitant administration of TRULOC IV 40 mg 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.

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 metabolites by 29 % and 69 % respectively.

Cisapride 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. This interaction did not alter the influence of cisapride on cardiac electrophysiology.

Medicines 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 twice daily) resulted in a doubling of exposure (AUC) to esomeprazole. Concomitant administration of TRULOC IV 40 mg and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. However, dose adjustment of TRULOC IV 40 mg is not required in either of these situations. A dose adjustment should be considered in patients with severe hepatic impairment and if long - term treatment is indicated.

Medicines which induce CYP2C19 and/or CYP3A4 Medicines known to induce CYP2C19 or CYP34A or both (such as rifampicin and St. Johnu2019s wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism. Investigated medicines with no clinically relevant interaction Amoxicillin or quinidine TRULOC IV 40 mg 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 (non - selective NSAID) or rofecoxib (COX - 2 - selective NSAID) did not identify any clinically relevant interaction.

Paediatric population Interaction studies have only been performed in adults.

Pregnancy Limited clinical data on exposed pregnancies are available for esomeprazole. A moderate amount of data on pregnant women (between 300 - 1000 pregnancy outcomes) indicated no malformative or foeto/neonatal toxicity of esomeprazole. However, caution should be exercised when prescribing TRULOC IV 40 mg to pregnant women.

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

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

TRULOC IV 40 mg has minor influence on the ability to drive or use machines. Adverse reactions such as dizziness and blurred vision have been reported less frequently (see section 4.8). If affected, patients should not drive or use machines.

Summary of the safety profile Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been frequently reported.

Tabulated list of adverse effects The following adverse reactions have been reported:

* 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.

a. Description of selected adverse reactions 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who - umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms The symptoms described in connection with deliberate esomeprazole, as in TRULOC IV 40 mg, overdose (limited experience of oral doses in excess of 240 mg/day) are transient. Single oral doses of 80 mg and intravenous doses of 308 mg TRULOC IV 40 mg over 24 hours were uneventful.

Management of overdose 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.