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The European List of Essential Medicines for Medical Education, a Protocol for a Modified Delphi Study

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-045635 review only Article Type: Protocol

Date Submitted by the 08-Oct-2020 Author:

Complete List of Authors: Donker, Erik; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy Brinkman, David; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy Richir, Milan; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy Papaioannidou, Paraskevi; Aristotle University of Thessaloniki Faculty of Health Sciences, Department of Pharmacology, School of Medicine Likic, Robert; University of Zagreb School of Medicine; University Hospital Centre Zagreb, Unit of Pharmacology Sanz, Emilio ; Universidad de La Laguna, School of Health Science Christiaens, Thierry; Ghent University, Department of Clinical Pharmacology

Costa, Joao; University of Lisbon, Department of Pharmacology and http://bmjopen.bmj.com/ Clinical Pharmacology De Ponti, Fabrizio; University of Bologna, Department of Medical and Surgical Sciences Gatti, Milo; University of Bologna, Department of Medical and Surgical Sciences Böttiger, Ylva; Linkopings universitet, Department of Medical and Health Sciences Kramers, Cornelis; Radboud University Medical Center, Department of

Pharmacology-Toxicology on October 1, 2021 by guest. Protected copyright. Garners, Sarah; WHO Regional Office for Europe, Health Technologies and Pharmaceuticals Programme Pandit, Rahul; University Medical Centre Utrecht Brain Centre, Department of Translational Neuroscience van Agtmael, Michiel; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy Tichelaar, Jelle; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy

EDUCATION & TRAINING (see Medical Education & Training), MEDICAL Keywords: EDUCATION & TRAINING, THERAPEUTICS

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5 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 The European List of Essential Medicines for Medical Education, a Protocol for a Modified Delphi 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Study 6 7 8 Corresponding and principle author 9 Erik (Martin) Donker 10 Amsterdam UMC, location VUmc 11 Dept. Internal medicine, Section Pharmacotherapy 12 De Boelelaan 1117 13 1081HV Amsterdam 14 The Netherlands. 15 [email protected] 16 17 18 Co-authors and affiliationsFor peer review only 19 David J. Brinkman1,2 20 Milan C. Richir1,2 21 Paraskevi Papaioannidou3 22 Robert Likic4 23 Emilio J Sanz5 24 Thierry Christiaens6 25 7 26 João N Costa 8 27 Fabrizio De Ponti 28 Milo Gatti8 29 Ylva Böttiger9 30 Cornelis Kramers10 31 Sarah Garner11 32 Rahul Padit12 33 Michiel A van Agtmael1,2 34 1,2 35 Jelle Tichelaar 36 37 1 Department of Internal Medicine, section Pharmacotherapy, Amsterdam UMC, location VUmc, http://bmjopen.bmj.com/ 38 Amsterdam, Netherlands 39 40 2 Research and Expertise Centre in Pharmacotherapy Education (RECIPE), Amsterdam, The 41 Netherlands. 42 43 44 3 Department of Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University 45 of Thessaloniki, Thessaloniki, Greece. on October 1, 2021 by guest. Protected copyright. 46 47 4 Unit of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb 48 and University of Zagreb School of Medicine, Zagreb, Croatia 49 50 5 School of Health Science, Universidad de La Laguna, Tenerife, Spain. 51 52 6 Department of Clinical Pharmacology, Ghent University, Ghent, Belgium. 53 54 55 7 Department of Pharmacology and Clinical Pharmacology, University of Lisbon, Lisbon, Portugal 56 57 8 Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, 58 University of Bologna 59 60 9 Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

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1 2 3 10 Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The 4

Netherlands. BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 6 7 11 Health Technologies and Pharmaceuticals Programme, WHO Regional Office for Europe, WHO, 8 Copenhagen, Denmark. 9 10 12 Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center 11 Utrecht, Utrecht University, Utrecht, The Netherlands 12 13 Word count: 1414 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Abstract 6 7 8 Introduction 9 10 Junior doctors are responsible for a substantial number of prescribing errors, and final-year medical 11 12 students lack sufficient prescribing knowledge and skills just before they graduate. Various national 13 14 and international projects have been initiated to reform the teaching of clinical pharmacology and 15 16 17 therapeutics (CP&T) during undergraduate medical training. However, there is as yet no list of 18 For peer review only 19 commonly prescribed and available medicines that European doctors should be able to 20 21 independently prescribe safely and effectively without direct supervision. Such a list could form the 22 23 basis for a European Prescribing Exam and would harmonize European CP&T education. Therefore, 24 25 26 the aim of this study is to reach consensus on a list of widely prescribed medicines, available in most 27 28 EU countries, that European junior doctors should be able to independently prescribe safely and 29 30 effectively without direct supervision: The European List of Essential Medicines for Medical 31 32 Education. 33 34 35 Methods and analysis 36 37 This modified Delphi study will recruit European CP&T teachers (expert group). Two Delphi rounds http://bmjopen.bmj.com/ 38 39 will be carried out to enable a list to be drawn up of medicines that are available in ≥80% of 40 41 European countries, which are considered standard prescribing practice, and which junior doctors 42 43 should be able to prescribe safely and effectively without supervision. 44 45 on October 1, 2021 by guest. Protected copyright. 46 Ethics and dissemination 47 48 The study has been approved by the Medical Ethics Review Committee of VU University Medical 49 50 Center (no. 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical 51 52 Education (Approved Project no. NVMO-ERB 2020.4.8). The European List of Medicines for Medical 53 54 55 Education will be presented at national and international conferences and will be submitted to 56 57 international peer-reviewed journals. It will also be used to develop and implement the European 58 59 Prescribing Exam. 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Strengths and weaknesses of this study 6 7 8 - To our knowledge, this will be the first study to reach consensus on a European list of 9 10 essential medicines for medical education. 11 12 - The Delphi method is the most suitable method to reach consensus anonymously with a 13 14 large group of experts working in different countries. 15 16 17 - The European List of Essential Medicines for Medical Education will help to harmonize CP&T 18 For peer review only 19 education in Europe. 20 21 - There is already strong collaboration between EACPT and WHO Europe, and the members 22 23 are recognized experts in the field of CP&T education 24 25 26 - Recruiting a sufficient number of participants from all European countries will be a challenge. 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Introduction 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Prescribing is a core task of junior doctors, who are responsible for most hospital prescriptions.1 2 6 7 8 With an ever-expanding therapeutic arsenal and an increasing number of patients with comorbidity 9 10 and polypharmacy, safe and effective prescribing has become an increasingly complex task. 11 12 International studies have shown that junior doctors are responsible for a substantial number of 13 14 prescribing errors 1 3 and that at the time of graduation, junior doctors not only feel insufficiently 15 16 17 prepared to prescribe safely and effectively but also have insufficient knowledge and skills to 18 For peer review only 19 perform this task.4-8 20 21 This has prompted various national and international projects to reform teaching in clinical 22 23 pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. For example, in the 24 25 26 United Kingdom and the Netherlands a prescribing assessment has been introduced for final-year 27 28 students, to ensure that they have acquired the necessary knowledge before graduation.9-11 Other 29 30 European countries might benefit from a similar initiative. As many countries do not have the time 31 32 and resources to implement an assessment at a national level, we initiated an Erasmus+ project 33 34 35 (2019-1 - NL01 - KA203-060492) to develop, test, and implement a standardized prescribing 36 37 assessment on safe prescribing (including knowledge and skills) for undergraduate medical students http://bmjopen.bmj.com/ 38 39 studying at medical schools in the European Union (i.e. European Prescribing Exam (EuroPE+)). For 40 41 more information, see http://www.prescribingeducation.eu/. 42 43 The assessment will be based on the ‘essential diseases in prescribing’ derived from a Delphi 44 45 on October 1, 2021 by guest. Protected copyright. 12 46 consensus study held in 2018. However, there is no consensus list of medicines that European 47 48 junior doctors should be able to independently prescribe safely and effectively without direct 49 50 supervision. This list will form the basis of the European Prescribing Assessment (especially the skills 51 52 part), and together with country specific adjustments to reform educational programs in CP&T in all 53 54 55 European countries. This will complement the wish of the European Association for Clinical 56 57 Pharmacology and Therapeutics (EACPT) to harmonize European training in CP&T13 and will be 58 59 included in a future revision of the Guide to Good Prescribing of the World Health Organisation.14 60

