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Pediatric utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research

Date Submitted by the 27-Jun-2019 Author:

Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Practice and Research, Department of Pharmacology and Pharmacy Man, Kenneth; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Pratt, Nicole; University of South Australia, Sansom Institute for Health Resarch Park, Rea Woong; Ajou University Cho, Soo-Yeon; Ajou University Li, Yu-Chuan (Jack); Taiwan Medical University, College of Medical Science and Technology Iqbal, Usman; Taipei Medical University, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology Nguyen, Phung-Anh; National Yang Ming University, Institute of Biomedical Informatics Schuemie, Martijn; Janssen Research and Development, Epidemiology Analytics; University of California, Los Angeles, Department of Biostatistics

Keywords: CLINICAL PHARMACOLOGY, EPIDEMIOLOGY, PAEDIATRICS

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1 2 3 Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and 4 5 6 Taiwan 7

8 a a,b b c 9 Authors: Ruth Brauer , PhD, Ian C.K. Wong , PhD, Kenneth Man , MPH, Nicole Pratt , PhD, 10 11 Rae Woong Parkd, MD, PhD, Soo-Yeon Chod, RN, MPH, Li, Yu-Chuan (Jack) Lie, MD, PhD, 12 13 Usman Iqbale, PhD, Alex Nguyene, PhD, Martijn Schuemief, PhD. 14 15 16 For peer review only 17 18 Affiliations: aUCL School of Pharmacy, London, United Kingdom; bUniversity of Hong Kong, Hong Kong; 19 20 c d 21 University of South Australia, Adelaide, Australia; Ajou University School of Medicine, Suwon, South- 22 23 Korea; eTaipei Medical University, Taipei, Taiwan; and fJanssen Research and Development, New Jersey. 24 25 26 27 Corresponding author: Martijn Schuemie ([email protected]) 28 29 30 31 32 Funding Source: No funding was secured for this study. 33 34 35 Word count: 2887 36 37 38 39 40 41 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 70

1 2 3 Abstract 4 5 6 Objective: To measure the pediatric user and prescription prevalence in inpatient and ambulatory 7 8 settings in South Korea, Hong Kong, Taiwan, Japan and Australia by age and gender. A further objective 9 was to list the most commonly used per , per country. 10 11 12 Design and setting: Hospital inpatient and insurance paediatric health care data from the following 13 14 databases were used to conduct this descriptive drug utilization study: (i) the South Korean Ajou 15 16 University School of MedicineFor (AUSOM)peer database; review (ii) the Hong Kong only Clinical Data Analysis and 17 Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s National Health 18 19 Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits Scheme (PBS). 20 21 Country specific data were transformed into the Observational Medical Outcomes Partnership (OMOP) 22 Common Data Model (CDM). 23 24 25 Patients: Follow-up of children with at least 1 day of observation in any of the respective databases 26 27 started in January 2009 and ended in December 2013. 28 29 30 Main outcome measures: For each drug class we assessed the per-protocol overall user and 31 prescription prevalence rates (per 1000 persons) per country and setting. 32 33 34 Results: Our dynamic study cohort comprised 1,574,524 children (52.9% male). The highest proportion 35 36 of dispensings was recorded in the youngest age category (<2 years) for inpatients (45.1%) with a 37 38 relatively high user prevalence of and . Adrenergics, , mucolytics and 39 were used in 10-15% of patients. For ambulatory patients, the highest proportion of 40 41 dispensings was recorded in the middle age category (2-11 years, 67.1%) with antibiotics the most 42 43 dispensed drug overall. 44 45 46 Conclusions: Important differences in drug pediatric utilization patterns were identified between four 47 East-Asian countries and Australia. The widespread east-Asian use of mucolytics warrants further 48 49 investigation. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 70 BMJ Open

1 2 3 Strengths and limitations of this study 4 5 6 7  We conducted the largest Western pacific pediatric drug utiIisation study to date using a 8 9 common data model (CDM) which allowed us to rank the user and prescription prevalence of 10 11 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia. 12 13  Our comprehensive overview of country-specific pharmacological agents used in both an 14 15 16 ambulatory andFor inpatient peer setting, by genderreview and age, included only data of 1,574,524 children and 17 18 identified important differences in drug pediatric utilization patterns. 19 20  Despite the differences in databases in terms of setting and study populations, we believe our 21 22 overview of prescription patterns and rankings is an important step to further investigate and 23 24 25 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. 26 27  Over the counter (OTC) prescribing in individual countries was not captured and we may have 28 29 underestimated the true drug utilization of agents, such as and some 30 31 antihistamines. 32 33 34  We collected data until the end of 2013 and acknowledge that, due to the rapid change in 35 36 pediatric licensing of therapeutic agents, some of our findings might be worthwhile replicating 37 38 with more current data. 39 40 41 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 4 of 70

1 2 3 Introduction 4 5 6 In the absence of large randomised controlled trials (RCTs), observational data in the form of electronic 7 8 health records and insurance claims data have been used successfully to investigate both medication 9 10 errors and adverse drug events through retrospective analysis of drug exposure in children[1 2]. 11 12 Pediatric drug utilization data from East Asian countries are currently lacking. 13 14 15 A network of observational healthcare databases in South Korea, Hong Kong, Taiwan, Japan and 16 For peer review only 17 18 Australia was used to measure and compare the prevalence of drug prescribing in East Asian and 19 20 Australian children. Country specific data were transformed into the Observational Medical Outcomes 21 22 Partnership (OMOP) Common Data Model (CDM). Our primary aim was to measure the pediatric user 23 24 and prescription prevalence in inpatient and ambulatory settings in the five aforementioned countries 25 26 by age and gender. A further objective was to list the most commonly used drugs per drug class, per 27 28 29 country, in both an inpatient and ambulatory setting. 30 31 32 Methods 33 34 35 Data sources 36 37 38 We conducted a drug utilisation study using pediatric patient populations from the following databases: 39 40 (i) Ajou University School of Medicine (AUSOM) from South Korea; (ii) the Hong Kong Clinical Data 41 42 Analysis and Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s 43 44 45 National Health Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits 46 47 Scheme (PBS). All data were anonymized to protect patient confidentiality. 48 49 50 The South Korean and Hong Kong databases, AUSOM and CDARS, collect and archive the electronic 51 52 health records (EHR) of hospital inpatients. Briefly, AUSOM is an EHR database of a Korean teaching 53 54 hospital with 1,096 patient beds and 23 operating rooms with data for over 2,073,120 individuals, 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 70 BMJ Open

1 2 3 collected since 1994. By contrast, CDARS contains the data from all public hospitals in Hong Kong and 4 5 6 their associated ambulatory and primary care clinics since 1995 [3-5]. The database was developed and 7 8 is maintained by the Hong Kong Hospital Authority, a statutory body providing health care services 9 10 available to all Hong Kong residents (over 7 million) and covering about 80% of all hospital admissions. 11 12 13 The Japanese, Taiwanese and Australian data were extracted from insurance research databases. The 14 15 Japanese JMDC comprises data from 60 Society-Managed Health Insurances covering workers aged 18 16 For peer review only 17 18 to 65 and their dependents (children and elderly). The monthly claims data are derived from claims 19 20 issued by clinics, hospitals and community pharmacies from July 2009 onwards. Australian data consist 21 22 of national pharmacy claims data from the Australian Government Department of Human Services 23 24 which provides information of medicines subsidized and dispensed under the Pharmaceutical Benefits 25 26 Scheme. PBS data are collected from pharmacies and private hospitals, and discharge or outpatient 27 28 29 dispensing from public hospitals, but do not include inpatient public hospital prescriptions. From 30 31 Taiwan, we extracted reimbursement data from the Bureau National Health Insurance (NHI) system, 32 33 which has registered all medical claims since 1995. More than 99% of the citizens of Taiwan are enrolled 34 35 in the NHI, which offers mandatory and comprehensive medical care coverage to all Taiwanese 36 37 38 residents. 39 40 41 Data collection 42 43 For this retrospective descriptive study we identified children below or equal to the age of 18 with at 44 45 46 least 1 day of observation in any of the respective databases. The follow-up period for all children 47 48 started in January 2009 or the start date of observation, whichever was last. Follow-up ended in 49 50 December 2013, the last date observation or the date a child turned 18, whichever was first. Specifically, 51 52 observation time was defined as: 1) The start of the first visit (inpatient, outpatient or ER) to the end of 53 54 55 the last visit for the Korean AUSOM database; 2) The date of birth until death in the Hong Kong CDARS 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 70

1 2 3 database and 3) The insurance enrollment date in the Japan JMDC, Taiwan NHIRD, and Australian PBS. 4 5 6 Data were available from the end of 2009 onwards for the Japanese JMDC and until December 2011 for 7 8 the Taiwanese database (NHIRD). We used randomly selected samples from CDARS, NHIRD and PBS as 9 10 only ~ 10% of the total data were made available for research. 11 12 13 Data extraction 14 15 16 Data extraction was performedFor peerthrough a shared review analysis program only combining R and SQL. This program 17 18 was distributed to the data partners, executed locally against the data in OMOP CDM format, and results 19 20 21 were returned to the central coordinating site (University of Hong Kong). Both the extraction software 22 23 and the analysis code are available as open source: 24 25 https://github.com/OHDSI/StudyProtocols/tree/master/DrugsInPeds. 26 27 28 Research ethics approval 29 30 31 This study had been approved by the Institutional Review Board of the University of Hong Kong/Hospital 32 33 Authority Hong Kong West Cluster (HKU/HA HKW IRB), reference number: UW 13-504. 34 35 36 37 Patient and Public Involvement 38 39 40 We did not involve patients or the public in our work. 41 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 Page 7 of 70 BMJ Open

1 2 3 Statistical analysis 4 5 6 Total follow-up time was calculated for each child, stratified by age group and by calendar year. Age was 7 8 9 assessed on a day-by-day basis, and grouped according to the guidelines of the International Conference 10 11 of Harmonization (ICH) as < 2 years, 2-11 years, and 12-18 years [6]. Drugs were classified according to a 12 13 custom defined drug classification (Supplemental Material 1). This classification was based on 14 15 pharmacological class, and where appropriate aggregated further by indication. For each drug class we 16 For peer review only 17 18 assessed the overall user and prescription prevalence rates (per 1000 persons) per country and setting 19 20 (inpatient or ambulatory) by counting the number of children using or number of 21 22 prescriptions/dispensings of a specific drug (numerator). We used the total person count per database 23 24 as the denominator to calculate prevalence rates. If a person was observed for at least one day in a 25 26 particular category (e.g. age group) that person was counted in the denominator for that category. Over 27 28 29 the study period, and within a calendar year, children could contribute to more than one age category. 30 31 Lastly, we identified the five drugs with the highest user prevalence per drug class in each country. 32 33 34 35 Results 36 37 Study population 38 39 40 41 Our dynamic study cohort comprised 1,574,524 children (52.9 % male). The total number of follow-up 42 43 years was 4,783,549 years, with a mean individual follow-up of 3.0 years. The database that contributed 44 45 most person years to the study was the Japanese JDMC (58 %) (Table 1). Altogether, we recorded close 46 47 to 9 million pediatric inpatient dispensings (8,848,699) and more than 44 million ambulatory 48 49 dispensings (44,652,871). The relative number of dispensings prescribed per age category differed 50 51 52 between the inpatient and ambulatory patient settings, with the highest proportion of dispensings 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 70

