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Medicines Q&As Q&A 41.6 How should continuous infusions of branded proton pump inhibitors be given for acute upper gastrointestinal bleeding? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: 7th October 2010BackgroundAcute upper gastrointestinal bleeding is associated with significant morbidity and mortality. In high-riskpatients, once the initial episode of bleeding has been controlled by endoscopic therapy, the goal is toprevent rebleeding and associated complications. The rebleeding rate after initial endoscopichaemostasis of upper gastrointestinal ulcers may be as high as 10% to 25% (1).Acid and pepsin impair the haemostatic process of ulcers and non-variceal upper gastrointestinallesions (1). It has been suggested that increasing and maintaining intragastric pH to ≥ 6.0 maydecrease the risk of rebleeding by increasing clot stability (2).Intravenous proton pump inhibitors (PPIs) have been shown to provide potent and long lasting acidsuppression, without the development of tolerance (1).AnswerIn the UK, intravenous formulations of omeprazole, pantoprazole and esomeprazole are currentlyavailable (3). Omeprazole and pantoprazole are not licensed to be given by continuous infusion (4,5).Intravenous esomeprazole is licensed for the prevention of rebleeding following therapeuticendoscopy for acute bleeding gastric or duodenal ulcers (6). No comparative studies of intravenousPPIs have been conducted in patients with peptic ulcer bleeding and therefore there is no efficacydata to recommend one PPI over another (2).DoseCurrent guidance from the Scottish Intercollegiate Guidelines Network (SIGN) recommends that “high-dose intravenous PPI therapy (e.g. omeprazole or pantoprazole 80mg bolus followed by 8mg/hourinfusion for 72 hours) should be used in patients with major peptic ulcer bleeding (active bleeding ornon-bleeding visible vessel) following endoscopic haemostatic therapy” (7). The British Society ofGastroenterology states that it has decided to commend the SIGN document and adopt it as astandard of care (8). International Consensus Recommendations advise the same regimen todecrease rebleeding and mortality in patients with high-risk stigmata who have undergone successfulendoscopic therapy (9).AdministrationThe administration details and stability data given below refer to the branded products stated.Omeprazole is available as Losec® intravenous infusion and Losec® IV injection, both as 40mg vials.The two preparations have different excipients and due to a lack of stability data the injection is notinterchangeable with the infusion. To avoid confusing the two varieties of the same injectable, theLosec® intravenous infusion preparation should be used for this indication.The exact administration details for the initial IV omeprazole 80mg dose followed by an 8mg/hourinfusion are not always stated in the published clinical trials. However, the BNF states thatomeprazole should be given as an initial intravenous infusion of 80mg over 40–60 minutes (3). Afterthe initial 80mg dose has been given, one 40mg intravenous infusion vial should be reconstituted withapproximately 5ml of sodium chloride 0.9%, immediately diluted to 100ml (4) and then administered ata rate of 8mg/hour, i.e. over 5 hours. This can then be repeated with a new vial each time until the 72 From the National Electronic Library for Medicines. www.nelm.nhs.uk 1
Medicines Q&Ashour period is completed. The manufacturer has information to show that the product is chemicallyand physically stable in sodium chloride 0.9% for 12 hours (4), and a published study shows stabilityfor up to 48 hours (10). Despite this the vial does not contain a preservative and the manufactureradvises from a microbiological point of view that the reconstituted solution should be used within 3hours (4). However none of the published studies that have utilised the omeprazole infusion regimenmake reference to limiting the infusion time to 3 hours.Pantoprazole is available as Protium® injection in a 40mg vial. Again, an 80mg injection is giveninitially, followed by a continuous infusion. For infusion one vial should be