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1 2 3 Previous studies of such lists have been based on the opinions of individuals or small groups of 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 experts or were specific to one country.15-18 Therefore, the aim of this study is to reach consensus on 6 7 8 a list of medicines that are widely prescribed and available in Europe and which European junior 9 10 doctors should be able to independently prescribe safely and effectively without direct supervision, 11 12 i.e. The European List of Essential Medicines for Medical Education. 13 14 15 16 17 Methods and analysis 18 For peer review only 19 A modified Delphi method will be used as it has been shown to be an effective and successful 20 21 method for reaching consensus on content of a CP&T curriculum.12 19-23 As the availability of 22 23 medicines differs between European countries, it is not possible to develop an all-encompassing list, 24 25 26 but one that can be considered as a basis for European CP&T education. Subsequently, each country 27 28 can adjust the list based on the availability of medicines in its country. The study will start in October 29 30 2020 and will comprise three phases: Phase 1, creating a drug list; selecting an European expert 31 32 panel; developing a web-based questionnaire in Castor EDC; Phase 2, sending a questionnaire to 33 34 35 appointed coordinators; Phase 3, Delphi consensus. 36 37 Patient and Public Involvement http://bmjopen.bmj.com/ 38 39 No patient involved. 40 41 Phase 1 42 43 Expert panel 44 45 on October 1, 2021 by guest. Protected copyright. 46 Through the Education Working Group of the European Association for Clinical Pharmacology and 47 48 Therapeutics (EACPT) and the affiliated Network of Teachers in Pharmacotherapy (NOTIP), all 49 50 coordinators (n= 393) from all European medical schools (n=297) who are responsible for teaching 51 52 CP&T to medical students will be approached to participate in the study. The coordinators will be 53 54 55 asked to participate in the study themselves and to select a group of experts within their own centre, 56 57 using the following criteria: 58 59 60

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1 2 3 - Two experienced (≥3 years of teaching experience) teachers explicitly engaged in CP&T 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 education for medical students, of which at least one teacher is registered as a clinical 6 7 8 pharmacologist; 9 10 - At least five medical specialists, preferably a surgeon (e.g. general surgeon); an internist (e.g. 11 12 general internist, gastroenterologists, pulmonologist, cardiologist); a general practitioner; a 13 14 specialist in geriatric medicine or geriatrician; 15 16 17 - Two recently graduated junior doctors (graduated ≤1 year ago) who prescribe drugs on a 18 For peer review only 19 daily basis. 20 21 There will be no restrictions regarding the work environment of the respondents (academic or 22 23 community hospitals). The principal investigator will invite the experts to participate via e-mail, 24 25 26 providing an information letter and a link to the online survey. Prior to participation, the experts will 27 28 be asked to sign a digital informed consent form. In total, we expect to recruit 200-250 experts. 29 30 Drug list 31 32 On the basis of the WHO Model List of Essential Medicines,24 guideline therapies for the ‘essential 33

34 15-18 + 35 diseases in prescribing’ (see appendix 1), a literature review, and a drug list from the EuroPE 36 25 37 project, a questionnaire will be developed regarding an extensive list of possible medicines that http://bmjopen.bmj.com/ 38 39 European junior doctors should be able to prescribe safely and effectively without supervision 40 41 directly after graduation (appendix 2). This list will be categorized into diseases. For each drug, the 42 43 most commonly used routes of administration will be listed separately. 44 45 on October 1, 2021 by guest. Protected copyright. 46 Phases 2 and 3 47 48 Study design and data collection 49 50 In phase 2, the coordinator(s) of each university will receive the list of medicines developed in phase 51 52 1 and will be asked to indicate which medicines are available in his or her country. On the basis of 53 54 55 this information, a second questionnaire will be drawn up consisting of the medicines that are 56 57 available in Europe. This questionnaire will be used for phase 3, a two-round Delphi study. In Round 58 59 1, all experts will be asked to evaluate two statements for each medicine (item): 1. ‘In my country, it 60

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1 2 3 is standard practice to prescribe this medicine to patients’; 2. ’A junior doctor should be able to 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 independently prescribe this medicine safely and effectively without direct supervision’. Respondents 6 7 8 will score both statements using a 5-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = neither 9 10 agree nor disagree; 4 = agree; 5 = strongly agree). Respondents will also be able to add missing 11 12 medicines that they consider should be included in Round 2, and to add arguments for their choices 13 14 in an open text box. 15 16 17 The questionnaire for Round 2 will have the same structure as in Round 1, but will also include the 18 For peer review only 19 average group score per medicine from Round 1, the suggested medicines, and the arguments for 20 21 their inclusion. The coordinator will be asked an additional question about the availability of the 22 23 suggested medicines in his or her country: ‘In my country, this medicine is available to prescribe to 24 25 26 patients’. 27 28 Statistics 29 30 A medicine will be included in the second questionnaire if that medicine is available in ≥80% of the 31 32 European countries. In accordance with previous studies,12 22 a medicine will be included in the final 33 34 35 European List of Essential Medicines for Medical Education if both statements about this medicine 36 37 are scored 4 or 5 by ≥80% of the respondents. If one statement about a medicine is scored 4 or 5 by http://bmjopen.bmj.com/ 38 39 ≥80% of the respondents but the other statement is scored 4 or 5 by ≥ 50% - <80% the respondents, 40 41 then this medicine will be reassessed in Delphi Round 2. This also applies to suggested medicines. 42 43 Medicines from Round 2 will be included in the European List of Essential Medicines for Medical 44 45 on October 1, 2021 by guest. Protected copyright. 46 Education if both statements regarding a medicine are given a score of 4 or 5 by ≥80% of the 47 48 respondents. Medicines suggested by respondents should also be available in ≥80% of European 49 50 countries. 51 52 Ethics and dissemination 53 54 55 Prior to participation, all experts will be asked to give their informed consent and provide the 56 57 following information: email address, medical school, profession with background, and years of 58 59 clinical and teaching experience. The data will be coded and stored for a maximum of 10 years in a 60

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1 2 3 secure folder on the hard disk of the Amsterdam UMC, location VUmc. Participation will not be 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 professionally advantageous or disadvantageous and there will be no compensation for participation. 6 7 8 Respondents can end their participation at any time, without giving a reason. The study has been 9 10 approved by the Medical Ethics Review Committee of Amsterdam UMC, location VUmc (no. 11 12 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education 13 14 (Approved Project no. NVMO-ERB 2020.4.8). 15 16 17 The results of the study will be presented at national and international conferences and will be 18 For peer review only 19 submitted to international peer-reviewed journals. The final European List of Essential Medicines for 20 21 Medical Education will be used to develop and implement the European Prescribing Exam. 22 23 24 25 26 References 27 28 1. Dornan T., Ashcroft D., Heathfield H., et al. An in depth investigation into causes of prescribing 29 errors by foundation trainees in relation to their medical education. EQUIP study. Available 30 at: http://www.gmc- 31 uk.org/FINAL_Report_prevalence_and_causes_of_prescribing_errors.pdf_28935150.pdf., 32 December 2009. 33 2. Ryan C, Ross S, Davey P, et al. Prevalence and causes of prescribing errors: the PRescribing 34 35 Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study. PLoS One 36 2014;9(1):e79802. doi: 10.1371/journal.pone.0079802 37 3. Lewis PJ, Dornan T, Taylor D, et al. Prevalence, incidence and nature of prescribing errors in http://bmjopen.bmj.com/ 38 hospital inpatients: a systematic review. Drug Saf 2009;32(5):379-89. doi: 39 10.2165/00002018-200932050-00002 [published Online First: 2009/05/08] 40 4. Han WH, Maxwell SR. Are medical students adequately trained to prescribe at the point of 41 graduation? Views of first year foundation doctors. Scott Med J 2006;51(4):27-32. doi: 42 10.1258/RSMSMJ.51.4.27 [published Online First: 2006/12/02] 43 5. Heaton A, Webb DJ, Maxwell SR. Undergraduate preparation for prescribing: the views of 2413 UK 44 45 medical students and recent graduates. British journal of clinical pharmacology on October 1, 2021 by guest. Protected copyright. 46 2008;66(1):128-34. doi: 10.1111/j.1365-2125.2008.03197.x [published Online First: 47 2008/05/22] 48 6. Rothwell C, Burford B, Morrison J, et al. Junior doctors prescribing: enhancing their learning in 49 practice. British journal of clinical pharmacology 2012;73(2):194-202. doi: 10.1111/j.1365- 50 2125.2011.04061.x [published Online First: 2011/07/15] 51 7. Brinkman DJ, Tichelaar J, Schutte T, et al. Essential competencies in prescribing: A first european 52 cross-sectional study among 895 final-year medical students. Clinical pharmacology and 53 54 therapeutics 2017;101(2):281-89. doi: 10.1002/cpt.521 [published Online First: 2016/09/21] 55 8. Brinkman DJ, Tichelaar J, Graaf S, et al. Do final-year medical students have sufficient prescribing 56 competencies? A systematic literature review. British journal of clinical pharmacology 57 2018;84(4):615-35. doi: 10.1111/bcp.13491 58 9. Kramers C, Janssen BJ, Knol W, et al. A Licence to Prescribe. British journal of clinical pharmacology 59 2017;83(8):1860-61. doi: 10.1111/bcp.13257 60