1 2 3 recorded in the youngest age category (<2 years) for inpatients (45.1%) and in the middle age category 4 5 6 (2-11 years) for ambulatory patients (67.1%). 7 8 9 User- and prescription prevalence 10 11 12 The recorded user- and prescription prevalence of all therapeutic agents was lower in the inpatient 13 14 population than the ambulatory population (Table 2a & Table 2b). Analgesics (including non-steroidal 15 16 anti-inflammatory drugsFor [NSAIDs]) peer had the highest review user prevalence only in Korea, Hong Kong and Taiwan in 17 18 the inpatient setting, however, antibiotics had the highest prescription prevalence in most countries 19 20 21 (Hong Kong, Japan and Taiwan). In the ambulatory setting, antibiotics had the highest user prevalence in 22 23 all countries, however, the highest prescription prevalence differed across countries. In Japan, the 24 25 highest prescription prevalence was recorded for corticosteroids, while in Taiwan the highest 26 27 prescription prevalence was for antihistamines and lastly, in Australia the highest prevalence was 28 29 30 recorded for antibiotics. 31 32 33 Inpatient user- and prescription prevalence 34 35 36 Overall, the inpatient user prevalence of analgesics and antibiotics was high relative to the user 37 38 prevalence of other agents in all countries (Table 2a). Adrenergics, antihistamines, mucolytics and 39 40 corticosteroids were used in 10-15% of patients while the remaining categories of medicines were used 41 42 in <5% of patients. The user prevalence of mucolytics in Korea and Japan was high compared the user 43 44 45 prevalence of other agents. Inpatient prescription prevalence for different classes of agents showed 46 47 patterns similar to those seen for the user prevalence. 48 49 50 Most drugs were more commonly used by males compared to females. The use of contraceptives, 51 52 antidiabetic, psychotherapeutic, antineoplastic and immunomodulating agents was more common in 53 54 females. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 70 BMJ Open

1 2 3 Results stratified by age show that the inpatient use of drugs was highest in the youngest age group (<2 4 5 6 years) in all but four classes (contraceptives, antidiabetic, psychotherapeutic, antineoplastic and 7 8 immunomodulating agents) (Figure 1). 9 10 11 Ambulatory user- and prescription prevalence 12 13 14 The pediatric use of different classes of drugs in an ambulatory setting was measured in Japan, Taiwan 15 16 and Australia (Table 2b).For The highest peer ambulatory review user prevalence acrossonly all drug classes was country 17 18 specific with antibiotics ranked high in Japan (22%) and Australia (46%), followed by corticosteroids 19 20 21 (20% and 23% respectively). In Taiwan the highest user prevalence of any drug class was measured for 22 23 analgesics (17%), closely followed by antihistamines (16%). The pattern of inpatient prescription 24 25 prevalence for different classes of agents was similar to the pattern seen for the user prevalence. A very 26 27 low prescription prevalence of antiinfectives was measured in all countries. 28 29 30 The ambulatory dispensing of drugs stratified by gender showed fewer marked differences between 31 32 33 males and females in all databases (Figure 2). In contrast to the gender difference seen in an inpatient 34 35 setting, the ambulatory use of agents, antihistamines and corticosteroids was marginally 36 37 higher in females. 38 39 40 The user prevalence by age showed a very different pattern when compared to inpatient use: The use of 41 42 most drugs, by class, was highest in the middle age category (2-11 years) in Japan and Australia. For 43 44 45 Taiwan, the highest use for many drug classes was measured in the youngest age category. The use of 46 47 contraceptives, antidiabetic, psychotherapeutic, antineoplastic and immunomodulating agents was 48 49 highest in the oldest age group across all three databases. 50 51 52 Most commonly used drugs by class in an inpatient setting 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 70

1 2 3 Paracetamol was the most prevalent used in all countries, however, the prevalence of 4 5 6 paracetamol users differed across countries with Hong Kong and Japan using mostly paracetamol while 7 8 Korea and Taiwan had a greater spread of analgesic product use (Table 3a). was the most 9 10 prescribed antiepileptic agent in three countries and the second most prescribed antiepileptic agent in 11 12 Taiwan. Chlorpheniramine was one of the most used antihistamines in all countries with the exception 13 14 of Japan. 15 16 For peer review only 17 18 Differences in the most used pediatric drugs in an inpatient setting were seen for drugs with a high user 19 20 prevalence overall, such as antibiotic and adrenergic agents. An outlying pattern of the user prevalence 21 22 for specific agents was seen in South Korea: The most used antibiotic () and adrenergic agent 23 24 () in Korea were not among the five drugs with the highest inpatient user prevalence in any of 25 26 the other East Asian countries. Furthermore, the most used mucolytic () and 27 28 29 () in Korea were less frequently used in other countries. 30 31 32 Most commonly used drugs by class in an ambulatory setting 33 34 35 As in the inpatient setting, the most commonly used analgesic in an ambulatory setting in Japan, Taiwan 36 37 and Australia was paracetamol (Table 3b). Overall, more similarities in the most commonly used drugs 38 39 per anatomical class were seen between Japan and Taiwan. For antibiotic agents, the use of , 40 41 42 cephalexin and erythoromicin was very similar in Taiwan and Australia. For other drug classes there was 43 44 less overlap. 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 Page 11 of 70 BMJ Open

1 2 3 Discussion 4 5 6 To our knowledge, this is the first comprehensive overview of pediatric drug use in Korea, Hong Kong, 7 8 Japan, Taiwan and Australia. This study has shown a high inpatient user prevalence of analgesics and 9 10 antibiotics relative to the user prevalence of other drug classes. The highest ambulatory user prevalence 11 12 across all drug classes was country specific with antibiotics and corticosteroids ranked high in Japan and 13 14 Australia. In Taiwan, the user prevalence of analgesics was highest followed by antihistamines. 15 16 For peer review only 17 Mucolytics were amongst the most frequently used drugs in Korea, Japan and Taiwan, but not in Hong 18 19 Kong and Australia. For pediatric inpatients, medication use was highest in males and the lowest age 20 21 category (<2 years), whilst for outpatients gender differences were less pronounced and medication use 22 23 was highest in 2-11 year olds in Japan and Australia. 24 25 26 Comparison with literature 27 28 29 30 Whilst we used a custom therapeutic classification, the most commonly used drugs in every class were 31 32 compared to those as reported by Sturkenboom in 2005[7]. Overall, the choice of specific pediatric 33 34 therapeutic agents differed widely between the aforementioned three European countries and the East 35 36 Asian countries in our study. Exceptions were similarities in the use of amoxicillin, and 37 38 39 paracetamol. 40 41 The inpatient study results (Tables 2a & 3a) were compared to results of a study by Rashed et al. (2015), 42 43 who reported on the drug utilization patterns of children admitted to a pediatric ward in the UK, 44 45 Germany, Australia, Hong Kong and Malaysia[2]. As in our study, antibacterials and analgesics were the 46 47 two most used therapeutic groups in all five countries. 48 49 50 51 Implications for Practice and Policy: Pediatric licensing of drugs in the Western Pacific region 52 53 54 National agencies responsible for regulating therapeutic goods often base their regulations on 55 56 international guidelines, especially for new drug licensing [8 9]. Results of the current study suggest that 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 70

1 2 3 the extent to which international pediatric prescribing guidelines affect local prescribing practices differs 4 5 6 from country to country. For instance, our study shows the widespread of mucolytics in children in 7 8 Korea, Japan and Taiwan. This is a finding of note as in 2010 several European drug agencies withdrew 9 10 the licenses for carbocysteine and for children younger than two years of age because 11 12 their use was associated with worsening of respiratory tract [10]. More recently, the 13 14 European Medicines Agency (EMA) published a revised assessment report on products containing 15 16 For peer review only 17 and bromhexine in which the use of these products in children below <2 years of age is 18 19 discouraged [11]. Our study showed that the use of mucolytics was very high in the youngest age group 20 21 in all countries but Hong Kong and Australia. 22 23 Another drug that is contraindicated for use in children in some European countries is 24 25 26 . This drug, a β2-, is licensed in seven countries worldwide for childhood [12 27 28 13]. In 2010, the European Medicines Agency refused a paediatric investigation plan for tulobuterol and 29 30 granted a waiver (restricting potential use to patients >18 years) as tulobuterol was considered likely to 31 32 be ineffective or unsafe in the pediatric population [14]. Yet, in this study tulobuterol was the most used 33 34 35 adrenergic agent in an outpatient setting in Japan. 36 37 A further finding of note was the relatively common ambulatory use of in Japan 38 39 and in Taiwan and Australia. Both codeine and dihydrocodeine are derivatives and 40 41 are contraindicated for use in children younger than 12 in Europe since 2013 [15]. This is mainly due to 42 43 44 the unpredictable of codeine to morphine [16]. At the time of data collection (2009-2012) 45 46 Australia already had prescribing guidelines in place in which it was recommended to restrict the use of 47 48 codeine in children under 12. 49 50 Lastly, we found that is still one of the most used antibiotic agents in Taiwan. 51 52 53 In many European countries, including the UK, the importance of the has decreased as a 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 70 BMJ Open

1 2 3 result of increasing bacterial resistance and their replacement by antibacterials which are generally 4 5 6 more active and less toxic[17]. 7 8 9 10 Strengths and limitations 11 12 We conducted the largest Western pacific pediatric drug utiIisation study to date. Data extraction was 13 14 performed through a shared analysis program and a standardized analysis process was applied to all 15 16 For peer review only 17 databases. Using a common data model (CDM), and CDM vocabulary concept identifiers, we were able 18 19 to use standardised drug codes across countries which allowed us to rank the user and prescription 20 21 prevalence of fifteen different drug classes in five different countries. We found some important 22 23 similarities and differences in country specific drug utilization patterns between Korea, Hong Kong, 24 25 26 Japan, Taiwan and Australia. 27 28 It is important to highlight that our study did not aim to directly compare the drug prevalence 29 30 rates between the countries in this study, rather we aimed to provide a comprehensive overview of the 31 32 country-specific pharmacological agents used in both an ambulatory and inpatient setting by gender and 33 34 35 age. Differences in user and prescription prevalence patterns between the five countries in our study 36 37 may reflect differences in the underlying prevalence of diseases, differences in physician prescribing 38 39 behavior and differences in medicine availability and data capture. Like other drug utilization studies 40 41 using electronic health records, we could not distinguish between these. Additionally, as medical 42 43 44 indications were not available in all data sets we were unable to report the reasons for prescriptions. 45 46 Formularies were different across countries as well, particularly with regard to which medicines were 47 48 subsidized in the data and for which indication. It is also worth noting that we did not distinguish 49 50 between formulations. Lastly, the five databases captured different source populations. 51 52 53 Despite the differences in databases in terms of setting and study populations, we believe our 54 55 overview of prescription patterns and rankings is an important step to further investigate and facilitate 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 70

1 2 3 the rational use of drugs in pediatric populations in East Asia and Australia. Standardizing medication 4 5 6 use across countries will help when implementing adverse event monitoring programs across the region. 7 8 Over the counter (OTC) prescribing in individual countries was not captured and we may have 9 10 underestimated the true drug utilization of agents, such as paracetamol and some antihistamines. OTC 11 12 prescribing is most likely to have affected any ambulatory drug utilization estimates. 13 14 We collected data until the end of 2013 and acknowledge that, due to the rapid change in 15 16 For peer review only 17 pediatric licensing of therapeutic agents, some of our findings might be worthwhile replicating with 18 19 more current data. 20 21 22 23 24 Conclusion 25 26 27 Important differences in drug pediatric utilization patterns were identified between four East-Asian 28 29 30 countries and Australia. The widespread east-Asian use of mucolytics and the use of tulobuterol in Japan 31 32 warrants further investigation. 33 34 35 36 37 38 39 40 41 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 Page 15 of 70 BMJ Open

1 2 3 4 5 6 Acknowledgments: The analysis is based in part on work from the Observational Health Sciences and 7 8 Informatics collaborative (OHDSI). OHDSI (http://ohdsi.org) is a multi-stakeholder, interdisciplinary 9 10 collaborative to create open-source solutions that bring out the value of observational health data 11 12 through large-scale analytics. 13 14 15 16 For peer review only 17 18 Financial Disclosure: Dr. Schuemie is an employee of Janssen Research & Development. None of the 19 20 remaining authors have financial relationships relevant to this article to disclose. 21 22 23 24 Potential Conflicts of Interest: The authors have no conflicts of interest relevant to this article to 25 26 disclose. 27 28 29 30 31 32 Author’s contribution: MS and ICKW designed the study. MS wrote the protocol for this study and was 33 34 responsible for the statistical programming. RB wrote the first draft of the manuscript. All authors ran 35 36 country specific analyses, contributed original data and provided comments. 37 38 39 40 41 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 16 of 70

