RANITIDINE AND OTHER HISTAMINE-H2-RECEPTOR ANTAGONISTS – A DRUG UTILISATION STUDY Main authors Katia Verhamme, MD, PhD Department of Medical Informatics EMC – Rotterdam Peter Rijnbeek, PhD Department of Medical Informatics EMC – Rotterdam Maria de Ridder, PhD Department of Medical Informatics EMC – Rotterdam Document Status Version 3.0 - Final Date of final version of the study 7th April 2020 report EU PAS register number EUPAS33397 1 Non-interventional PASS Ranitidine – Final Study Report Confidential Version 3.0 –2020 PASS information Title Ranitidine and other histamine H2-receptor antagonists – a drug utilisation study Report version identifier Version 3.0 Date of last version of protocol 2020-01-17 EU PAS register number EUPAS33397 Active Ingredient Ranitidine Cimetidine Famotidine Nizatidine Niperotidine Roxatidine Ranitidine bismuth citrate Lafutidine Medicinal product Ranitidine Product reference Not applicable Procedure number Not applicable Marketing authorisation holder(s) Not applicable Joint PASS Not applicable Research question and objectives Ranitidine is a competitive and reversible inhibitor of the action of histamine and indicated for the management of peptic ulceration, Gastro-Esophageal Reflux Disease (GERD), reflux oesophagitis and Zollinger-Ellison syndrome. Results of a preliminary laboratory analysis have shown the presence of N-Nitrosodimethylamine (NDMA), a human carcinogen, in ranitidine. With this drug utilisation study, we aim to determine drug utilisation and prescription patterns of medicinal products containing H2-receptor antagonists. These data will give insight on the number of patients using ranitidine and thus potentially at risk of NDMA. In particular we will: 1. Study the prevalence and incidence prescribing of H2-receptor antagonists as a class and by individual drug 2. Explore the characteristics of H2-receptor antagonist use with regard to age (10-years age 2 Non-interventional PASS Ranitidine – Final Study Report Confidential Version 3.0 –2020 categories), sex, formulation, daily dose, duration and cumulative exposure by class level and individual ingredient 3. Explore the indication of use of H2-receptor antagonist by class level, individual ingredient and by formulation 4. Explore the proportion of patients treated with H2-receptor antagonists suffering from chronic renal impairment by class level and by individual ingredient. Belgium, France, Germany, The Netherlands, UK, Country(-ies) of study Spain Katia Verhamme Department of Medical Informatics Author EMC Rotterdam – The Netherlands Marketing authorisation holder(s) Marketing authorisation holder(s) Not applicable MAH contact person Not applicable 3 Non-interventional PASS Ranitidine – Final Study Report Confidential Version 3.0 –2020 Table of contents 1 List of abbreviations ...................................................................................................................... 7 2 Abstract ......................................................................................................................................... 8 3 Investigators ................................................................................................................................ 12 4 Milestones ................................................................................................................................... 14 5 Rationale and background ........................................................................................................... 15 6 Research question and objectives ................................................................................................ 16 7 Amendments and updates to the protocol ................................................................................... 17 8 Research methods ........................................................................................................................ 18 8.1. Study design ............................................................................................................................ 18 8.2. Setting ..................................................................................................................................... 18 8.3. Variables ................................................................................................................................. 18 Drug Exposure............................................................................................................................. 18 Prevalent and incident use of H2-receptor antagonists ............................................................... 18 Duration of use of H2-receptor antagonists ................................................................................ 19 Dose of H2-receptor antagonists ................................................................................................. 20 Covariates .................................................................................................................................... 23 8.4. Data sources ............................................................................................................................ 24 8.5. Data management.................................................................................................................... 26 8.6. Data analysis ........................................................................................................................... 26 Handling of missing data............................................................................................................. 27 9 Protection of human subjects ...................................................................................................... 28 10 Results ......................................................................................................................................... 29 10.1. Number of patients during study period .............................................................................. 29 10.2. Incidence and prevalence of use of H2RA (by class and by individual drug) ..................... 29 Incident use of H2RA (by class and by individual drug) ................................................................... 29 Prevalent use of H2RA (by class and by individual drug) ................................................................. 32 10.3. Cumulative drug exposure of H2RA, ranitidine and other H2RA ....................................... 37 10.4. PDD/DDD ratio for H2RA as class, ranitidine and other H2RA ......................................... 44 10.5. Cumulative DDD for ranitidine and other H2RA ................................................................ 47 10.6. Cumulative dose in gram for H2RA, ranitidine and other individual H2RA ....................... 50 10.7. Cumulative dose in gram for ranitidine by ICH duration ................................................... 55 10.8. Cumulative annual dose for H2RA, ranitidine and other individual H2RA ........................ 57 10.9. Indication of use of H2RA, ranitidine and other individual H2RA...................................... 60 10.10. History of renal impairment in patients treated with H2RA, ranitidine and other individual H2RA 63 11 Discussion ................................................................................................................................... 64 12 Conclusions ................................................................................................................................. 66 13 References ................................................................................................................................... 67 Annex 1. List of stand-alone documents............................................................................................ 69 Annex 2. ENCePP checklist for study protocols ............................................................................... 70 Annex 3. DRUG_STRENGTH table ................................................................................................. 71 Annex 4. Concept Sets ....................................................................................................................... 73 1. DA-FRANCE ................................................................................................................................. 73 1.1. GERD ................................................................................................................................... 73 1.2. Gastric Or Duodenal Ulcer ................................................................................................... 73 1.3. Chronic Renal Impairment ................................................................................................... 74 2. DA-GERMANY ............................................................................................................................ 75 2.1. GERD ................................................................................................................................... 75 4 Non-interventional PASS Ranitidine – Final Study Report Confidential Version 3.0 –2020 2.2. Gastric Or Duodenal Ulcer ................................................................................................... 75 2.3. Chronic Renal Impairment ................................................................................................... 78 3. IMRD ............................................................................................................................................