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1 2 3 10. Jansen DRM, Keijsers C, Kornelissen MO, et al. Towards a "prescribing license" for medical 4 students: development and quality evaluation of an assessment for safe prescribing. Eur J BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Clin Pharmacol 2019 doi: 10.1007/s00228-019-02686-1 [published Online First: 2019/05/20] 6 7 11. Maxwell SRJ, Cameron IT, Webb DJ. Prescribing safety: ensuring that new graduates are 8 prepared. Lancet 2015;385(9968):579-81. doi: 10.1016/S0140-6736(14)62339-4 [published 9 Online First: 2015/02/24] 10 12. Jansen BHE, Disselhorst GW, Schutte T, et al. Essential diseases in prescribing: A national Delphi 11 study towards a core curriculum in pharmacotherapy education. British journal of clinical 12 pharmacology 2018;84(11):2645-50. doi: 10.1111/bcp.13730 [published Online First: 13 2018/08/05] 14 13. Brinkman DJ, Tichelaar J, Okorie M, et al. Pharmacology and Therapeutics Education in the 15 European Union Needs Harmonization and Modernization: A Cross-sectional Survey Among 16 17 185 Medical Schools in 27 Countries. Clinical pharmacology and therapeutics 18 2017;102(5):815-22.For doi: peer 10.1002/cpt.682 review [published Online only First: 2017/03/16] 19 14. Tichelaar J, Richir MC, Garner S, et al. WHO guide to good prescribing is 25 years old: quo vadis? 20 European Journal of Clinical Pharmacology 2020;76(4):507-13. doi: 10.1007/s00228-019- 21 02823-w 22 15. Audi S, Burrage DR, Lonsdale DO, et al. The 'top 100' drugs and classes in England: an updated 23 'starter formulary' for trainee prescribers. British journal of clinical pharmacology 24 2018;84(11):2562-71. doi: 10.1111/bcp.13709 [published Online First: 2018/07/06] 25 26 16. Baker E, Roberts AP, Wilde K, et al. Development of a core drug list towards improving prescribing 27 education and reducing errors in the UK. British journal of clinical pharmacology 28 2011;71(2):190-8. doi: 10.1111/j.1365-2125.2010.03823.x [published Online First: 29 2011/01/12] 30 17. Ross S, Maxwell S. Prescribing and the core curriculum for tomorrow's doctors: BPS curriculum in 31 clinical pharmacology and prescribing for medical students. British journal of clinical 32 pharmacology 2012;74(4):644-61. doi: 10.1111/j.1365-2125.2012.04186.x [published Online 33 First: 2012/02/01] 34 35 18. Orme M, Frolich J, Vrhovac B, et al. Towards a core curriculum in clinical pharmacology for 36 undergraduate medical students in Europe. Eur J Clin Pharmacol 2002;58(9):635-40. doi: 37 10.1007/s00228-002-0531-9 [published Online First: 2002/12/17] http://bmjopen.bmj.com/ 38 19. Walley T, Webb DJ. Developing a core curriculum in clinical pharmacology and therapeutics: a 39 Delphi study. British journal of clinical pharmacology 1997;44(2):167-70. doi: 10.1046/j.1365- 40 2125.1997.00669.x [published Online First: 1997/08/01] 41 20. Ross S, Loke YK. Development of learning outcomes for an undergraduate prescribing curriculum 42 (British Pharmacological Society prescribing initiative). British journal of clinical 43 pharmacology 2010;70(4):604-8. doi: 10.1111/j.1365-2125.2009.03581.x [published Online 44 45 First: 2010/09/16] on October 1, 2021 by guest. Protected copyright. 46 21. Midlov P, Hoglund P, Eriksson T, et al. Developing a Competency-based Curriculum in Basic and 47 Clinical Pharmacology--A Delphi Study among Physicians. Basic Clin Pharmacol Toxicol 48 2015;117(6):413-20. doi: 10.1111/bcpt.12436 [published Online First: 2015/07/01] 49 22. Brinkman DJ, Tichelaar J, Mokkink LB, et al. Key Learning Outcomes for Clinical Pharmacology and 50 Therapeutics Education in Europe: A Modified Delphi Study. Clinical pharmacology and 51 therapeutics 2018;104(2):317-25. doi: 10.1002/cpt.962 [published Online First: 2017/12/06] 52 23. Brinkman D, Disselhorst G, Jansen B, et al. What Should Junior Doctors Know about the Drugs 53 54 they Frequently Prescribe? A Delphi Study among Physicians in the Netherlands. Basic Clin 55 Pharmacol Toxicol 2016;118(6):456-61. doi: 10.1111/bcpt.12508 [published Online First: 56 2015/10/28] 57 24. Organization WH. World Health Organization Model List of Essential Medicines, 21st List. Geneva, 58 2019. 59 25. European Prescribing Exam 2020 [Available from: 60 http://www.prescribingeducation.eu/european-prescribing-exam/.

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1 2 3 Authors’ contributions 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 ED, DB, MR and JT were involved in devising the study design and writing the protocol. 6 7 8 TC, YB, FD, RL, KK, JC, ES, PP, MvA MG, RP and SG have reviewed and approved the manuscript. 9 10 Funding statement 11 12 This work was supported by Erasmus+, grant number 2019-1 - NL01 - KA203-060492 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Appendix 1 4 5 All guideline medicines to treat the ‘essential diseases’, ordered alphabetically. When note down BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 7 more than once, means that there is more than one indication. 8 9 Acenocoumarol Diazepam 10 Acenocoumarol Diclofenac 11 Acetylsalicylic acid Diclofenac 12 Acetylsalysilic acid Diclofenac 13 Alendronic acid Diclofenac 14 Aluminium acetotartrate -eardrip Digoxin 15 Aluminum hydroxide/magnesium hydroxide Diltiazem 16 17 Amitriptyline Diltiazem 18 Amlodipine For peer reviewDipyridamole only 19 Amoxicillin Domperidone 20 Amoxicillin Domperidone 21 Amoxicillin Doxycycline 22 Amoxicillin Doxycycline 23 Amoxicillin/clavulanate Doxycycline 24 Amoxicillin/clavulanate Doxycycline 25 Amoxicillin/clavulanate Emollients (e.g. Cremor vaselini 26 27 Atorvastatin cetomacrogolis) 28 Azithromycin Emollients (e.g. Cremor vaselini 29 Azithromycin cetomacrogolis) 30 Azithromycin Emollients (e.g. Cremor vaselini 31 Azithromycin cetomacrogolis) 32 Azithromycin Enalapril 33 Beclometasone Epinephrine (adrenaline) 34 Betamethasone Epinephrine (adrenaline) 35 36 Butylscopolamine Esomeprazole 37 Carbasalate calcium Ethinylestradiol/levonorgestrel (oral) http://bmjopen.bmj.com/ 38 Chloramphenicol Etonogestrel (s.c. Implant) 39 Ciprofloxacin Ferrous fumarate 40 Citalopram Flucloxacillin 41 Clarithromycin Flucloxacillin 42 Clarithromycin Flucloxacillin 43 Claritromycin Fluconazole 44

Clemastine Fluticasone on October 1, 2021 by guest. Protected copyright. 45 46 Clemastine Fluticasone 47 Clomipramine Folic acid (vitamin b9) 48 Clopidogrel Formoterol 49 Clopidogrel Fosfomycin 50 Clotrimazole Fusidic acid 51 Codeine Gliclazide 52 Colchicine Glucagon 53 Colecalciferol (with/without) calcium Glucose solution 54 55 Desloratadine Glyceryl trinitrate (nitroglycerine) 56 Desloratadine Haloperidol 57 Desloratadine Hydrochlorothiazide 58 Desogestrel (oral) Hydrocortisone 59 Dexamethason Hydrocortisone 60 Dexamethason Hydrocortisone/acetic acid