References 1 2 3 1. Wong IC, Murray ML. The potential of UK clinical databases in enhancing paediatric medication research. British 4 journal of clinical pharmacology 2005;59(6):750-5 doi: 10.1111/j.1365-2125.2005.02450.x[published Online 5 6 First: Epub Date]|. 7 2. Rashed AN, Wong IC, Wilton L, et al. Drug Utilisation Patterns in Children Admitted to a Paediatric General Medical 8 Ward in Five Countries. Drugs - real world outcomes 2015;2(4):397-410 doi: 10.1007/s40801-015-0049- 9 y[published Online First: Epub Date]|. 10 3. Chan EW, Lau WC, Leung WK, et al. Prevention of -Related Gastrointestinal Bleeding With Gastroprotective 11 Agents: A Population-Based Study. Gastroenterology 2015;149(3):586-95 e3 doi: 12 10.1053/j.gastro.2015.05.002[published Online First: Epub Date]|. 13 4. Chui CS, Man KK, Cheng CL, et al. An investigation of the potential association between retinal detachment and oral 14 15 fluoroquinolones: a self-controlled case series study. The Journal of antimicrobial 16 2014;69(9):2563-7 doi:For 10.1093/jac/dku145[published peer review Online First: only Epub Date]|. 17 5. Man KK, Chan EW, Coghill D, et al. and the risk of trauma. Pediatrics 2015;135(1):40-8 doi: 18 10.1542/peds.2014-1738[published Online First: Epub Date]|. 19 6. Rose K, Stötter H. ICH E 11: clinical investigation of medicinal products in the paediatric population. In: Rose K, JN vdA, 20 eds. Guide to paediatric clinical research. Basel: KArger, 2007:33-37. 21 7. Sturkenboom MC, Verhamme KM, Nicolosi A, et al. Drug use in children: cohort study in three European countries. 22 Bmj 2008;337:a2245 doi: 10.1136/bmj.a2245[published Online First: Epub Date]|. 23 8. Woo Y, Kim HE, Chung S, et al. Pediatric medication error reports in Korea adverse event reporting system database, 24 25 1989-2012: comparing with adult reports. Journal of Korean medical science 2015;30(4):371-7 doi: 26 10.3346/jkms.2015.30.4.371[published Online First: Epub Date]|. 27 9. Taiwan Food and Drugs Administration. 2016 Taiwan Food and Drug Administration Annual Report. Secondary 2016 28 Taiwan Food and Drug Administration Annual Report. October 2016. 29 http://www.fda.gov.tw/upload/ebook/AnnuaReport/2016. 30 10. Mallet P, Mourdi N, Dubus JC, et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine 31 and carbocysteine systemic use in paediatric patients: a national survey. PloS one 2011;6(7):e22792 doi: 32 10.1371/journal.pone.0022792[published Online First: Epub Date]|. 33 34 11. European Medicines Agency (EMA). Revised assessment report: Ambroxol and bromhexine containing medicinal 35 products. Secondary Revised assessment report: Ambroxol and bromhexine containing medicinal products. 10 36 September 2015. 37 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ambroxol_and_bromhexine_ 38 31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500184106.pdf 39 12. Schmiedl S, Fischer R, Ibanez L, et al. Utilisation and off-label prescriptions of respiratory drugs in children. PloS one 40 2014;9(9):e105110 doi: 10.1371/journal.pone.0105110[published Online First: Epub Date]|. 41 13. Arakawa H, Hamasaki Y, Kohno Y, et al. Japanese guidelines for childhood asthma 2017. Allergology international : 42 43 official journal of the Japanese Society of Allergology 2017 doi: 10.1016/j.alit.2016.11.003[published Online 44 First: Epub Date]|. 45 14. European Medicines Agency (EMA). Opinion of the Paediatric Committee on the refusal of a Paediatric Investigation 46 Plan and on the granting of a product-specific waiver. Secondary Opinion of the Paediatric Committee on the 47 refusal of a Paediatric Investigation Plan and on the granting of a product-specific waiver. 6 July 2010. 48 http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500095327.pdf. 49 15. European Medicines Agency (EMA). Assessment report: Codeine containing medicinal products for the treatment of 50 cough and/or cold in paediatric patients. Secondary Assessment report: Codeine containing medicinal products 51 for the treatment of cough and/or cold in paediatric patients. 12 March 2015. 52 53 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Codeine_cough_or_cold_in_c 54 hildren/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500186522.pdf. 55 16. Ciszkowski C, Madadi P, Phillips MS, et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. The 56 New England journal of medicine 2009;361(8):827-8 doi: 10.1056/NEJMc0904266[published Online First: Epub 57 Date]|. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 70 BMJ Open

17. British National Formulary (BNF). . Secondary CLARITHROMYCIN 30-03-2017. 1 https://www.evidence.nhs.uk/formulary/bnf/current/5-infections/51-antibacterial-drugs/515- 2 3 /clarithromycin. 4 5 6 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 34 35 36 37 38 39 40 41 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 18 of 70

Tables and Figures 1 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 Page 19 of 70 BMJ Open

1 2 Table 1. Patient characteristics, person years and number of prescription by age and calendar year 3 4 Korea (AUSOM) Hong Kong (CDARS)* Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 5 (n = 220,076) (n = 18,634) (n = 913,006) (n = 235,214) (n = 187,594) 6 Gender (number of children) 7 8 Female, n (%) 98,921 (44.9) 8,389 (45.0) 433,918 (47.5) 113,179 (48.1) 87,129 (46.4) 9 Male, n (%) 121,155 (55.1) 9,656 (51.8) 479,088 (52.5) 122,035 (51.9) 100,465 (53.6) 10 Age (number of person years) 11 Total 259,750 71,502 3,006,825 630,051 774,420 12 <2 years, n (%) For32,909 (12.7) peer 7,937review (11.1) 304,672 only (10.1) 42,445 (6.7) 86,181 (11.1) 13 14 2-11 years, n (%) 152,352 (58.7) 34,767 (48.6) 1,613,909 (53.7) 305,543 (48.5) 462,755 (59.8) 15 12-18 years, n (%) 74,489 (28.7) 28,798 (40.3) 1,088,244 (36.2) 282,063 (44.8) 225,484 (29.1) 16 Calendar year (number of person 17 years) 18 19 2009, n (%) 72,472 (27.9) 14,148 (19.8) 311,734 (10.4) 216,660 (34.4) 149,157 (19.3) 20 2010, n (%) 66,090 (25.4) 14,147 (19.8) 644,681 (21.4) 211,666 (33.6) 152,689 (19.7) 21 2011, n (%) 57,515 (22.1) 14,274 (20.0) 665,955 (22.2) 201,725 (32.0) 155,597 (20.1) 22 2012, n (%) 44,161 (17.1) 14,459 (20.2) 686,775 (22.8) - 158,117 (20.4) 23 24 2013, n (%) 19,512 (7.5) 14,475 (20.2) 697,680 (23.2) - 158,861 (20.5) 25 Number of drugs dispensed 26 (inpatient) 27 Total 3,126,567 48,166 5,311,981 361,985 - 28 <2 years, n (%) 1,354,036 (43.3) 17,816 (37.0) 2,523,959 (47.5) 92,518 (25.6) - 29 30 2-11 years, n (%) 1,158,851 (37.1) 12,852 (26.7) 1,980,742 (37.3) 156,401 (43.2) - 31 12-18 years, n (%) 613,680 (19.6) 17,498 (36.3) 807,280 (15.2) 113,066 (31.2) - 32 Number of drugs dispensed 33 (ambulatory) 34 Total - 19,511,710 23,520,356 1,620,805 35 36 <2 years, n (%) - 1,346,903 (6.9) 2,880,951 (12.2) 187,486 (11.5) 37 2-11 years, n (%) - 14,036,081 (71.9) 14,984,130 (63.7) 950,984 (58.7) 38 12-18 years, n (%) - 4,128,726 (21.2) 5,655,275 (24.0) 482,335 (29.8) 39 40 41 42 43 *For 589 children in CDARS gender was not recorded at admission 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 70 Table 2a. User prevalence & prescription prevalence and in an inpatient setting by therapeutic level: Prevalence per 1000 persons Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 Class* User Prescription User Prescription User Prescription User Prescription 2 prevalence prevalence prevalence prevalence prevalence prevalence prevalence prevalence 3 (%)** (%)*** (%)** (%)*** (%)** (%)*** (%)** (%)*** 4 Analgesics (inc. NSAIDs) 109 (23) 1269 (23) 131 (36) 314 (19) 31 (19) 380 (24) 43 (25) 195 (23) 5 6 Antibiotics 107 (22) 1141 (20) 91 (25) 634 (37) 43 (26) 496 (31) 37 (21) 233 (27) 7 8 Adrenergics 65 (14) 520 (9) 31 (9) 101 (6) 23 (14) 161 (10) 23 (13) 110 (13) 9 10 Antihistamines 53 (11) 520 (9) 55 (15) 136 (8) 11 (7) 48 (3) 23 (13) 77 (9) 11 12 Mucolytics 53 (11) For614 (11) peer4 (1) review7 (0) 22 (13) only168 (11) 19 (11) 69 (8) 13 14 Corticosteroids 45 (9) 425 (8) 21 (6) 89 (5) 15 (9) 89 (6) 18 (10) 72 (8) 15 16 Antiinfectives (excluding 9 (2) 130 (2) 14 (4) 48 (3) 2 (1) 28 (2) 2 (1) 15 (2) 17 antibiotics and ) 18 Antiepileptics 8 (2) 431 (8) 3 (1) 36 (2) 2 (1) 27 (2) 2 (1) 23 (3) 19 20 8 (2) 170 (3) 3 (1) 39 (2) 2 (1) 42 (3) 2 (1) 14 (2) 21 22 Anticlotting and 7 (1) 188 (3) 1 (0) 25 (1) 12 (7) 99 (6) 2 (1) 8 (1) 23 antifibrinolytic agents 24 Antidiabetic drugs 4 (1) 19 (0) 0 (0) 7 (0) 1 (1) 4 (0) 1 (1) 5 (1) 25 26 Psychotherapeutic agents 2 (0) 65 (1) 3 (1) 138 (8) 2 (1) 17 (1) 1 (1) 14 (2) 27 28 Antineoplastic and 2 (0) 100 (2) 1 (0) 61 (4) 1 (1) 26 (2) 0 (0) 14 (2) 29 immunomodulating 30 agents 31 Central 1 (0) 20 (0) 2 (1) 62 (4) 0 (0) 2 (0) 0 (0) 3 (0) 32 33 Contraceptives 0 (0) 2 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 34 35 *custom classification, see Supplemental Material 1 36 37 **% of the total country specific user prevalence 38 ***% of the total country specific prescription prevalence 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 70 BMJ Open

1 2 Table 2b. User prevalence & prescription prevalence and in an ambulatory setting by therapeutic level (prevalence per 1000 persons) 3 Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 4 5 Class* User prevalence Prescription User prevalence Prescription User prevalence Prescription 6 (%)** prevalence (%)** prevalence (%)** prevalence 7 (%)*** (%)*** (%)*** 8 Antibiotics 440 (22) 882 (25) 796 (14) 2010 (8) 679 (46) 918 (52) 9 10 Corticosteroids 401 (20) 954 (27) 701 (13) 1352 (6) 348 (23) 281 (16) 11 12 Analgesics (inc. NSAIDs) For333 (16) peer428 (12) review933 (17) only5889 (24) 96 (6) 61 (3) 13 14 Adrenergics 242 (12) 405 (11) 814 (15) 4666 (19) 184 (12) 193 (11) 15 16 Antihistamines 261 (13) 415 (12) 883 (16) 6246 (26) 3 (0) 1 (0) 17 18 Mucolytics 240 (12) 353 (10) 756 (14) 3053 (13) 0 (0) 0 (0) 19 Antiinfectives (excluding antibiotics 20 91 (4) 60 (2) 490 (9) 842 (3) 72 (5) 25 (1) 21 and vaccines) 22 Contraceptives 1 (0) 1 (0) 23 (0) 17 (0) 34 (2) 27 (2) 23 24 Psychotherapeutic agents 2 (0) 7 (0) 23 (0) 41 (0) 33 (2) 86 (5) 25 26 Central nervous system stimulants 3 (0) 5 (0) 20 (0) 65 (0) 25 (2) 117 (7) 27 Antineoplastic and 28 4 (0) 7 (0) 9 (0) 15 (0) 1 (0) 3 (0) immunomodulating agents 29 30 Antiepileptics 2 (0) 5 (0) 15 (0) 44 (0) 6 (0) 41 (2) 31 32 Anticlotting and antifibrinolytic agents 3 (0) 2 (0) 13 (0) 10 (0) 1 (0) 2 (0) 33 34 Diuretics 0 (0) 1 (0) 4 (0) 5 (0) 2 (0) 2 (0) 35 36 Antidiabetic drugs 0 (0) 1 (0) 2 (0) 8 (0) 3 (0) 5 (0) 37 *custom classification, see Supplemental Material 1 38 **% of the total country specific user prevalence 39 40 ***% of the total country specific prescription prevalence 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 22 of 70