reconstituted with 10mlsodium chloride 0.9% and then further diluted with 100ml sodium chloride 0.9% or glucose 5%. TheSPC states that the reconstituted solution is chemically and physically stable for 12 hours (5), yet apublished study again shows chemical stability for up to 48 hours (10). However, note that the SPCalso states that, from a microbiological point of view, the reconstituted product should be usedimmediately. If not, in-use storage times and conditions prior to use are the responsibility of the user(5).In a pilot study, each 40mg pantoprazole vial was reconstituted with 10ml sodium chloride 0.9% andan initial bolus injection of 80mg (two reconstituted vials, total 20ml) was given intravenously over 2minutes. Following this initial dose, three reconstituted vials of 40mg pantoprazole in 30ml sodiumchloride 0.9% was infused, protected from direct light, at a constant rate of 8mg/hour and a freshsolution prepared every 12 hours until the end of the infusion (72 hours) (11). No stability data weregiven and this concentration of pantoprazole infusion is not licensed by the manufacturer.Esomeprazole is available as Nexium® IV 40mg powder for solution for injection/infusion. Followingtherapeutic endoscopy, 80mg should be administered intravenously over 30 minutes, followed by acontinuous intravenous infusion of 8mg/hour given over 71.5 hours (total infusion time is therefore 72hours). A solution for infusion of 80mg is prepared by dissolving the contents of two vials ofesomeprazole 40mg in up to 100ml of 0.9% sodium chloride for intravenous use. After reconstitution,chemical and physical in-use stability has been demonstrated for 12 hours at 30°C. From amicrobiological point of view, the product should be used immediately (6).Summary♦Current guidance recommends that high-dose intravenous PPI therapy (80mg bolus followed by8mg/hour infusion for 72 hours) should be used in patients with major peptic ulcer bleeding followingendoscopic haemostatic therapy (7,8,9).♦Omeprazole and pantoprazole are not licensed to be given by continuous intravenous infusion (4,5)and use in this way is therefore the responsibility of the prescribing physician. Intravenousesomeprazole is licensed for the prevention of rebleeding following therapeutic endoscopy for acutebleeding gastric or duodenal ulcers (6).♦After administration of the initial 80mg dose, the continuous infusion can be prepared byreconstituting a 40mg vial of either omeprazole (Losec® infusion) or pantoprazole (Protium®) andfurther diluting in 100ml of sodium chloride 0.9%. This can be given at a rate of 8mg/hour (i.e. over 5hours), and repeated with a fresh vial after that time. Depending on the host organisation’s attitude tomicrobiological stability, infusions could be made up and run over 24-48 hours if necessary sinceomeprazole (Losec®) and pantoprazole (Protium®) are chemically stable in sodium chloride 0.9% forthis period (10).♦After administration of the initial intravenous dose of 80mg esomeprazole, the contents of two 40mgvials of esomeprazole are dissolved in up to 100ml of 0.9% sodium chloride and given at a rate of8mg/hour (i.e. over 10 hours). This is repeated with fresh vials after that time (6).♦No comparative studies of intravenous PPIs have been conducted in patients with peptic ulcerbleeding and therefore there is no efficacy data to recommend one PPI over another (2). From the National Electronic Library for Medicines. www.nelm.nhs.uk 2
Medicines Q&AsLimitations♦This Q&A has concentrated on the technical details of how intravenous PPIs are given and not theevidence to support their use for the indications described, their relative efficacy, nor their safetyprofiles. A Cochrane review on this topic is currently being updated (12).♦The administration details and stability data included in this Q&A refer to the branded productsstated.♦Cost-effectiveness studies, the use of IV PPIs prior to endoscopy and studies in children have notbeen considered.