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1 2 3 Hydroxocobalamin (vitamin b12) Omeprazole, pantoprazole, esomeprazole) 4 Ibuprofen Ors (oral rehydration solution) BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Ibuprofen Ors (oral rehydration solution) 6 7 Ibuprofen Oxazepam 8 Ibuprofen Oxycodone 9 Influenza vaccine Pantoprazole 10 Insulin aspart Paracetamol 11 Insulin glargine Paracetamol 12 Ipratropium bromide Paroxetine 13 Ipratropium bromide Perindopril 14 Isosorbide dinitrate Pheneticillin 15 Isosorbide mononitrate Pheneticillin 16 17 Ispaghula (psylla seeds) Pheneticillin 18 Lactulose For peer reviewPhenprocoumon only 19 Levocabastine Phenprocoumon 20 Levocetirizine Prednisolone 21 Levocetirizine Prednisolone 22 Levocetirizine Prednisolone 23 Levonorgestrel (iud) Prensisolone 24 Levothyroxine Propranolol 25 26 Lidocaine creme Ranitidine 27 Lisinopril Risedronic acid 28 Loperamide Rosuvastatin 29 Loperamide Salbutamol 30 Lorazepam Salbutamol 31 Losartan Salbutamol 32 Macrogol Salbutamol 33 Macrogol Salbutamol 34 Mebeverine Salbutamol 35 36 Medroxyprogesterone (s.c. Depot) Salmeterol 37 Menthol in aqueous cream Simvastatin http://bmjopen.bmj.com/ 38 Menthol in aqueous cream Sodium chloride solution 39 Metformin Spironolactone 40 Metocloperamide Temazepam 41 Metocloperamide Tetanus toxoid 42 Metoprolol Thiamine (vit b1) 43 Metoprolol Tiotropium bromide 44 45 Metronidazole Tramadol on October 1, 2021 by guest. Protected copyright. 46 Miconazol Triamcinolone 47 Midazolam (i.m.) Triamcinolone/acetic acid 48 Mometasone Trimethoprim 49 Nadroparin Trimethoprim/polymyxine b 50 Nadroparin Trimethoprim/sulfamethoxazole 51 Naproxen Trimethoprim/sulfamethoxazole 52 Naproxen Trimethoprim/sulfamethoxazole 53 54 Naproxen Verapamil 55 Naproxen Verapamil 56 Nitrofurantoin Xylometazoline nasalspray 57 Omeprazole Xylometazoline nasalspray 58 Omeprazole, pantoprazole Zolpidem 59 60

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1 2 3 Route of Route of Route of Route of 4 List of medicines administration administration administration administration 5 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Miconazole Oral 7 Aluminium hydroxide/magnesium 8 hydroxide Oral 9 Magnesium hydroxide Oral 10 Ranitidine Oral 11 12 Misoprostol Oral 13 Omeprazole Oral 14 Pantoprazole Oral 15 Esomeprazole Oral IV 16 17 Mebeverine Oral 18 Atropine For peerIV review only 19 Butylscopolamine Oral 20 Metoclopramide Oral IV Rectal 21 22 Domperidone Oral 23 Ondansetron Oral IV Rectal 24 Bisacodyl Oral Rectal 25 Ispaghula husk Oral 26 27 Lactulose Oral 28 Macrogol Oral 29 Nystatin Oral 30 Oral rehydration solution (ORS) Oral 31 32 Loperamide Oral 33 Insulin SC 34 Insulin aspart SC 35 Protamine (novomix) SC 36 37 Insulin glargine SC http://bmjopen.bmj.com/ 38 Metformin Oral 39 Gliclazide Oral 40 Glimepiride Oral 41 42 Acarbose Oral 43 Pioglitazone Oral 44 Sitagliptin Oral 45 on October 1, 2021 by guest. Protected copyright. Linagliptin Oral 46 47 Exenatide SC 48 Liraglutide SC 49 Canagliflozin Oral 50 Empagliflozin Oral 51 52 Repaglinide Oral 53 Cholecalciferol Oral 54 Thiamine (vit B1) Oral IV 55 Calcium/vitamin D Oral 56 57 Potassium chloride Oral 58 Fenprocoumon SC 59 Acenocoumarol SC 60 Heparin IV

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1 2 3 Enoxaparin SC 4

5 Nadroparin SC BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Clopidogrel Oral 7 Dipyridamole Oral 8 Carbasalate calcium Oral 9 10 Prasugrel Oral 11 Dabigatran Oral 12 Rivaroxaban Oral 13 Apixaban Oral 14 15 Fondaparinux SC IV 16 Tranexamic acid Oral IV 17 Vitamin K Oral IV 18 For peer review only Prothrombin complex concentrate IV 19 20 Ferrous fumarate Oral 21 Hydroxocobalamin (vitamin B12) SC IM 22 Folium acid (vitamin B9) Oral 23 Glucose solution IV 24 25 Potassium chloride IV 26 Digoxin Oral IV 27 Flecainide Oral 28 Amiodarone Oral IV 29 30 Epinephrine (adrenaline) IM 31 Nitroglycerine SL 32 Isosorbide dinitrate Oral SL 33 Isosorbide mononitrate Oral 34 35 Methyldopa Oral 36 Hydrochlorothiazide Oral http://bmjopen.bmj.com/ 37 Chlorthalidone Oral 38 Furosemide Oral IV 39 40 Bumetanide Oral IV 41 Spironolactone Oral 42 Propranolol Oral 43 Sotalol Oral 44 45 Metoprolol Oral IV on October 1, 2021 by guest. Protected copyright. 46 Atenolol Oral 47 Bisoprolol Oral 48 Labetolol Oral IV 49 50 Amlodipine Oral 51 Nifedipine Oral 52 Barnidipine Oral 53 Lercanidipine Oral 54 55 Nicardipine IV 56 Verapamil Oral IV 57 Diltiazem Oral 58 Enalapril Oral 59 60 Lisinopril Oral

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1 2 3 Perindopril Oral 4

5 Ramipril Oral BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Fosinopril Oral 7 Losartan Oral 8 Valsartan Oral 9 10 Irbesartan Oral 11 Candesartan Oral 12 Simvastatin Oral 13 Pravastatin Oral 14 15 Atorvastatin Oral 16 Rosuvastatin Oral 17 Gemfibrozil Oral 18 For peer review only Colestyramine Oral 19 20 Ezetimibe Oral 21 Evolocumab SC 22 Miconazole Cutaneous 23 Emollients (e.g. Cremor vaseline 24 cetomacrogolis) Cutaneous 25 26 Zink oxide Cutaneous 27 Vaseline and other Cutaneous 28 Lidocaine creme Cutaneous 29 Menthol in hydrophilic ointment Cutaneous 30 31 Fusidic acid Cutaneous 32 Hydrocortisone Cutaneous 33 Triamcinolone Cutaneous 34 Betamethasone Cutaneous 35 36 Mometasone Cutaneous 37 Clobetasole Cutaneous http://bmjopen.bmj.com/ 38 Clotrimazole Cutaneous 39 Miconazole Cutaneous 40 41 IUD with progestogen IUD 42 Ethinylestradiol/levonorgestrel Oral 43 Medroxyprogesterone (s.c. Depot) SC 44 Etonogestrel (s.c. Implant) SC

on October 1, 2021 by guest. Protected copyright. 45 46 Desogestrel Oral 47 Levonorgestrel Oral 48 Estradiol Oral 49 Oxybutynin Oral 50 51 Solifenacin Oral 52 Tamsulosin Oral 53 Finasteride Oral 54 Betamethasone Oral IV 55 56 Dexamethasone Oral IV 57 Prednisolone Oral IV 58 Hydrocortisone Oral IV 59 Levothyroxine Oral 60

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1 2 3 Glucagon IM 4

5 Doxycycline Oral BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Amoxicillin Oral IV 7 Feneticillin Oral IV 8 Flucloxacillin Oral IV 9 10 Amoxicillin/clavulanic acid Oral IV 11 Meropenem IV 12 Trimethoprim Oral 13 Co-trimoxazole Oral IV 14 15 Trimethoprim/sulfametoxazole Oral IV 16 Erythromycin Oral IV 17 Clarithromycin Oral IV 18 For peer review only Azithromycin Oral IV 19 20 Gentamycin IV 21 Ciprofloxacin Oral IV 22 Vancomycin IV 23 Fusidic acid Oral 24 25 Nitrofurantoin Oral 26 Fosfomycin Oral 27 Fluconazole Oral IV 28 Rifampicin Oral IV 29 30 Acyclovir Oral IV 31 Valaciclovir Oral 32 Oseltamivir Oral 33 Tetanus toxoid IM 34 35 Methotrexate Oral IV IM SC 36 Diclofenac Oral http://bmjopen.bmj.com/ 37 Ibuprofen Oral 38 Naproxen Oral 39 40 Ibuprofen Cutaneous 41 Diclofenac Cutaneous 42 Allopurinol Oral 43 Colchicine Oral 44 45 Alendronic acid Oral on October 1, 2021 by guest. Protected copyright. 46 Risedronic acid Oral 47 Denosumab SC 48 Fentanyl IV 49 50 Lidocaine SC 51 Epinephrine (adrenaline) SC 52 Morphine Oral IV SC 53 Oxycodone Oral SC 54 55 Fentanyl Oral Cutaneous Nasal SL 56 Tramadol Oral Rectal 57 Piritramide SC 58 Acetylsalicylic acid Oral IV 59 60 Calcium carbasalate Oral IV