Table 3a. Most commonly used drugs per anatomical class, per country, in an inpatient setting 1 2 Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 3 Drug name Number Drug name Number Drug name Number Drug name Number per 4 per 1000 per 1000 per 1000 1000 users 5 users users users 6 Antibiotics Ceftriaxone 27.02 Amoxicillin 34.08 10.09 Cefazolin 15.17 7 19.03 18.09 9.2 Amoxicillin 10.9 8 9 17.11 G 14.33 5.56 Gentamicin Sulfate 8.79 10 16.84 12.72 Clarithromycin 5.25 Ampicillin 7 11 Clarithromycin 10.9 Ampicillin 12.4 4.61 Cephalexin 6.64 12 Analgesics (inc. Paracetamol For50.94 peerParacetamol review127.67 Paracetamol only 19.32 Paracetamol 30.17 13 14 NSAIDs) 50.45 4.99 7.34 17.94 15 Tramadol 28.9 Ibuprofen 4.78 5.2 Ibuprofen 15.07 16 26.85 Diclofenac 1.66 4.39 Meperidine 5.21 17 19.11 1.29 3.91 Ketorolac 4.81 18 19 Adrenergics Formoterol 27.63 Albuterol 22.81 Tulobuterol 10.32 8.09 20 Epinephrine 26.85 6.01 8.12 Pseudoephedrine 7.79 21 14.97 1.02 Albuterol 7.51 Procaterol 7.5 22 Albuterol 14.64 Terbutaline 0.97 Epinephrine 4.62 4.97 23 24 Pseudoephedrine 6.12 Phenylephrine 0.59 1.8 Albuterol 4.74 25 Antihistamines Chlorpheniramine 51.7 Chlorpheniramine 38.37 5.23 Cyproheptadine 14.26 26 4.02 19.59 1.24 Chlorpheniramine 4.4 27 1.85 6.01 Ketotifen 1.12 Diphenhydramine 3.01 28 29 1.23 2.36 Diphenhydramine 1 1.94 30 1 0.8 0.77 Cetirizine 1.91 31 Mucolytics Bromhexine 39.3 Bromhexine 2.09 Carbocysteine 18.93 Acetylcysteine 11.04 32 Acetylcysteine 24.28 Acetylcysteine 1.02 Ambroxol 8.23 Ambroxol 7.18 33 34 4.7 Carbocysteine 0.48 Bromhexine 4.6 Bromhexine 3.32 35 3.54 0.27 Acetylcysteine 0.21 Mannitol 1.16 36 Carbocysteine 0.69 - - 0.17 Carbocysteine 0.22 37 Corticosteroids Dexamethasone 23.48 9.34 prednisolone 4.09 Prednisolone 4.92 38 39 15.45 7.89 Methylprednisolone 3.95 Hydrocortisone 4.61 40 Prednisolone 12.11 Beclomethasone 3.6 Dexamethasone 3.36 Dexamethasone 4.4 41 Hydrocortisone 10.15 Dexamethasone 2.9 Hydrocortisone 3.17 4.13 42 Prednicarbate 7.74 Budesonide 1.29 1.95 Methylprednisolone 3.61 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 23 of 70 BMJ Open

Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 2 3 Antiinfectives Oseltamivir 3.27 Hep.B hyp. globulin 4.35 Oseltamivir 0.5 0.62 4 Acyclovir 2.53 Oseltamivir 2.84 lysozyme 0.31 Nystatin 0.54 5 Fluconazole 1.3 Acyclovir 2.15 0.26 Fluconazole 0.37 6 Palivizumab 0.55 2.09 Acyclovir 0.24 Clotrimazole 0.29 7 0.49 Nystatin 1.82 Fluconazole 0.2 Acyclovir 0.24 8 9 Anticlotting and 5.98 Heparin 0.91 Heparin 11.5 Heparin 1.33 10 antifibrinolytic III 1.59 0.32 Dipyridamole 0.28 0.19 11 agents Streptokinase 0.6 0.27 0.25 Urokinase 0.11 12 Urokinase For0.54 peerWarfarin review0.16 Antithrombin only III 0.24 Dipyridamole 0.1 13 14 Enoxaparin 0.1 Enoxaparin 0.11 Urokinase 0.07 Warfarin 0.06 15 Antiepileptics Phenobarbital 3.64 Phenobarbital 1.18 Phenobarbital 0.95 0.66 16 2.58 Phenytoin 0.7 0.63 Phenobarbital 0.59 17 2.41 Carbamazepine 0.64 0.15 0.51 18 19 1.38 Levetiracetam 0.59 Levetiracetam 0.14 0.23 20 0.8 Topiramate 0.32 Clonazepam 0.14 Topiramate 0.19 21 Diuretics 6.54 Furosemide 2.41 Furosemide 1.78 Furosemide 1.58 22 1.32 Spironolactone 1.45 Spironolactone 0.87 Spironolactone 0.17 23 24 1.2 0.43 0.06 0.03 25 Hydrochlorothiazide 0.08 - Hydrochlorothiazide 0.02 Trichlormethiazide 0.02 26 - - Torsemide 0.02 0.01 27 Psychotherapeutic 0.58 1.34 0.79 Haloperidol 0.34 28 agents 29 Risperidone 0.52 Haloperidol 1.02 0.37 Risperidone 0.2 30 0.42 0.75 Risperidone 0.26 Quetiapine 0.13 31 0.3 0.48 olanzapine 0.11 0.09 32 Fluoxetine 0.28 0.43 Haloperidol 0.1 0.08 33 34 Antineoplastic & 0.68 0.43 0.16 Methotrexate 0.2 35 immunomodulating Methotrexate 0.5 0.38 Vincristine 0.14 0.16 36 agents 0.45 Methotrexate 0.32 Cyclophosphamide 0.14 Filgrastim 0.16 37 Vincristine 0.35 Cyclophosphamide 0.32 0.13 Vincristine 0.14 38 39 Cyclosporine 0.34 Cytarabine 0.32 Cyclosporine 0.13 Cyclophosphamide 0.14 40 Central nervous 0.66 Caffeine 1.4 Caffeine 0.1 0.27 41 system stimulants Methylphenidate 0.23 Methylphenidate 0.8 0.03 Methylphenidate 0.08 42 0.05 Tomoxetine 0.11 Methylphenidate 0.02 atomoxetine <0.01 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 24 of 70

Drug class Korea (AUSOM) Hong Japan (JMDC) Taiwan Drug Korea (AUSOM) Hong Kong 1 Kong (NHIRD) class (CDARS) 2 3 (CDARS) 4 Antidiabetic drugs Regular 3.24 0.27 0.5 Regular Insulin 0.54 5 0.32 Insulin Detemir 0.11 0.06 Insulin Glargine 0.09 6 Insulin Glargine 0.12 0.11 0.04 Metformin 0.05 7 Metformin 0.06 - Metformin 0.01 Insulin Detemir 0.04 8 9 Insuline Glulisine 0.05 - Insuline Glulisine 0.01 0.01 10 Contraceptives 0.16 0.16 Norethindrone <0.01 Medroxyprogeste 0.02 11 Medroxyprogeste 0.04 Medroxyprogeste 0.05 Medroxyprogeste <0.01 Megestrol 0.01 12 - For peerNorethindrone review0.05 - only - 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 70 BMJ Open

Table 3b. Most commonly used drugs per anatomical class, per country, in an ambulatory setting 1 2 Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 3 Drug name Number Drug name Number Drug name Number 4 per 1000 per per 1000 5 users 1000 users 6 users 7 Antibiotics Clarithromycin 112.34 Amoxicillin 443.86 Amoxicillin 506.88 8 9 Gentamicin 109.87 Cephalexin 276.72 Cephalexin 279.23 10 Cefcapene 84.12 Sulfamethoxazole 217.87 148.45 11 Gentamicin Sulfate 73.38 170.63 Erythromycin 147.04 12 Ofloxacin 72.45 168.23 116.35 13 14 Corticosteroids Betamethasone 232.34 Betamethasone 353.29 Prednisolone 165.53 15 Dexamethasone 154.65 Dexamethasone 285.17 Hydrocortisone 83.38 16 HydrocortisoneFor peer64.61 reviewTriamcinolone only198.38 71.28 17 Prednisolone 60.3 Prednisolone 194.59 Betamethasone 65.42 18 19 57.76 Fluorometholone 180.39 Dexamethasone 63.29 20 Analgesics (inc. Paracetamol 253.67 Paracetamol 879.68 Paracetamol 72.78 21 NSAIDs) Loxoprofen 63.76 Diclofenac 679.67 Codeine 27.87 22 42.91 Ibuprofen 615.18 Ibuprofen 9.71 23 24 Dihydrocodeine 34.9 Codeine 194.02 6.08 25 31.47 101.18 Diclofenac 4.85 26 Antihistamines Cyproheptadine 75.51 461.81 Cyproheptadine 3.11 27 Ketotifen 57.63 Cyproheptadine 442.32 Promethazine 0.07 28 29 48.02 Cetirizine 381.81 - - 30 46.31 Mequitazine 338.95 - - 31 Mequitazine 35.14 Chlorpheniramine 309.08 - - 32 Adrenergics Tulobuterol 103.78 Pseudoephedrine 728.27 Albuterol 164.14 33 34 Epinephrine 86.05 Fenoterol 301.3 32.61 35 Procaterol 70.65 Procaterol 279.84 9.54 36 Albuterol 57.82 209.47 Epinephrine 4.15 37 Phenylephrine 9.87 Terbutaline 177.29 Terbutaline 3.04 38 39 Mucolytics Carbocysteine 175.47 Ambroxol 546.33 0.19 40 Ambroxol 78.67 Bromhexine 335.46 Mannitol 0.01 41 Bromhexine 49.24 Eprazinone 274.49 Acetylcysteine 0.01 42 Eprazinone 8.95 Acetylcysteine 265.77 Mesna 0.01 43 44 Acetylcysteine 8.46 Carbocysteine 197.11 - - 45 Antiinfectives Oseltamivir 41.17 Lysozyme 377.54 Nystatin 63.5 46 Lysozyme 25.34 Oseltamivir 73.71 Acyclovir 1.78 47 Acyclovir 14.65 Econazole 44.27 Terbinafine 1.43 48 49 6.63 Clotrimazole 29.53 Amphotericin B 1.41 50 Valacyclovir 5.05 29 Ketoconazole 1.4 51 Psychotherapeutic Risperidone 0.72 Sulpiride 7.64 Fluoxetine 9 52 agents Sulpiride 0.37 3.24 Risperidone 6.59 53 54 Imipramine 0.32 2.27 Sertraline 5.8 55 Aripiprazole 0.32 Fluoxetine 2.12 Escitalopram 4.3 56 0.27 Risperidone 2.06 3.4 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 70

Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 1 2 Contraceptives Norethindrone 0.48 Norethindrone 15.18 Levonorgestrel 26.22 3 0.29 Medroxyprogesterone 9.53 7.82 4 - - 0.09 Medroxyprogesterone 4.81 5 - - Megestrol <0.01 Norethindrone 3.73 6 7 - - - - Megestrol 0.01 8 Central nervous Caffeine 2.11 Methylphenidate 13.54 Methylphenidate 21.24 9 system stimulants Methylphenidate 0.68 Piracetam 3.22 6.09 10 Atomoxetine 0.32 Caffeine 3.2 Atomoxetine 3.28 11 12 0.01 Atomoxetine 1.36 Modafinil 0.02 13 0.01 Modafinil 0.02 - - 14 Antineoplastic and Tacrolimus 3.44 6.81 Methotrexate 0.52 15 immunomodulating Cyclosporine 0.26 Tacrolimus 0.93 0.29 16 agents For peer review only 17 Leuprolide 0.21 Methotrexate 0.38 0.2 18 Methotrexate 0.09 Azathioprine 0.29 Cyclosporine 0.16 19 Vincristine 0.08 Leuprolide 0.15 Tacrolimus 0.15 20 Antiepileptics Phenobarbital 1.19 Phenobarbital 9.4 Carbamazepine 2.51 21 22 Carbamazepine 0.63 Clonazepam 2.56 Lamotrigine 1.47 23 Zonisamide 0.15 Oxcarbazepine 0.99 Levetiracetam 1.18 24 Clonazepam 0.15 Carbamazepine 0.99 Topiramate 1.09 25 Levetiracetam 0.13 Topiramate 0.98 Phenytoin 0.41 26 27 Anticlotting and Heparin 2.66 Streptokinase 9.55 Warfarin 0.42 28 antifibrinolytic Dipyridamole 0.12 Dipyridamole 1.82 Enoxaparin 0.27 29 agents Warfarin 0.11 Heparin 0.94 0.14 30 0.04 Epoprostenol 0.16 Dipyridamole 0.02 31 32 0.02 Warfarin 0.12 Dalteparin 0.01 33 Diuretics Furosemide 0.42 Furosemide 1.78 Furosemide 0.82 34 Spironolactone 0.27 Spironolactone 1.52 Spironolactone 0.51 35 Trichlormethiazide 0.02 Hydrochlorothiazide 0.49 Hydrochlorothiazide 0.51 36 37 Hydrochlorothiazide 0 Trichlormethiazide 0.4 0.12 38 Torsemide 0 Bumetanide 0.06 Amiloride 0.03 39 Antidiabetic drugs Regular Insulin, 0.09 Metformin 0.76 Metformin 1.46 40 Human 41 Insulin Glargine 0.07 Gliclazide 0.49 Insulin Glargine 0.98 42 43 Insulin Lispro 0.04 Regular Insulin, 0.36 Regular Insulin, 0.79 44 Human Human 45 Metformin 0.01 0.26 Insulin Detemir 0.64 46 0.01 0.25 Insulin Lispro 0.22 47 48 *custom classification, see Supplemental Material 1 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 70 BMJ Open

Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 1 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 28 of 70

1 2 3 4 5 6 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 Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 33 34 35 36 37 38 39 40 41 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 Page 29 of 70 BMJ Open

1 2 3 4 5 6 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 34 35 36 37 38 39 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 40 41 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 30 of 70

1 2 3 Concept ID Name Class 4 5 1319998 Adrenergics 6 1154343 Albuterol Adrenergics 7 930021 Adrenergics 8 919986 Adrenergics 9 10 1111220 Adrenergics 11 1314002 Adrenergics 12 19034275 Adrenergics 13 1322081 Adrenergics 14 15 1338005 Adrenergics 16 915542 Adrenergics 17 21603320 Adrenergics 18 950370 CarteololFor peer review onlyAdrenergics 19 20 1346823 Adrenergics 21 19097824 Adrenergics 22 1398937 Clonidine Adrenergics 23 19086622 Adrenergics 24 25 19061088 Adrenergics 26 990009 Dipivefrin Adrenergics 27 1337720 Adrenergics 28 1363053 Adrenergics 29 30 1143374 Ephedrine Adrenergics 31 1343916 Epinephrine Adrenergics 32 19063575 Adrenergics 33 19053979 Fenoterol Adrenergics 34 35 1196677 formoterol Adrenergics 36 1366237 Adrenergics 37 1344965 Adrenergics 38 19068969 Adrenergics 39 40 1181809 Isoetharine Adrenergics 41 21603309 , combinations Adrenergics 42 1183554 Isoproterenol Adrenergics 43 1386957 Adrenergics 44 45 1192218 Levalbuterol Adrenergics 46 932815 Adrenergics 47 1123995 metaproterenol Adrenergics 48 19009365 Adrenergics 49 50 1305447 Adrenergics 51 905531 Adrenergics 52 1307046 Adrenergics 53 1308368 Adrenergics 54 55 42873636 Adrenergics 56 1313200 Adrenergics 57 21603310 , combinations Adrenergics 58 19026274 p-Hydroxyamphetamine Adrenergics 59 60 1327978 Adrenergics

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1 2 3 1335301 Adrenergics 4 5 1335539 Adrenergics 6 1135766 Phenylephrine Adrenergics 7 1345858 Adrenergics 8 1125449 Adrenergics 9 10 1350489 Adrenergics 11 19028950 Procaterol Adrenergics 12 1353766 Propranolol Adrenergics 13 1154332 Pseudoephedrine Adrenergics 14 15 19035396 Adrenergics 16 1137529 salmeterol Adrenergics 17 19012925 Adrenergics 18 924566 tamsulosinFor peer review onlyAdrenergics 19 20 1341238 Adrenergics 21 1236744 Terbutaline Adrenergics 22 21603325 terbutaline, combinations Adrenergics 23 902427 Adrenergics 24 25 778474 Adrenergics 26 21603319 tretoquinol Adrenergics 27 19043191 tulobuterol Adrenergics 28 43532539 Adrenergics 29 30 19029393 Analgesics (inc. NSAIDs) 31 19029398 Analgesics (inc. NSAIDs) 32 1125315 Acetaminophen Analgesics (inc. NSAIDs) 33 21603946 Analgesics (inc. NSAIDs) 34 35 19059528 Analgesics (inc. NSAIDs) 36 19018431 Analgesics (inc. NSAIDs) 37 1103552 Analgesics (inc. NSAIDs) 38 19018432 Analgesics (inc. NSAIDs) 39 , combinations excl. 40 21604337 Analgesics (inc. NSAIDs) 41 aminophenazone, combinations with 42 21604341 psycholeptics Analgesics (inc. NSAIDs) 43 44 19125628 Aminopyrine Analgesics (inc. NSAIDs) 45 1036059 Antipyrine Analgesics (inc. NSAIDs) 46 19136654 Apazone Analgesics (inc. NSAIDs) 47 1112807 Aspirin Analgesics (inc. NSAIDs) 48 49 40254364 avocado and soyabean oil, unsaponifiables Analgesics (inc. NSAIDs) 50 19016435 Analgesics (inc. NSAIDs) 51 21603972 Analgesics (inc. NSAIDs) 52 19019620 Analgesics (inc. NSAIDs) 53 54 21604279 Analgesics (inc. NSAIDs) 55 1139179 Analgesics (inc. NSAIDs) 56 21604346 Analgesics (inc. NSAIDs) 57 21604350 bucetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 58 59 21604353 bucetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 60 19032724 Analgesics (inc. NSAIDs)

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1 2 3 19039703 Analgesics (inc. NSAIDs) 4 5 1133201 Analgesics (inc. NSAIDs) 6 1133732 Analgesics (inc. NSAIDs) 7 21604363 Analgesics (inc. NSAIDs) 8 21604318 carbasalate Analgesics (inc. NSAIDs) 9 combinations excl. 10 21604324 psycholeptics Analgesics (inc. NSAIDs) 11 12 1118084 Analgesics (inc. NSAIDs) 13 1395573 Chondroitin Analgesics (inc. NSAIDs) 14 19018512 Analgesics (inc. NSAIDs) 15 1201620 Codeine Analgesics (inc. NSAIDs) 16 17 21604268 codeine, combinations with psycholeptics Analgesics (inc. NSAIDs) 18 21603980 dexibuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 19056874 Analgesics (inc. NSAIDs) 20 19021940 Analgesics (inc. NSAIDs) 21 , combinations with 22 21604282 psycholeptics Analgesics (inc. NSAIDs) 23 24 19088393 Analgesics (inc. NSAIDs) 25 19088915 diacetylrhein Analgesics (inc. NSAIDs) 26 21604262 DIAMORPHINE Analgesics (inc. NSAIDs) 27 1124300 Diclofenac Analgesics (inc. NSAIDs) 28 29 21603952 Analgesics (inc. NSAIDs) 30 1126128 Analgesics (inc. NSAIDs) 31 1189596 dihydrocodeine Analgesics (inc. NSAIDs) 32 1126557 Analgesics (inc. NSAIDs) 33 34 21604370 dihydroergotamine, combinations Analgesics (inc. NSAIDs) 35 21604313 Analgesics (inc. NSAIDs) 36 21604323 dipyrocetyl, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 37 21604328 dipyrocetyl, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 39 19056645 Analgesics (inc. NSAIDs) 40 1189697 Analgesics (inc. NSAIDs) 41 1145379 Analgesics (inc. NSAIDs) 42 21604372 ergotamine, combinations with psycholeptics Analgesics (inc. NSAIDs) 43 44 19059506 Analgesics (inc. NSAIDs) 45 21604322 ethenzamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 46 21604327 ethenzamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 47 1195492 Analgesics (inc. NSAIDs) 48 49 19011355 Analgesics (inc. NSAIDs) 50 19095703 Analgesics (inc. NSAIDs) 51 1153928 Analgesics (inc. NSAIDs) 52 1154029 Fentanyl Analgesics (inc. NSAIDs) 53 54 21603950 Analgesics (inc. NSAIDs) 55 19135796 Analgesics (inc. NSAIDs) 56 21604014 feprazone, combinations Analgesics (inc. NSAIDs) 57 19054931 Analgesics (inc. NSAIDs) 58 59 19110711 Analgesics (inc. NSAIDs) 60 21604374 Analgesics (inc. NSAIDs)

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1 2 3 21603981 Analgesics (inc. NSAIDs) 4 5 19064698 Analgesics (inc. NSAIDs) 6 1156378 Flurbiprofen Analgesics (inc. NSAIDs) 7 19113015 fonazine Analgesics (inc. NSAIDs) 8 1189458 Analgesics (inc. NSAIDs) 9 10 21604356 Analgesics (inc. NSAIDs) 11 1360332 Analgesics (inc. NSAIDs) 12 21604004 glucosaminoglycan polysulfate Analgesics (inc. NSAIDs) 13 21604317 Analgesics (inc. NSAIDs) 14 15 1174888 Analgesics (inc. NSAIDs) 16 1126658 Analgesics (inc. NSAIDs) 17 21604295 hydromorphone and antispasmodics Analgesics (inc. NSAIDs) 18 1177480 IbuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 21603979 Analgesics (inc. NSAIDs) 21 19069104 -2-hydroxybenzoate Analgesics (inc. NSAIDs) 22 21603958 , combinations Analgesics (inc. NSAIDs) 23 1178663 Indomethacin Analgesics (inc. NSAIDs) 24 25 21603976 Analgesics (inc. NSAIDs) 26 19113032 Analgesics (inc. NSAIDs) 27 19069191 Analgesics (inc. NSAIDs) 28 21604270 Analgesics (inc. NSAIDs) 29 30 21604293 ketobemidone and antispasmodics Analgesics (inc. NSAIDs) 31 1185922 Ketoprofen Analgesics (inc. NSAIDs) 32 21603985 ketoprofen, combinations Analgesics (inc. NSAIDs) 33 1136980 Ketorolac Analgesics (inc. NSAIDs) 34 35 1189766 Analgesics (inc. NSAIDs) 36 19071933 Analgesics (inc. NSAIDs) 37 19049709 Analgesics (inc. NSAIDs) 38 19071936 loxoprofen Analgesics (inc. NSAIDs) 39 40 21603997 Analgesics (inc. NSAIDs) 41 19125097 Analgesics (inc. NSAIDs) 42 19125195 Analgesics (inc. NSAIDs) 43 1150345 Analgesics (inc. NSAIDs) 44 45 40254075 meloxicam, combinations Analgesics (inc. NSAIDs) 46 1102527 Meperidine Analgesics (inc. NSAIDs) 47 19003010 Analgesics (inc. NSAIDs) 48 sodium, combinations excl. 49 21604336 psycholeptics Analgesics (inc. NSAIDs) 50 metamizole sodium, combinations with 51 21604340 psycholeptics Analgesics (inc. NSAIDs) 52 1103640 Analgesics (inc. NSAIDs) 53 54 21604280 methadone, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 55 19005257 Analgesics (inc. NSAIDs) 56 1106740 Analgesics (inc. NSAIDs) 57 19072129 Analgesics (inc. NSAIDs) 58 59 19072152 Analgesics (inc. NSAIDs) 60 1110410 Morphine Analgesics (inc. NSAIDs)