♦Only the use of IV PPIs for the management of non-variceal upper gastrointestinal bleeding hasbeen addressed.Disclaimer • Medicines Q&As are intended for healthcare professionals and reflect UK practice. • Each Q&A relates only to the clinical scenario described. • Q&As are believed to accurately reflect the medical literature at the time of writing. • The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM. You must use your judgement to determine the accuracy and relevance of the information they contain. • See NeLM for full disclaimer.References(1) Kovacs TOG, Jensen DM. The short-term medical management of non-variceal upper gastrointestinal bleeding. Drugs 2008;68(15):2105-2111.(2) Bardou M, Martin J, Barkun A. Intravenous proton pump inhibitors. An evidence-based review of their use in gastrointestinal disorders. Drugs 2009;69(4):435-448.(3) British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. No 60. September 2010. Electronic edition. London: BMJ Publishing Group Ltd and RPS Publishing. Accessed via http://www.bnf.org/ on 13th October 2010.(4) Summary of Product Characteristics. Losec Infusion 40mg (omeprazole). AstraZeneca UK Ltd. Accessed via http://www.emc.medicines.org.uk/ on 19th October 2010. SPC last updated on the eMC on 21st February 2008.(5) Summary of Product Characteristics. Protium 40mg i.v. Powder for Solution for Injection (pantoprazole). Nycomed UK Ltd. Accessed via http://www.emc.medicines.org.uk/ on 19th October 2010. SPC last updated on the eMC on 6th September 2010.(6) Summary of Product Characteristics. Nexium I.V. 40mg Powder for solution for injection/infusion (esomeprazole). AstraZeneca UK Ltd. Accessed via http://www.emc.medicines.org.uk/ on 19th October 2010. SPC last updated on the eMC on 26th October 2009.(7) Scottish Intercollegiate Guidelines Network (SIGN). Management of acute upper and lower gastrointestinal bleeding A national clinical guideline. SIGN Guideline 105. September 2008. Accessed on 7th October 2010 via http://www.sign.ac.uk/pdf/sign105.pdf(8) British Society of Gastroenterology. Accessed via http://www.bsg.org.uk/clinical- guidelines/endoscopy/guidelines-for-non-variceal-upper-gastrointestinal-haemorrhage.html on 13th October 2010.(9) Barkun AN, Bardou M, Kuipers EJ et al for the International Consensus Upper Gastrointestinal Bleeding Conference Group. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010;152:101-113.(10)Carpenter JF, McNulty MA, Dusci LJ et al. Stability of omeprazole sodium and pantoprazole sodium diluted for intravenous infusion. Journal of Pharmaceutical Technology 2006;22: 95-98.(11)Van Rensburg CJ, Hartmann M, Thorpe A et al. Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer. Am J Gastroenterol 2003;98(12):2635-2641.(12) Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database of Systematic Reviews 2006, Issue 1. Art No:CD002094. DOI:10.1002/14651858.CD002094.pub3. Date of most recent amendment Nov 2005 (currently being updated). From the National Electronic Library for Medicines. www.nelm.nhs.uk 3
Medicines Q&AsQuality AssurancePrepared byKate Pickett (based in earlier work by Louisa Rowlands and Sandra Hicks), Medicines Q&APharmacist, Wessex Drug and Medicines Information Centre, Southampton University Hospitals NHSTrust.Date Prepared7th October 2010Checked bySue Gough, Critical Evaluation Pharmacist, Wessex Drug and Medicines Information Centre,Southampton University Hospitals NHS Trust.Date of check26th October 2010Search strategyMedline via NLH Search 2.0: [exp INFUSIONS, PARENTERAL/ OR exp INFUSIONS,INTRAVENOUS/] AND [exp OMEPRAZOLE/; OR pantoprazole.af OR esomeprazole.af]. Limits: H=Yand LG=EN since 01/01/2000.Embase via NLH Search 2.0: exp CONTINUOUS INFUSION/ AND exp PROTON PUMP INHIBITOR.Limits: H=Y and LG=EN.Manufacturer - AstraZeneca contacted via email on 19th October 2010.Electronic Medicines Compendium accessed via www.medicines.org.uk/emcNICE website accessed via www.nice.orgSIGN website accessed via www.sign.ac.ukNHS Evidence accessed via www.library.nhs.ukCochrane Database accessed via http://www.thecochranelibrary.com/view/0/index.htmlBritish Society of Gastroenterology website accessed via www.bsg.org.ukBNF No 60 September 2010 accessed via www.bnf.org From the National Electronic Library for Medicines. www.nelm.nhs.uk 4
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