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1 2 3 Paracetamol Oral IV Rectal 4

5 Sumatriptan Oral Nasal SC BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Valproic acid Oral IV 7 Levetiracetam Oral IV 8 Pregabalin Oral IV 9 10 Haloperidol Oral IV 11 Clozapine Oral 12 Olanzapine Oral 13 Quetiapine Oral 14 15 Lithium Oral 16 Risperidone Oral IM 17 Diazepam Oral Rectal 18 For peer review only Oxazepam Oral 19 20 Lorazepam Oral IM IV 21 Temazepam Oral 22 Midazolam Oral IV 23 Zolpidem Oral 24 25 Clomipramine Oral 26 Amitriptyline Oral 27 Nortriptyline Oral 28 Fluoxetine Oral 29 30 Citalopram Oral 31 Paroxetine Oral 32 Sertraline Oral 33 Escitalopram Oral 34 35 Mirtazapine Oral 36 Venlafaxine Oral http://bmjopen.bmj.com/ 37 Metronidazole Oral IV 38 Xylometazoline Nasal 39 40 Levocabastine Ocular 41 Beclomethasone Nasal 42 Budesonide Nasal 43 Mometasone Nasal 44 45 Fluticasone Nasal on October 1, 2021 by guest. Protected copyright. 46 Salbutamol Inhalation 47 Salmeterol Inhalation 48 Formoterol Inhalation 49 50 Beclometasone Inhalation 51 Budesonide Inhalation 52 Fluticasone Inhalation 53 Ciclesonide Inhalation 54 55 Ipratropium bromide Inhalation 56 Tiotropium bromide Inhalation 57 Tiotropium Inhalation 58 Codeine Oral 59 60 Clemastine Oral IV

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1 2 3 Meclozine Oral 4

5 Levocetirizine Oral BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Desloratadine Oral 7 Chloramphenicol Ocular 8 Fusidic acid Ocular 9 10 Erythromycin Ocular 11 Trimethoprim/polymyxin B Ocular 12 Dexamethasone (Ocular) Ocular 13 Prednisolone (Ocular) Ocular 14 15 Levocabastine Ocular 16 Aluminium acetate Ear 17 Miconazole Oral 18 For peer review only Hydrocortisone/acetic acid Ear 19 20 Triamcinolone/acetic acid Ear 21 Protamine IV 22 Naloxone IV 23 Flumazenil IV 24 25 Ticagrelor Oral IV 26 Cefuroxime IV 27 Cefotaxime IV 28 Ceftriaxone IV 29 30 Ceftazidime IV 31 Clindamycin Oral IV 32 Sodium chloride IV 33 Ringer’s lactate IV 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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The European List of Essential Medicines for Medical Education, a Protocol for a Modified Delphi Study

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-045635.R1 review only Article Type: Protocol

Date Submitted by the 03-Mar-2021 Author:

Complete List of Authors: Donker, Erik; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy; Research and Expertise Centre in Pharmacotherapy Education (RECIPE) Brinkman, David; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy; Research and Expertise Centre in Pharmacotherapy Education (RECIPE) Richir, Milan; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy; Research and Expertise Centre in Pharmacotherapy Education (RECIPE) Papaioannidou, Paraskevi; Aristotle University of Thessaloniki Faculty of Health Sciences, Department of Pharmacology, School of Medicine Likic, Robert; University of Zagreb School of Medicine; University Hospital Centre Zagreb, Department of Internal Medicine, Unit of Clinical

Pharmacology http://bmjopen.bmj.com/ Sanz, Emilio ; Universidad de La Laguna, School of Health Science Christiaens, Thierry; Ghent University, Department of Clinical Pharmacology Costa, Joao; University of Lisbon, Department of Pharmacology and Clinical Pharmacology De Ponti, Fabrizio; University of Bologna, Department of Medical and Surgical Sciences, Pharmacology Unit Gatti, Milo; University of Bologna, Department of Medical and Surgical

Sciences, Pharmacology Unit on October 1, 2021 by guest. Protected copyright. Böttiger, Ylva; Linkopings universitet, Department of Medical and Health Sciences Kramers, Cornelis; Radboud University Medical Center, Department of Internal Medicine and Pharmacology-Toxicology Garners, Sarah; WHO Regional Office for Europe, Health Technologies and Pharmaceuticals Programme Pandit, Rahul; University Medical Centre Utrecht Brain Centre, Department of Translational Neuroscience van Agtmael, Michiel; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy; Research and Expertise Centre in Pharmacotherapy Education (RECIPE) Tichelaar, Jelle; Amsterdam UMC Locatie VUmc, Department of Internal Medicine, section Pharmacotherapy; Research and Expertise Centre in Pharmacotherapy Education (RECIPE)

Primary Subject Medical education and training Heading:

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1 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 2 3 Secondary Subject Heading: Pharmacology and therapeutics 4 5 EDUCATION & TRAINING (see Medical Education & Training), MEDICAL Keywords: 6 EDUCATION & TRAINING, THERAPEUTICS 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on October 1, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 19

1 2 3 4

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1 2 3 10 Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The 4

Netherlands. BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 6 7 11 Health Technologies and Pharmaceuticals Programme, WHO Regional Office for Europe, WHO, 8 Copenhagen, Denmark. 9 10 12 Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center 11 Utrecht, Utrecht University, Utrecht, The Netherlands 12 13 Word count: 1504 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Introduction 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Prescribing is a core task of junior doctors, who are responsible for most hospital prescriptions.1 2 6 7 8 With an ever-expanding therapeutic arsenal and an increasing number of patients with comorbidity 9 10 and polypharmacy, safe and effective prescribing has become an increasingly complex task. 11 12 International studies have shown that junior doctors are responsible for a substantial number of 13 14 prescribing errors 1 3 and that at the time of graduation, junior doctors not only feel insufficiently 15 16 17 prepared to prescribe safely and effectively but also have insufficient knowledge and skills to 18 For peer review only 19 perform this task.4-8 20 21 This has prompted various national and international projects to reform teaching in clinical 22 23 pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. For example, in the 24 25 26 United Kingdom and the Netherlands a prescribing assessment has been introduced for final-year 27 28 students, to ensure that they have acquired the necessary knowledge before graduation.9-11 Other 29 30 European countries might benefit from a similar initiative. As many countries do not have the time 31 32 and resources to implement an assessment at a national level, we initiated an Erasmus+ project 33 34 35 (2019-1 - NL01 - KA203-060492) to develop, test, and implement a standardized prescribing 36 37 assessment on safe prescribing (including knowledge and skills) for undergraduate medical students http://bmjopen.bmj.com/ 38 39 studying at medical schools in the European Union (i.e. European Prescribing Exam (EuroPE+)). For 40 41 more information, see http://www.prescribingeducation.eu/. 42 43 The assessment will be based on the ‘essential diseases in prescribing’ derived from a Delphi 44 45 on October 1, 2021 by guest. Protected copyright. 12 46 consensus study held in 2018. However, there is no consensus list of medicines that European 47 48 junior doctors should be able to independently prescribe safely and effectively without direct 49 50 supervision. This list will form the basis of the European Prescribing Exam (especially the skills part), 51 52 and together with country specific adjustments to reform educational programs in CP&T in all 53 54 55 European countries. This will complement the wish of the European Association for Clinical 56 57 Pharmacology and Therapeutics (EACPT) to harmonize European training in CP&T13 and will be 58 59 included in a future revision of the Guide to Good Prescribing of the World Health Organisation.14 60