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1 2 3 21604292 morphine and antispasmodics Analgesics (inc. NSAIDs) 4 5 19056115 MORPHOLINE SALICYLATE Analgesics (inc. NSAIDs) 6 1113648 Analgesics (inc. NSAIDs) 7 1114122 Analgesics (inc. NSAIDs) 8 40254094 Analgesics (inc. NSAIDs) 9 10 1115008 Naproxen Analgesics (inc. NSAIDs) 11 40254098 naproxen and Analgesics (inc. NSAIDs) 12 1118117 Analgesics (inc. NSAIDs) 13 19015602 Analgesics (inc. NSAIDs) 14 15 909795 Analgesics (inc. NSAIDs) 16 21604259 Analgesics (inc. NSAIDs) 17 21604334 Analgesics (inc. NSAIDs) 18 19019023 NiflumicFor Acid peer review onlyAnalgesics (inc. NSAIDs) 19 20 19069425 Analgesics (inc. NSAIDs) 21 923829 Analgesics (inc. NSAIDs) 22 19082874 orgotein Analgesics (inc. NSAIDs) 23 19003691 Analgesics (inc. NSAIDs) 24 25 21603953 Analgesics (inc. NSAIDs) 26 1118045 Analgesics (inc. NSAIDs) 27 19082880 Analgesics (inc. NSAIDs) 28 1124957 Oxycodone Analgesics (inc. NSAIDs) 29 30 1125765 Analgesics (inc. NSAIDs) 31 19025925 Analgesics (inc. NSAIDs) 32 19129648 Papaveretum Analgesics (inc. NSAIDs) 33 19003570 Analgesics (inc. NSAIDs) 34 35 1130585 Pentazocine Analgesics (inc. NSAIDs) 36 21604294 and antispasmodics Analgesics (inc. NSAIDs) 37 21604274 pethidine, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 19033710 Analgesics (inc. NSAIDs) 39 40 21604349 phenacetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 41 21604352 phenacetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 42 19132884 Analgesics (inc. NSAIDs) 43 21604335 , combinations excl. psycholeptics Analgesics (inc. NSAIDs) 44 45 21604339 phenazone, combinations with psycholeptics Analgesics (inc. NSAIDs) 46 1135710 Analgesics (inc. NSAIDs) 47 19134009 Pirinitramide Analgesics (inc. NSAIDs) 48 1146810 Analgesics (inc. NSAIDs) 49 50 21603974 Analgesics (inc. NSAIDs) 51 19047076 Pizotyline Analgesics (inc. NSAIDs) 52 19029327 Analgesics (inc. NSAIDs) 53 21604347 Analgesics (inc. NSAIDs) 54 55 1153664 Propoxyphene Analgesics (inc. NSAIDs) 56 19029322 Analgesics (inc. NSAIDs) 57 propyphenazone, combinations excl. 58 21604338 psycholeptics Analgesics (inc. NSAIDs) 59 propyphenazone, combinations with 60 21604342 psycholeptics Analgesics (inc. NSAIDs)

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1 2 3 21604005 Analgesics (inc. NSAIDs) 4 5 19016749 remifentanil Analgesics (inc. NSAIDs) 6 21604355 Analgesics (inc. NSAIDs) 7 1154077 Analgesics (inc. NSAIDs) 8 1189754 Analgesics (inc. NSAIDs) 9 10 1164108 salicylamide Analgesics (inc. NSAIDs) 11 21604321 salicylamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 12 21604326 salicylamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 13 1137460 Analgesics (inc. NSAIDs) 14 15 19078219 Sufentanil Analgesics (inc. NSAIDs) 16 1236607 Analgesics (inc. NSAIDs) 17 1140643 Analgesics (inc. NSAIDs) 18 1036636 SuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 19026459 Analgesics (inc. NSAIDs) 21 21604011 Analgesics (inc. NSAIDs) 22 19041220 Analgesics (inc. NSAIDs) 23 19002431 Analgesics (inc. NSAIDs) 24 25 19042155 Analgesics (inc. NSAIDs) 26 1102917 Analgesics (inc. NSAIDs) 27 1103314 Tramadol Analgesics (inc. NSAIDs) 28 1103374 Analgesics (inc. NSAIDs) 29 30 21604358 viminol Analgesics (inc. NSAIDs) 31 19005061 Analgesics (inc. NSAIDs) 32 1116031 Analgesics (inc. NSAIDs) 33 19102108 Analgesics (inc. NSAIDs) 34 35 19123877 Amdinocillin Antibiotics 36 19088223 Amdinocillin Pivoxil Antibiotics 37 1790868 Antibiotics 38 1713332 Amoxicillin Antibiotics 39 40 1717327 Ampicillin Antibiotics 41 21602839 ampicillin, combinations Antibiotics 42 40255264 aspoxicillin Antibiotics 43 19018516 Antibiotics 44 45 1734104 Antibiotics 46 45893479 azithromycin, fluconazole and secnidazole Antibiotics 47 19015123 Antibiotics 48 1715117 Antibiotics 49 50 1734205 Antibiotics 51 915175 Antibiotics 52 40255908 Antibiotics 53 21602924 Antibiotics 54 55 19018742 Antibiotics 56 1740546 Antibiotics 57 40255589 Antibiotics 58 21602879 Antibiotics 59 60 1768849 Cefaclor Antibiotics

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1 2 3 1769535 Antibiotics 4 5 19070174 Antibiotics 6 19070680 Antibiotics 7 21602875 Antibiotics 8 1771162 Cefazolin Antibiotics 9 10 40255561 Antibiotics 11 21602911 cefcapene Antibiotics 12 1796458 Antibiotics 13 1747005 Antibiotics 14 15 1748975 Antibiotics 16 45893466 cefepime and amikacin Antibiotics 17 19028241 Antibiotics 18 1796435 CefiximeFor peer review onlyAntibiotics 19 20 21602899 Antibiotics 21 19072255 Antibiotics 22 40255560 Antibiotics 23 19028286 Antibiotics 24 25 19072857 Antibiotics 26 1773402 Antibiotics 27 21602913 cefoperazone, combinations Antibiotics 28 19028288 Antibiotics 29 30 1774470 Cefotaxime Antibiotics 31 45893191 cefotaxime, combinations Antibiotics 32 1774932 Antibiotics 33 19051271 Antibiotics 34 35 1775741 Antibiotics 36 21602917 Antibiotics 37 21602905 Antibiotics 38 19001904 Antibiotics 39 40 1749008 Antibiotics 41 1738366 Antibiotics 42 21602880 Antibiotics 43 19051345 Antibiotics 44 45 40230597 ceftaroline Antibiotics 46 1776684 Antibiotics 47 21602881 Antibiotics 48 1749083 Antibiotics 49 50 1777254 Antibiotics 51 21602928 medocaril Antibiotics 52 45892599 ceftolozane Antibiotics 53 1777806 Ceftriaxone Antibiotics 54 55 21602912 ceftriaxone, combinations Antibiotics 56 1778162 Cefuroxime Antibiotics 57 21603039 cefuroxime and Antibiotics 58 1786621 Cephalexin Antibiotics 59 60 19052683 Antibiotics

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1 2 3 19086759 Cephalothin Antibiotics 4 5 19086790 Cephapirin Antibiotics 6 1786842 Cephradine Antibiotics 7 990069 Chloramphenicol Antibiotics 8 19095043 Antibiotics 9 10 997496 Antibiotics 11 1797513 Antibiotics 12 45893269 ciprofloxacin and metronidazole Antibiotics 13 45893270 ciprofloxacin and Antibiotics 14 15 45893513 ciprofloxacin and Antibiotics 16 1750500 Clarithromycin Antibiotics 17 997881 Clindamycin Antibiotics 18 19047240 clofoctolFor peer review onlyAntibiotics 19 20 21602847 clometocillin Antibiotics 21 19047265 Antibiotics 22 1800835 Antibiotics 23 1701677 colistimethate Antibiotics 24 25 901845 Antibiotics 26 21602811 combinations of Antibiotics 27 45774861 Antibiotics 28 1789517 dalfopristin Antibiotics 29 30 1786617 Antibiotics 31 1714527 Antibiotics 32 19023508 Antibiotics 33 1724666 Antibiotics 34 35 1790024 Antibiotics 36 1713905 Antibiotics 37 1738521 Antibiotics 38 1743222 Antibiotics 39 40 21602826 Antibiotics 41 1717963 Antibiotics 42 1746940 Erythromycin Antibiotics 43 43534793 Antibiotics 44 45 40239985 Antibiotics 46 19050750 Antibiotics 47 40255562 Antibiotics 48 19054936 Floxacillin Antibiotics 49 50 19064329 Antibiotics 51 21602982 Antibiotics 52 956653 Antibiotics 53 45893495 furazidin Antibiotics 54 55 21603026 Antibiotics 56 1789276 Antibiotics 57 1716721 Antibiotics 58 45892419 Gentamicin Antibiotics 59 60 919345 Gentamicin Sulfate (USP) Antibiotics

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1 2 3 1747032 Antibiotics 4 5 19101402 habekacin Antibiotics 6 19069006 Antibiotics 7 21602933 Antibiotics 8 1778262 Antibiotics 9 10 21603004 Antibiotics 11 19123240 Antibiotics 12 1784749 Kanamycin Antibiotics 13 1742253 Antibiotics 14 15 43534794 levofloxacin and ornidazole Antibiotics 16 1790692 Antibiotics 17 1736887 Antibiotics 18 1707800 lomefloxacinFor peer review onlyAntibiotics 19 20 1708100 Antibiotics 21 19092353 Antibiotics 22 992716 Antibiotics 23 19008870 Antibiotics 24 25 1709170 Antibiotics 26 19003644 Methacycline Antibiotics 27 19072054 methampicillin Antibiotics 28 904356 Methenamine Antibiotics 29 30 1707164 Metronidazole Antibiotics 31 19007701 Antibiotics 32 19072122 Antibiotics 33 1708880 Antibiotics 34 35 19009138 Antibiotics 36 19126622 Moxalactam Antibiotics 37 1716903 Antibiotics 38 951511 Antibiotics 39 40 1713930 Antibiotics 41 915981 Antibiotics 42 19017585 Antibiotics 43 21603059 Antibiotics 44 45 920293 Antibiotics 46 45893503 nitrofurantoin, combinations Antibiotics 47 19015464 Antibiotics 48 1721543 Antibiotics 49 50 45893468 norfloxacin and tinidazole Antibiotics 51 923081 Ofloxacin Antibiotics 52 45893194 ofloxacin and ornidazole Antibiotics 53 19023254 Antibiotics 54 55 45776147 Antibiotics 56 19024197 Ornidazole Antibiotics 57 1724703 Antibiotics 58 19129642 Antibiotics 59 60 925952 Antibiotics

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1 2 3 21602926 and betamipron Antibiotics 4 5 21603025 Antibiotics 6 19027679 Antibiotics 7 21602846 Antibiotics 8 19126544 Penicillin Antibiotics 9 10 1728416 Penicillin G Antibiotics 11 1729720 Penicillin V Antibiotics 12 , combinations with other 13 21603037 antibacterials Antibiotics 14 21602808 Antibiotics 15 19088795 phenethicillin Antibiotics 16 17 1746114 Antibiotics 18 21603030 piromidicFor acid peer review onlyAntibiotics 19 19047071 Antibiotics 20 948582 B Antibiotics 21 22 19125201 Antibiotics 23 19096054 Antibiotics 24 21603024 Antibiotics 25 1789515 quinupristin Antibiotics 26 27 991003 Antibiotics 28 21603003 Antibiotics 29 1763204 Rifampin Antibiotics 30 19136008 Antibiotics 31 32 1735947 Antibiotics 33 21602980 Antibiotics 34 19136024 Antibiotics 35 19036545 Antibiotics 36 37 19063874 Roxithromycin Antibiotics 38 21603017 Antibiotics 39 966956 silver Antibiotics 40 19136044 Antibiotics 41 42 40256175 Antibiotics 43 1733765 Antibiotics 44 1701651 Antibiotics 45 19070251 Antibiotics 46 47 21603040 spiramycin and metronidazole Antibiotics 48 21602993 Antibiotics 49 1836191 Antibiotics 50 1836241 Sulbactam Antibiotics 51 52 19000817 Antibiotics 53 1036252 Antibiotics 54 1836391 Sulfadiazine Antibiotics 55 21602966 sulfadiazine and Antibiotics 56 57 21602962 sulfadiazine and Antibiotics 58 19000818 Antibiotics 59 21602965 and trimethoprim Antibiotics 60

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1 2 3 19136423 Antibiotics 4 5 21602958 Antibiotics 6 19136426 Antibiotics 7 21602967 sulfamerazine and trimethoprim Antibiotics 8 19136429 Sulfamethazine Antibiotics 9 10 1036425 Antibiotics 11 1836430 Sulfamethoxazole Antibiotics 12 19000820 Antibiotics 13 21602952 Antibiotics 14 15 21602953 Antibiotics 16 21602963 and trimethoprim Antibiotics 17 19136481 Antibiotics 18 21602964 sulfamoxoleFor and peer trimethoprim review onlyAntibiotics 19 20 1036475 Antibiotics 21 21602955 Antibiotics 22 21602957 Antibiotics 23 19136493 Antibiotics 24 25 1036487 Antibiotics 26 21602942 Antibiotics 27 19000821 Antibiotics 28 1836503 Sulfisoxazole Antibiotics 29 30 19040627 Antibiotics 31 19002077 Antibiotics 32 1741122 Antibiotics 33 45775686 Antibiotics 34 35 19078399 Antibiotics 36 40166675 Antibiotics 37 1702911 Antibiotics 38 19041153 Antibiotics 39 40 19100438 Antibiotics 41 1836948 Antibiotics 42 45893484 tetracycline and oleandomycin Antibiotics 43 19137362 Antibiotics 44 45 21602817 thiamphenicol, combinations Antibiotics 46 1702364 Antibiotics 47 1742432 Antibiotics 48 1702559 Tinidazole Antibiotics 49 50 902722 Antibiotics 51 1705674 Trimethoprim Antibiotics 52 19006043 Antibiotics 53 1712549 Antibiotics 54 55 1707687 Antibiotics 56 19102105 Antibiotics 57 19047423 Anticlotting and antifibrinolytic 58 19024063 Anticlotting and antifibrinolytic 59 60

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1 2 3 acetylsalicylic acid, combinations with proton 4 40252642 pump inhibitors Anticlotting and antifibrinolytic 5 1347450 Anticlotting and antifibrinolytic 6 7 19024544 Anticlotting and antifibrinolytic 8 19044890 Anticlotting and antifibrinolytic 9 1436169 Antithrombin III Anticlotting and antifibrinolytic 10 43013024 Anticlotting and antifibrinolytic 11 12 1322207 Anticlotting and antifibrinolytic 13 19069137 bemiparin Anticlotting and antifibrinolytic 14 21601002 beraprost Anticlotting and antifibrinolytic 15 19084670 Anticlotting and antifibrinolytic 16 17 21601012 Anticlotting and antifibrinolytic 18 46275677 cangrelorFor peer review onlyAnticlotting and antifibrinolytic 19 1350310 Anticlotting and antifibrinolytic 20 1322184 clopidogrel Anticlotting and antifibrinolytic 21 22 21600987 Anticlotting and antifibrinolytic 23 21600969 Anticlotting and antifibrinolytic 24 40228152 dabigatran etexilate Anticlotting and antifibrinolytic 25 1301065 Dalteparin Anticlotting and antifibrinolytic 26 27 19026343 Anticlotting and antifibrinolytic 28 42898933 Anticlotting and antifibrinolytic 29 21601029 Anticlotting and antifibrinolytic 30 19011712 desirudin Anticlotting and antifibrinolytic 31 32 1325124 Dicumarol Anticlotting and antifibrinolytic 33 21600970 Anticlotting and antifibrinolytic 34 1331270 Dipyridamole Anticlotting and antifibrinolytic 35 21600986 Anticlotting and antifibrinolytic 36 37 1731597 Anticlotting and antifibrinolytic 38 1301025 Enoxaparin Anticlotting and antifibrinolytic 39 1354118 Epoprostenol Anticlotting and antifibrinolytic 40 1322199 Anticlotting and antifibrinolytic 41 42 21600968 Anticlotting and antifibrinolytic 43 19113013 fluindione Anticlotting and antifibrinolytic 44 1315865 Anticlotting and antifibrinolytic 45 1367571 Heparin Anticlotting and antifibrinolytic 46 47 21600984 heparin, combinations Anticlotting and antifibrinolytic 48 19069107 Anticlotting and antifibrinolytic 49 19092139 Anticlotting and antifibrinolytic 50 21601023 melagatran Anticlotting and antifibrinolytic 51 52 19001014 Nadroparin Anticlotting and antifibrinolytic 53 19008276 parnaparin Anticlotting and antifibrinolytic 54 19033934 Anticlotting and antifibrinolytic 55 19035344 Anticlotting and antifibrinolytic 56 57 21600988 Anticlotting and antifibrinolytic 58 954696 Plasmin Anticlotting and antifibrinolytic 59 40163718 Anticlotting and antifibrinolytic 60

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1 2 3 42801108 Anticlotting and antifibrinolytic 4 5 19024191 Anticlotting and antifibrinolytic 6 19129274 reviparin Anticlotting and antifibrinolytic 7 40241331 Anticlotting and antifibrinolytic 8 21601014 Anticlotting and antifibrinolytic 9 10 19136187 Streptokinase Anticlotting and antifibrinolytic 11 21600982 Anticlotting and antifibrinolytic 12 19098548 Anticlotting and antifibrinolytic 13 40241186 Anticlotting and antifibrinolytic 14 15 1302398 Ticlopidine Anticlotting and antifibrinolytic 16 1308473 tinzaparin Anticlotting and antifibrinolytic 17 19018364 Anticlotting and antifibrinolytic 18 19017067 tirofibanFor peer review onlyAnticlotting and antifibrinolytic 19 20 19042778 Anticlotting and antifibrinolytic 21 1307515 Urokinase Anticlotting and antifibrinolytic 22 44818499 Anticlotting and antifibrinolytic 23 1310149 Warfarin Anticlotting and antifibrinolytic 24 25 21601024 Anticlotting and antifibrinolytic 26 1529331 Acarbose Antidiabetic drugs 27 1530014 Antidiabetic drugs 28 44816332 Antidiabetic drugs 29 30 43013884 Antidiabetic drugs 31 19035533 Antidiabetic drugs 32 21600748 Antidiabetic drugs 33 43526465 Antidiabetic drugs 34 35 19033498 Antidiabetic drugs 36 1594973 Antidiabetic drugs 37 21600734 combinations Antidiabetic drugs 38 44785829 Antidiabetic drugs 39 40 45774751 Antidiabetic drugs 41 1583722 Antidiabetic drugs 42 43534752 Antidiabetic drugs 43 19001409 Antidiabetic drugs 44 45 19059796 Gliclazide Antidiabetic drugs 46 1597756 glimepiride Antidiabetic drugs 47 1560171 Antidiabetic drugs 48 19097821 Antidiabetic drugs 49 50 21600760 Antidiabetic drugs 51 1559684 Glyburide Antidiabetic drugs 52 19001441 glymidine Antidiabetic drugs 53 1000979 guar gum Antidiabetic drugs 54 55 21600730 insulin (beef) Antidiabetic drugs 56 43534747 Antidiabetic drugs 57 44819155 insulin degludec and Antidiabetic drugs 58 1516976 insulin detemir Antidiabetic drugs 59 60 1502905 Insulin Glargine Antidiabetic drugs

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1 2 3 1550023 Insulin Lispro Antidiabetic drugs 4 5 1544838 Insulin, Glulisine, Human Antidiabetic drugs 6 42899447 Insulin, Pork Antidiabetic drugs 7 40239216 Antidiabetic drugs 8 45893517 linagliptin and empagliflozin Antidiabetic drugs 9 10 40170911 Antidiabetic drugs 11 44506754 Antidiabetic drugs 12 21600759 Antidiabetic drugs 13 1503297 Metformin Antidiabetic drugs 14 15 45893467 metformin and acarbose Antidiabetic drugs 16 45893267 metformin and canagliflozin Antidiabetic drugs 17 43534751 metformin and dapagliflozin Antidiabetic drugs 18 45893491 metforminFor and peer gemigliptin review onlyAntidiabetic drugs 19 20 21600773 metformin and Antidiabetic drugs 21 1510202 Antidiabetic drugs 22 21600796 Antidiabetic drugs 23 1502826 Antidiabetic drugs 24 25 19033909 Antidiabetic drugs 26 21600766 phenformin and sulfonamides Antidiabetic drugs 27 1525215 Antidiabetic drugs 28 43534748 pioglitazone and Antidiabetic drugs 29 30 1517998 Antidiabetic drugs 31 1596977 Regular Insulin, Human Antidiabetic drugs 32 1516766 Antidiabetic drugs 33 1547504 Antidiabetic drugs 34 35 40166035 Antidiabetic drugs 36 1580747 sitagliptin Antidiabetic drugs 37 1502809 Antidiabetic drugs 38 1502855 Tolbutamide Antidiabetic drugs 39 40 19042191 Antidiabetic drugs 41 1515249 Antidiabetic drugs 42 19122137 vildagliptin Antidiabetic drugs 43 21600778 voglibose Antidiabetic drugs 44 45 19112534 Antiepileptics 46 19018520 Antiepileptics 47 740275 Carbamazepine Antiepileptics 48 798874 Clonazepam Antiepileptics 49 50 19054995 dipropylacetamide Antiepileptics 51 44507780 eslicarbazepine Antiepileptics 52 750119 Antiepileptics 53 750146 Antiepileptics 54 55 40239995 ezogabine Antiepileptics 56 795661 Antiepileptics 57 713192 fosphenytoin Antiepileptics 58 797399 Antiepileptics 59 60 19087394 Antiepileptics

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1 2 3 705103 lamotrigine Antiepileptics 4 5 711584 Levetiracetam Antiepileptics 6 702661 Antiepileptics 7 702685 Mephobarbital Antiepileptics 8 19004254 Antiepileptics 9 10 759401 methsuximide Antiepileptics 11 718122 oxcarbazepine Antiepileptics 12 19021932 Antiepileptics 13 42904177 Antiepileptics 14 15 19023286 Antiepileptics 16 734275 Phenobarbital Antiepileptics 17 19023842 Antiepileptics 18 740910 PhenytoinFor peer review onlyAntiepileptics 19 20 734354 Antiepileptics 21 751347 Antiepileptics 22 19095776 Antiepileptics 23 19006586 Antiepileptics 24 25 19000921 sulthiame Antiepileptics 26 715458 Antiepileptics 27 742267 topiramate Antiepileptics 28 19005629 Antiepileptics 29 30 19010963 Valproic Acid Antiepileptics 31 19020002 Antiepileptics 32 744798 zonisamide Antiepileptics 33 1140123 Antihistamines 34 35 951237 Antihistamines 36 1150770 Antihistamines 37 1133993 Antihistamines 38 934075 Antihistamines 39 40 19034280 Antihistamines 41 40166571 Antihistamines 42 40256760 Antihistamines 43 1139216 bromodiphenhydramine Antihistamines 44 45 1130863 Brompheniramine Antihistamines 46 21603466 brompheniramine, combinations Antihistamines 47 19081195 Antihistamines 48 21603499 buclizine, combinations Antihistamines 49 50 1141018 Antihistamines 51 1149196 Cetirizine Antihistamines 52 990413 Antihistamines 53 19049437 Antihistamines 54 55 21603478 chloropyramine, combinations Antihistamines 56 1192710 Chlorpheniramine Antihistamines 57 19049707 Antihistamines 58 21603456 chlorphenoxamine, combinations Antihistamines 59 60 1197677 Clemastine Antihistamines