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1 2 3 Previous studies of such lists have been based on the opinions of individuals or small groups of 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 experts or were specific to one country.15-18 Therefore, the aim of this study is to reach consensus on 6 7 8 a list of medicines that are widely prescribed and available in Europe and which European junior 9 10 doctors should be able to independently prescribe safely and effectively without direct supervision, 11 12 i.e. The European List of Essential Medicines for Medical Education. 13 14 15 16 17 Methods and analysis 18 For peer review only 19 A modified Delphi method will be used as it has been shown to be an effective and successful 20 21 method for reaching consensus on content of a CP&T curriculum.12 19-23 As the availability of 22 23 medicines differs between European countries, it is not possible to develop an all-encompassing list, 24 25 26 but one that can be considered as a basis for European CP&T education. Subsequently, each country 27 28 can adjust the list based on the availability of medicines in its country. The study will start in October 29 30 2020 and will comprise three phases: Phase 1, creating a drug list; selecting an European expert 31 32 panel; developing a web-based questionnaire in Castor EDC; Phase 2, sending a questionnaire to 33 34 35 appointed coordinators; Phase 3, Delphi consensus. 36 37 Patient and Public Involvement http://bmjopen.bmj.com/ 38 39 No patient involved. 40 41 Phase 1 42 43 Drug list 44 45 on October 1, 2021 by guest. Protected copyright. 24 46 On the basis of the WHO Model List of Essential Medicines, guideline therapies for the ‘essential 47 48 diseases in prescribing’ (see appendix 1), a literature review,15-18 and a drug list from the EuroPE+ 49 50 project,25 a questionnaire will be developed regarding an extensive list of possible medicines that 51 52 European junior doctors should be able to prescribe safely and effectively without supervision 53 54 55 directly after graduation (appendix 2). This list will be categorized into diseases. For each drug, the 56 57 most commonly used routes of administration will be listed separately. 58 59 60

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1 2 3 Expert panel 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Through the Education Working Group of the European Association for Clinical Pharmacology and 6 7 8 Therapeutics (EACPT) and the affiliated Network of Teachers in Pharmacotherapy (NOTIP), all 9 10 coordinators (n= 393) from all European medical schools (n=297) who are responsible for teaching 11 12 CP&T to medical students will be approached to participate in the study. The coordinators will be 13 14 asked to participate in the study themselves and to select a group of experts within their own centre, 15 16 17 using the following criteria: 18 For peer review only 19 - Two experienced (≥3 years of teaching experience) teachers explicitly engaged in CP&T 20 21 education for medical students, of which at least one teacher is registered as a clinical 22 23 pharmacologist; 24 25 26 - At least five healthcare professionals, preferably a surgeon (e.g. general surgeon); an 27 28 internist (e.g. general internist, gastroenterologists, pulmonologist, cardiologist); a general 29 30 practitioner; a specialist in geriatric medicine or geriatrician; a (hospital)pharmacist; 31 32 - Two recently graduated junior doctors (graduated ≤1 year ago) who prescribe drugs on a 33 34 35 daily basis. 36 37 There will be no restrictions regarding the work environment of the respondents (academic or http://bmjopen.bmj.com/ 38 39 community hospitals). The principal investigator will invite the experts to participate via e-mail, 40 41 providing an information letter and a link to the online survey. Prior to participation, the experts will 42 43 be asked to sign a digital informed consent form. 44 45 on October 1, 2021 by guest. Protected copyright. 22 26 46 Based on previous studies with this dedicated group of experts, we expect a response rate of 25% 47 48 for the coordinators, representing all European countries. Assuming 5-6 recruited experts per 49 50 coordinator and a response rate of 25% as well, we expect in total 200-250 experts to complete the 51 52 study.” 53 54 55 Phases 2 and 3 56 57 Study design and data collection 58 59 60

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1 2 3 In phase 2, the coordinator(s) of each university will receive the list of medicines developed in phase 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 1 and will be asked to indicate which medicines are available in his or her country. On the basis of 6 7 8 this information, a second questionnaire will be drawn up consisting of the medicines that are 9 10 available in Europe. This questionnaire will be used for phase 3, a two-round Delphi study. In Round 11 12 1, all experts will be asked to evaluate two statements for each medicine (item): 1. ‘In my country, it 13 14 is standard practice to prescribe this medicine to patients’; 2. ’A junior doctor should be able to 15 16 17 independently prescribe this medicine safely and effectively without direct supervision’. Respondents 18 For peer review only 19 will score both statements using a 5-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = neither 20 21 agree nor disagree; 4 = agree; 5 = strongly agree). Respondents will also be able to add missing 22 23 medicines that they consider should be included in Round 2, and to add arguments for their choices 24 25 26 in an open text box. 27 28 The questionnaire for Round 2 will have the same structure as in Round 1, but will also include the 29 30 average group score per medicine from Round 1, the suggested medicines, and the arguments for 31 32 their inclusion. The coordinator will be asked an additional question about the availability of the 33 34 35 suggested medicines in his or her country: ‘In my country, this medicine is available to prescribe to 36 37 patients’. http://bmjopen.bmj.com/ 38 39 In order to minimize participant drop-out, the list of medicines will be structured and participants are 40 41 allowed to complete a portion of the survey and return later to finish the remaining part. The list 42 43 must be completed within two weeks, a reminder will be send after one week. 44 45 on October 1, 2021 by guest. Protected copyright. 46 Statistics 47 48 A medicine will be included in the second questionnaire if that medicine is available in ≥80% of the 49 50 European countries. In accordance with previous studies,12 22 a medicine will be included in the final 51 52 European List of Essential Medicines for Medical Education if both statements about this medicine 53 54 55 are scored 4 or 5 by ≥80% of the respondents. If one statement about a medicine is scored 4 or 5 by 56 57 ≥80% of the respondents but the other statement is scored 4 or 5 by ≥ 50% - <80% the respondents, 58 59 then this medicine will be reassessed in Delphi Round 2. This also applies to suggested medicines. 60

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1 2 3 Medicines from Round 2 will be included in the European List of Essential Medicines for Medical 4 BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Education if both statements regarding a medicine are given a score of 4 or 5 by ≥80% of the 6 7 8 respondents. Medicines suggested by respondents should also be available in ≥80% of European 9 10 countries. 11 12 13 14 Ethics and dissemination 15 16 17 Prior to participation, all experts will be asked to give their informed consent and provide the 18 For peer review only 19 following information: email address, medical school, profession with background, and years of 20 21 clinical and teaching experience. The data will be coded and stored for a maximum of 10 years in a 22 23 secure folder on the hard disk of the Amsterdam UMC, location VUmc. Participation will not be 24 25 26 professionally advantageous or disadvantageous and there will be no compensation for participation. 27 28 Respondents can end their participation at any time, without giving a reason. The study has been 29 30 approved by the Medical Ethics Review Committee of Amsterdam UMC, location VUmc (no. 31 32 2020.335) and by the Ethical Review Board of the Netherlands Association for Medical Education 33 34 35 (Approved Project no. NVMO-ERB 2020.4.8). 36 37 The results of the study will be presented at national and international conferences and will be http://bmjopen.bmj.com/ 38 39 submitted to international peer-reviewed journals. The final European List of Essential Medicines for 40 41 Medical Education will be used to develop and implement the European Prescribing Exam. 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 References 47 48 1. Dornan T., Ashcroft D., Heathfield H., et al. An in depth investigation into causes of prescribing 49 errors by foundation trainees in relation to their medical education. EQUIP study. Available 50 at: http://www.gmc- 51 uk.org/FINAL_Report_prevalence_and_causes_of_prescribing_errors.pdf_28935150.pdf., 52 December 2009. 53 54 2. Ryan C, Ross S, Davey P, et al. Prevalence and causes of prescribing errors: the PRescribing 55 Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study. PLoS One 56 2014;9(1):e79802. doi: 10.1371/journal.pone.0079802 57 3. Lewis PJ, Dornan T, Taylor D, et al. Prevalence, incidence and nature of prescribing errors in 58 hospital inpatients: a systematic review. Drug Saf 2009;32(5):379-89. doi: 59 10.2165/00002018-200932050-00002 [published Online First: 2009/05/08] 60

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1 2 3 4. Han WH, Maxwell SR. Are medical students adequately trained to prescribe at the point of 4 graduation? Views of first year foundation doctors. Scott Med J 2006;51(4):27-32. doi: BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 10.1258/RSMSMJ.51.4.27 [published Online First: 2006/12/02] 6 7 5. Heaton A, Webb DJ, Maxwell SR. Undergraduate preparation for prescribing: the views of 2413 UK 8 medical students and recent graduates. British journal of clinical pharmacology 9 2008;66(1):128-34. doi: 10.1111/j.1365-2125.2008.03197.x [published Online First: 10 2008/05/22] 11 6. Rothwell C, Burford B, Morrison J, et al. Junior doctors prescribing: enhancing their learning in 12 practice. British journal of clinical pharmacology 2012;73(2):194-202. doi: 10.1111/j.1365- 13 2125.2011.04061.x [published Online First: 2011/07/15] 14 7. Brinkman DJ, Tichelaar J, Schutte T, et al. Essential competencies in prescribing: A first european 15 cross-sectional study among 895 final-year medical students. Clinical pharmacology and 16 17 therapeutics 2017;101(2):281-89. doi: 10.1002/cpt.521 [published Online First: 2016/09/21] 18 8. Brinkman DJ, TichelaarFor J, Graaf peer S, et al. Do review final-year medical onlystudents have sufficient prescribing 19 competencies? A systematic literature review. British journal of clinical pharmacology 20 2018;84(4):615-35. doi: 10.1111/bcp.13491 21 9. Kramers C, Janssen BJ, Knol W, et al. A Licence to Prescribe. British journal of clinical pharmacology 22 2017;83(8):1860-61. doi: 10.1111/bcp.13257 23 10. Jansen DRM, Keijsers C, Kornelissen MO, et al. Towards a "prescribing license" for medical 24 students: development and quality evaluation of an assessment for safe prescribing. Eur J 25 26 Clin Pharmacol 2019 doi: 10.1007/s00228-019-02686-1 [published Online First: 2019/05/20] 27 11. Maxwell SRJ, Cameron IT, Webb DJ. Prescribing safety: ensuring that new graduates are 28 prepared. Lancet 2015;385(9968):579-81. doi: 10.1016/S0140-6736(14)62339-4 [published 29 Online First: 2015/02/24] 30 12. Jansen BHE, Disselhorst GW, Schutte T, et al. Essential diseases in prescribing: A national Delphi 31 study towards a core curriculum in pharmacotherapy education. British journal of clinical 32 pharmacology 2018;84(11):2645-50. doi: 10.1111/bcp.13730 [published Online First: 33 2018/08/05] 34 35 13. Brinkman DJ, Tichelaar J, Okorie M, et al. Pharmacology and Therapeutics Education in the 36 European Union Needs Harmonization and Modernization: A Cross-sectional Survey Among 37 185 Medical Schools in 27 Countries. Clinical pharmacology and therapeutics http://bmjopen.bmj.com/ 38 2017;102(5):815-22. doi: 10.1002/cpt.682 [published Online First: 2017/03/16] 39 14. Tichelaar J, Richir MC, Garner S, et al. WHO guide to good prescribing is 25 years old: quo vadis? 40 European Journal of Clinical Pharmacology 2020;76(4):507-13. doi: 10.1007/s00228-019- 41 02823-w 42 15. Audi S, Burrage DR, Lonsdale DO, et al. The 'top 100' drugs and classes in England: an updated 43 'starter formulary' for trainee prescribers. British journal of clinical pharmacology 44 45 2018;84(11):2562-71. doi: 10.1111/bcp.13709 [published Online First: 2018/07/06] on October 1, 2021 by guest. Protected copyright. 46 16. Baker E, Roberts AP, Wilde K, et al. Development of a core drug list towards improving prescribing 47 education and reducing errors in the UK. British journal of clinical pharmacology 48 2011;71(2):190-8. doi: 10.1111/j.1365-2125.2010.03823.x [published Online First: 49 2011/01/12] 50 17. Ross S, Maxwell S. Prescribing and the core curriculum for tomorrow's doctors: BPS curriculum in 51 clinical pharmacology and prescribing for medical students. British journal of clinical 52 pharmacology 2012;74(4):644-61. doi: 10.1111/j.1365-2125.2012.04186.x [published Online 53 54 First: 2012/02/01] 55 18. Orme M, Frolich J, Vrhovac B, et al. Towards a core curriculum in clinical pharmacology for 56 undergraduate medical students in Europe. Eur J Clin Pharmacol 2002;58(9):635-40. doi: 57 10.1007/s00228-002-0531-9 [published Online First: 2002/12/17] 58 19. Walley T, Webb DJ. Developing a core curriculum in clinical pharmacology and therapeutics: a 59 Delphi study. British journal of clinical pharmacology 1997;44(2):167-70. doi: 10.1046/j.1365- 60 2125.1997.00669.x [published Online First: 1997/08/01]

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1 2 3 20. Ross S, Loke YK. Development of learning outcomes for an undergraduate prescribing curriculum 4 (British Pharmacological Society prescribing initiative). British journal of clinical BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 pharmacology 2010;70(4):604-8. doi: 10.1111/j.1365-2125.2009.03581.x [published Online 6 7 First: 2010/09/16] 8 21. Midlov P, Hoglund P, Eriksson T, et al. Developing a Competency-based Curriculum in Basic and 9 Clinical Pharmacology--A Delphi Study among Physicians. Basic Clin Pharmacol Toxicol 10 2015;117(6):413-20. doi: 10.1111/bcpt.12436 [published Online First: 2015/07/01] 11 22. Brinkman DJ, Tichelaar J, Mokkink LB, et al. Key Learning Outcomes for Clinical Pharmacology and 12 Therapeutics Education in Europe: A Modified Delphi Study. Clinical pharmacology and 13 therapeutics 2018;104(2):317-25. doi: 10.1002/cpt.962 [published Online First: 2017/12/06] 14 23. Brinkman D, Disselhorst G, Jansen B, et al. What Should Junior Doctors Know about the Drugs 15 they Frequently Prescribe? A Delphi Study among Physicians in the Netherlands. Basic Clin 16 17 Pharmacol Toxicol 2016;118(6):456-61. doi: 10.1111/bcpt.12508 [published Online First: 18 2015/10/28] For peer review only 19 24. Organization WH. World Health Organization Model List of Essential Medicines, 21st List. Geneva, 20 2019. 21 25. European Prescribing Exam 2020 [Available from: 22 http://www.prescribingeducation.eu/european-prescribing-exam/. 23 26. Bakkum MJ, Tichelaar J, Papaioannidou P, et al. Harmonizing and improving European education 24 in prescribing: An overview of digital educational resources used in clinical pharmacology and 25 26 therapeutics. British journal of clinical pharmacology 2020 doi: 10.1111/bcp.14453 27 [published Online First: 2020/07/09] 28 29 Authors’ contributions 30 31 ED, DB, MR and JT were involved in devising the study design and writing the protocol. 32 33 TC, YB, FD, RL, CK, JC, ES, PP, MvA, MG, RP and SG have reviewed and approved the manuscript. 34 35 Funding statement 36 37 http://bmjopen.bmj.com/ 38 This work was funded by Erasmus+, grant number 2019-1 - NL01 - KA203-060492 39 40 Competing interests: SG reports her employment at WHO Europe, all other authors declare no 41 42 conflict of interest. 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Hydroxocobalamin (vitamin b12) Omeprazole, pantoprazole, esomeprazole 4 Ibuprofen Ors (oral rehydration solution) BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 5 Ibuprofen Ors (oral rehydration solution) 6 7 Ibuprofen Oxazepam 8 Ibuprofen Oxycodone 9 Influenza vaccine Pantoprazole 10 Insulin aspart Paracetamol 11 Insulin glargine Paracetamol 12 Ipratropium bromide Paroxetine 13 Ipratropium bromide Perindopril 14 Isosorbide dinitrate Pheneticillin 15 Isosorbide mononitrate Pheneticillin 16 17 Ispaghula (psylla seeds) Pheneticillin 18 Lactulose For peer reviewPhenprocoumon only 19 Levocabastine Phenprocoumon 20 Levocetirizine Prednisolone 21 Levocetirizine Prednisolone 22 Levocetirizine Prednisolone 23 Levonorgestrel (iud) Prensisolone 24 Levothyroxine Propranolol 25 26 Lidocaine creme Ranitidine 27 Lisinopril Risedronic acid 28 Loperamide Rosuvastatin 29 Loperamide Salbutamol 30 Lorazepam Salbutamol 31 Losartan Salbutamol 32 Macrogol Salbutamol 33 Macrogol Salbutamol 34 Mebeverine Salbutamol 35 36 Medroxyprogesterone (s.c. Depot) Salmeterol 37 Menthol in aqueous cream Simvastatin http://bmjopen.bmj.com/ 38 Menthol in aqueous cream Sodium chloride solution 39 Metformin Spironolactone 40 Metocloperamide Temazepam 41 Metocloperamide Tetanus toxoid 42 Metoprolol Thiamine (vit b1) 43 Metoprolol Tiotropium bromide 44 45 Metronidazole Tramadol on October 1, 2021 by guest. Protected copyright. 46 Miconazol Triamcinolone 47 Midazolam (i.m.) Triamcinolone/acetic acid 48 Mometasone Trimethoprim 49 Nadroparin Trimethoprim/polymyxine b 50 Nadroparin Trimethoprim/sulfamethoxazole 51 Naproxen Trimethoprim/sulfamethoxazole 52 Naproxen Trimethoprim/sulfamethoxazole 53 54 Naproxen Verapamil 55 Naproxen Verapamil 56 Nitrofurantoin Xylometazoline nasalspray 57 Omeprazole Xylometazoline nasalspray 58 Omeprazole, pantoprazole Zolpidem 59 60

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1 2 3 Enoxaparin SC 4

5 Nadroparin SC BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Clopidogrel Oral 7 Dipyridamole Oral 8 Carbasalate calcium Oral 9 10 Prasugrel Oral 11 Dabigatran Oral 12 Rivaroxaban Oral 13 Apixaban Oral 14 15 Fondaparinux SC IV 16 Tranexamic acid Oral IV 17 Vitamin K Oral IV 18 For peer review only Prothrombin complex concentrate IV 19 20 Ferrous fumarate Oral 21 Hydroxocobalamin (vitamin B12) SC IM 22 Folic acid (vitamin B9) Oral 23 Glucose solution IV 24 25 Potassium chloride IV 26 Digoxin Oral IV 27 Flecainide Oral 28 Amiodarone Oral IV 29 30 Epinephrine (adrenaline) IM 31 Nitroglycerine SL 32 Isosorbide dinitrate Oral SL 33 Isosorbide mononitrate Oral 34 35 Methyldopa Oral 36 Hydrochlorothiazide Oral http://bmjopen.bmj.com/ 37 Chlorthalidone Oral 38 Furosemide Oral IV 39 40 Bumetanide Oral IV 41 Spironolactone Oral 42 Propranolol Oral 43 Sotalol Oral 44 45 Metoprolol Oral IV on October 1, 2021 by guest. Protected copyright. 46 Atenolol Oral 47 Bisoprolol Oral 48 Labetolol Oral IV 49 50 Amlodipine Oral 51 Nifedipine Oral 52 Barnidipine Oral 53 Lercanidipine Oral 54 55 Nicardipine IV 56 Verapamil Oral IV 57 Diltiazem Oral 58 Enalapril Oral 59 60 Lisinopril Oral

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1 2 3 Perindopril Oral 4

5 Ramipril Oral BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Fosinopril Oral 7 Losartan Oral 8 Valsartan Oral 9 10 Irbesartan Oral 11 Candesartan Oral 12 Simvastatin Oral 13 Pravastatin Oral 14 15 Atorvastatin Oral 16 Rosuvastatin Oral 17 Gemfibrozil Oral 18 For peer review only Colestyramine Oral 19 20 Ezetimibe Oral 21 Evolocumab SC 22 Miconazole Cutaneous 23 Emollients (e.g. Cremor vaseline 24 cetomacrogolis) Cutaneous 25 26 Zinc oxide Cutaneous 27 Petroleum jelly Cutaneous 28 Lidocaine creme Cutaneous 29 Menthol in hydrophilic ointment Cutaneous 30 31 Fusidic acid Cutaneous 32 Hydrocortisone Cutaneous 33 Triamcinolone Cutaneous 34 Betamethasone Cutaneous 35 36 Mometasone Cutaneous 37 Clobetasole Cutaneous http://bmjopen.bmj.com/ 38 Clotrimazole Cutaneous 39 IUD with progestogen IUD 40 41 Ethinylestradiol/levonorgestrel Oral 42 Medroxyprogesterone (s.c. Depot) SC 43 Etonogestrel (s.c. Implant) SC 44 Desogestrel Oral

on October 1, 2021 by guest. Protected copyright. 45 46 Levonorgestrel Oral 47 Estradiol Oral 48 Oxybutynin Oral 49 Solifenacin Oral 50 51 Tamsulosin Oral 52 Finasteride Oral 53 Betamethasone Oral IV 54 Dexamethasone Oral IV 55 56 Prednisolone Oral IV 57 Hydrocortisone Oral IV 58 Levothyroxine Oral 59 Glucagon IM 60

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1 2 3 Doxycycline Oral 4

5 Amoxicillin Oral IV BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Feneticillin Oral IV 7 Flucloxacillin Oral IV 8 Amoxicillin/clavulanic acid Oral IV 9 10 Meropenem IV 11 Trimethoprim Oral 12 Co-trimoxazole Oral IV 13 Trimethoprim/sulfametoxazole Oral IV 14 15 Erythromycin Oral IV 16 Clarithromycin Oral IV 17 Azithromycin Oral IV 18 For peer review only Gentamycin IV 19 20 Ciprofloxacin Oral IV 21 Vancomycin IV 22 Fusidic acid Oral 23 Nitrofurantoin Oral 24 25 Fosfomycin Oral 26 Fluconazole Oral IV 27 Rifampicin Oral IV 28 Acyclovir Oral IV 29 30 Valaciclovir Oral 31 Oseltamivir Oral 32 Tetanus toxoid IM 33 Methotrexate Oral IV IM SC 34 35 Diclofenac Oral 36 Ibuprofen Oral http://bmjopen.bmj.com/ 37 Naproxen Oral 38 Ibuprofen Cutaneous 39 40 Diclofenac Cutaneous 41 Allopurinol Oral 42 Colchicine Oral 43 Alendronic acid Oral 44 45 Risedronic acid Oral on October 1, 2021 by guest. Protected copyright. 46 Denosumab SC 47 Fentanyl IV 48 Lidocaine SC 49 50 Epinephrine (adrenaline) SC 51 Morphine Oral IV SC 52 Oxycodone Oral SC 53 Fentanyl Oral Cutaneous Nasal SL 54 55 Tramadol Oral Rectal 56 Piritramide SC 57 Acetylsalicylic acid Oral IV 58 Calcium carbasalate Oral IV 59 60 Paracetamol Oral IV Rectal

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1 2 3 Sumatriptan Oral Nasal SC 4

5 Valproic acid Oral IV BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Levetiracetam Oral IV 7 Pregabalin Oral IV 8 Haloperidol Oral IV 9 10 Clozapine Oral 11 Olanzapine Oral 12 Quetiapine Oral 13 Lithium Oral 14 15 Risperidone Oral IM 16 Diazepam Oral Rectal 17 Oxazepam Oral 18 Lorazepam For peerOral review IM onlyIV 19 20 Temazepam Oral 21 Midazolam Oral IV 22 Zolpidem Oral 23 Clomipramine Oral 24 25 Amitriptyline Oral 26 Nortriptyline Oral 27 Fluoxetine Oral 28 Citalopram Oral 29 30 Paroxetine Oral 31 Sertraline Oral 32 Escitalopram Oral 33 Mirtazapine Oral 34 35 Venlafaxine Oral 36 Metronidazole Oral IV http://bmjopen.bmj.com/ 37 Xylometazoline Nasal 38 Levocabastine Ocular 39 40 Beclomethasone Nasal 41 Budesonide Nasal 42 Mometasone Nasal 43 Fluticasone Nasal 44 45 Salbutamol Inhalation on October 1, 2021 by guest. Protected copyright. 46 Salmeterol Inhalation 47 Formoterol Inhalation 48 Beclometasone Inhalation 49 50 Budesonide Inhalation 51 Fluticasone Inhalation 52 Ciclesonide Inhalation 53 Ipratropium bromide Inhalation 54 55 Tiotropium bromide Inhalation 56 Tiotropium Inhalation 57 Codeine Oral 58 Clemastine Oral IV 59 60 Meclozine Oral

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1 2 3 Levocetirizine Oral 4

5 Desloratadine Oral BMJ Open: first published as 10.1136/bmjopen-2020-045635 on 4 May 2021. Downloaded from 6 Chloramphenicol Ocular 7 Fusidic acid Ocular 8 Erythromycin Ocular 9 10 Trimethoprim/polymyxin B Ocular 11 Dexamethasone (Ocular) Ocular 12 Prednisolone (Ocular) Ocular 13 Levocabastine Ocular 14 15 Aluminium acetate Ear 16 Miconazole Oral 17 Hydrocortisone/acetic acid Ear 18 For peer review only Triamcinolone/acetic acid Ear 19 20 Protamine IV 21 Naloxone IV 22 Flumazenil IV 23 Ticagrelor Oral IV 24 25 Cefuroxime IV 26 Cefotaxime IV 27 Ceftriaxone IV 28 Ceftazidime IV 29 30 Clindamycin Oral IV 31 Sodium chloride IV 32 Ringer’s lactate IV 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on October 1, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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