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1 2 3 21603455 clemastine, combinations Antihistamines 4 5 909358 Antihistamines 6 21603500 cyclizine, combinations Antihistamines 7 1110727 Cyproheptadine Antihistamines 8 21603516 Antihistamines 9 10 1103006 Antihistamines 11 1188052 Antihistamines 12 21603469 dexbrompheniramine, combinations Antihistamines 13 1188114 dexchlorpheniramine Antihistamines 14 15 21603467 dexchlorpheniramine, combinations Antihistamines 16 19028947 Dimethindene Antihistamines 17 1129625 Diphenhydramine Antihistamines 18 21603454 diphenhydramine,For peer combinations review onlyAntihistamines 19 20 19090000 Antihistamines 21 21603457 diphenylpyraline, combinations Antihistamines 22 738818 Antihistamines 23 40254475 doxylamine, combinations Antihistamines 24 25 19092433 ebastine Antihistamines 26 903893 Antihistamines 27 943634 epinastine Antihistamines 28 1153428 fexofenadine Antihistamines 29 30 21603472 Antihistamines 31 21603477 histapyrrodine, combinations Antihistamines 32 21603484 Antihistamines 33 21603490 hydroxyethylpromethazine, combinations Antihistamines 34 35 19003593 Antihistamines 36 986117 Ketotifen Antihistamines 37 1136422 levocetirizine Antihistamines 38 1107830 Antihistamines 39 40 19008999 mebhydroline Antihistamines 41 994341 Antihistamines 42 21603501 meclozine, combinations Antihistamines 43 19009145 mequitazine Antihistamines 44 45 19004158 Antihistamines 46 19009250 Antihistamines 47 19086100 Antihistamines 48 915855 olopatadine Antihistamines 49 50 19071314 Antihistamines 51 21603487 Antihistamines 52 1123534 Antihistamines 53 933952 Antihistamines 54 55 19093165 Antihistamines 56 1153013 Promethazine Antihistamines 57 21603489 promethazine, combinations Antihistamines 58 1159811 Pyrilamine Antihistamines 59 60 21603510 Antihistamines

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1 2 3 21603529 pyrrobutamine, combinations Antihistamines 4 5 43534851 Antihistamines 6 21603527 Antihistamines 7 43534852 sequifenadine Antihistamines 8 21603465 Antihistamines 9 10 1150836 Antihistamines 11 21603506 Antihistamines 12 21603528 thenalidine, combinations Antihistamines 13 21603485 thiazinam Antihistamines 14 15 1037358 Antihistamines 16 43012162 Antihistamines 17 19005570 Trimeprazine Antihistamines 18 942799 trimethobenzamideFor peer review onlyAntihistamines 19 20 1105853 Antihistamines 21 1105889 Triprolidine Antihistamines 22 19101651 Antihistamines 23 Antiinfectives (excluding antibiotics 24 1736971 abacavir and vaccines) 25 Antiinfectives (excluding antibiotics 26 1703687 Acyclovir and vaccines) 27 Antiinfectives (excluding antibiotics 28 21603125 and vaccines) 29 Antiinfectives (excluding antibiotics 30 1726228 aminosalicylic acid and vaccines) 31 Antiinfectives (excluding antibiotics 32 1717240 Amphotericin B and vaccines) 33 Antiinfectives (excluding antibiotics 34 1789428 Amprenavir and vaccines) 35 Antiinfectives (excluding antibiotics 36 19026450 anidulafungin and vaccines) 37 Antiinfectives (excluding antibiotics 38 19063179 Agents and vaccines) 39 Antiinfectives (excluding antibiotics 40 46233931 asunaprevir and vaccines) 41 Antiinfectives (excluding antibiotics 42 1727223 Atazanavir and vaccines) 43 44 Antiinfectives (excluding antibiotics 45 43012518 and vaccines) 46 Antiinfectives (excluding antibiotics 47 40238770 boceprevir and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601251 botulinum antitoxin and vaccines) 50 Antiinfectives (excluding antibiotics 51 19122130 and vaccines) 52 Antiinfectives (excluding antibiotics 53 958396 butenafine and vaccines) 54 Antiinfectives (excluding antibiotics 55 939784 butoconazole and vaccines) 56 Antiinfectives (excluding antibiotics 57 21603094 calcium aminosalicylate and vaccines) 58 Antiinfectives (excluding antibiotics 59 1718054 Caspofungin and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1745072 and vaccines) 5 Antiinfectives (excluding antibiotics 6 21603171 and vaccines) 7 Antiinfectives (excluding antibiotics 8 1798476 and vaccines) 9 Antiinfectives (excluding antibiotics 10 1000632 Clotrimazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 586491 cytomegalovirus immune globulin and vaccines) 13 Antiinfectives (excluding antibiotics 14 46221696 daclatasvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1711759 and vaccines) 17 Antiinfectives (excluding antibiotics 18 1756831 darunavirFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 45893458 darunavir and cobicistat and vaccines) 21 Antiinfectives (excluding antibiotics 22 44819157 and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 1747157 and vaccines) 26 Antiinfectives (excluding antibiotics 27 1724869 Didanosine and vaccines) 28 Antiinfectives (excluding antibiotics 29 19031041 Diphtheria Antitoxin and vaccines) 30 Antiinfectives (excluding antibiotics 31 43560385 dolutegravir and vaccines) 32 Antiinfectives (excluding antibiotics 33 940864 Econazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1738135 and vaccines) 36 Antiinfectives (excluding antibiotics 37 45775080 efinaconazole and vaccines) 38 Antiinfectives (excluding antibiotics 39 42874212 elvitegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 1703069 emtricitabine and vaccines) 42 Antiinfectives (excluding antibiotics 43 21601270 encephalitis, tick borne immunoglobulin and vaccines) 44 Antiinfectives (excluding antibiotics 45 1717002 enfuvirtide and vaccines) 46 Antiinfectives (excluding antibiotics 47 1711246 and vaccines) 48 Antiinfectives (excluding antibiotics 49 1749301 and vaccines) 50 Antiinfectives (excluding antibiotics 51 21603117 ethambutol and and vaccines) 52 Antiinfectives (excluding antibiotics 53 1750074 and vaccines) 54 Antiinfectives (excluding antibiotics 55 1758536 etravirine and vaccines) 56 Antiinfectives (excluding antibiotics 57 45893487 faldaprevir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703603 and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1754994 Fluconazole and vaccines) 5 Antiinfectives (excluding antibiotics 6 1755112 Flucytosine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1736829 fosamprenavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724700 and vaccines) 11 Antiinfectives (excluding antibiotics 12 21603147 fosfonet and vaccines) 13 Antiinfectives (excluding antibiotics 14 1757803 and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601252 gas-gangrene sera and vaccines) 17 Antiinfectives (excluding antibiotics 18 21601269 hepatitisFor A immunoglobulin peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 501343 B immune globulin and vaccines) 21 Antiinfectives (excluding antibiotics 22 19078156 and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 1711523 and vaccines) 26 Antiinfectives (excluding antibiotics 27 19083285 Pranobex and vaccines) 28 Antiinfectives (excluding antibiotics 29 1782521 isoniazid and vaccines) 30 Antiinfectives (excluding antibiotics 31 1703653 Itraconazole and vaccines) 32 Antiinfectives (excluding antibiotics 33 985708 Ketoconazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1704183 and vaccines) 36 Antiinfectives (excluding antibiotics 37 45893193 lamivudine and and vaccines) 38 Antiinfectives (excluding antibiotics 39 45893478 lamivudine, abacavir and dolutegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 43534799 lamivudine, tenofovir disoproxil and efavirenz and vaccines) 42 Antiinfectives (excluding antibiotics 43 44507693 luliconazole and vaccines) 44 Antiinfectives (excluding antibiotics 45 43532424 lysozyme and vaccines) 46 Antiinfectives (excluding antibiotics 47 1787101 maraviroc and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601244 and vaccines) 50 Antiinfectives (excluding antibiotics 51 21601272 measles immunoglobulin and vaccines) 52 Antiinfectives (excluding antibiotics 53 21603129 metisazone and vaccines) 54 Antiinfectives (excluding antibiotics 55 19018013 micafungin and vaccines) 56 Antiinfectives (excluding antibiotics 57 907879 and vaccines) 58 Antiinfectives (excluding antibiotics 59 21603113 and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 19010924 and vaccines) 5 Antiinfectives (excluding antibiotics 6 40252180 and vaccines) 7 Antiinfectives (excluding antibiotics 8 21601273 mumps immunoglobulin and vaccines) 9 Antiinfectives (excluding antibiotics 10 914053 naftifine and vaccines) 11 Antiinfectives (excluding antibiotics 12 21601277 nebacumab and vaccines) 13 Antiinfectives (excluding antibiotics 14 1715472 Nelfinavir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1769389 Nevirapine and vaccines) 17 Antiinfectives (excluding antibiotics 18 922570 NystatinFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 1799139 Oseltamivir and vaccines) 21 Antiinfectives (excluding antibiotics 22 918222 oxiconazole and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 537647 palivizumab and vaccines) 26 Antiinfectives (excluding antibiotics 27 981654 and vaccines) 28 Antiinfectives (excluding antibiotics 29 21601271 pertussis immunoglobulin and vaccines) 30 Antiinfectives (excluding antibiotics 31 21603192 pleconaril and vaccines) 32 Antiinfectives (excluding antibiotics 33 1704139 and vaccines) 34 Antiinfectives (excluding antibiotics 35 19135812 and vaccines) 36 Antiinfectives (excluding antibiotics 37 1759455 and vaccines) 38 Antiinfectives (excluding antibiotics 39 19135830 rabies immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 1712889 raltegravir and vaccines) 42 Antiinfectives (excluding antibiotics 43 43013193 and vaccines) 44 Antiinfectives (excluding antibiotics 45 535714 Rho(D) Immune Globulin and vaccines) 46 Antiinfectives (excluding antibiotics 47 1762711 and vaccines) 48 Antiinfectives (excluding antibiotics 49 1777417 and vaccines) 50 , pyrazinamide, ethambutol and Antiinfectives (excluding antibiotics 51 21603120 isoniazid and vaccines) 52 Antiinfectives (excluding antibiotics 53 19035924 SV and vaccines) 54 Antiinfectives (excluding antibiotics 55 19035953 and vaccines) 56 Antiinfectives (excluding antibiotics 57 40238930 Rilpivirine and vaccines) 58 Antiinfectives (excluding antibiotics 59 1763339 and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1748921 Ritonavir and vaccines) 5 Antiinfectives (excluding antibiotics 6 21601264 rubella immunoglobulin and vaccines) 7 Antiinfectives (excluding antibiotics 8 1746244 Saquinavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 939134 sertaconazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 44785086 simeprevir and vaccines) 13 Antiinfectives (excluding antibiotics 14 44785094 sofosbuvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601266 staphylococcus immunoglobulin and vaccines) 17 Antiinfectives (excluding antibiotics 18 1781406 StavudineFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 21603187 stavudine, lamivudine and nevirapine and vaccines) 21 Antiinfectives (excluding antibiotics 22 940535 sulconazole and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 45776537 tavaborole and vaccines) 26 Antiinfectives (excluding antibiotics 27 40239330 telaprevir and vaccines) 28 Antiinfectives (excluding antibiotics 29 1758392 and vaccines) 30 Antiinfectives (excluding antibiotics 31 1710281 tenofovir disoproxil and vaccines) 32 Antiinfectives (excluding antibiotics 33 1741309 terbinafine and vaccines) 34 Antiinfectives (excluding antibiotics 35 941472 terconazole and vaccines) 36 Antiinfectives (excluding antibiotics 37 19078424 and vaccines) 38 Antiinfectives (excluding antibiotics 39 561401 Tetanus immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 45893523 and vaccines) 42 Antiinfectives (excluding antibiotics 43 21603118 thioacetazone and isoniazid and vaccines) 44 Antiinfectives (excluding antibiotics 45 21603107 tiocarlide and vaccines) 46 Antiinfectives (excluding antibiotics 47 942028 tioconazole and vaccines) 48 Antiinfectives (excluding antibiotics 49 1736999 tipranavir and vaccines) 50 Antiinfectives (excluding antibiotics 51 19101679 and vaccines) 52 Antiinfectives (excluding antibiotics 53 45893141 umifenovir and vaccines) 54 Antiinfectives (excluding antibiotics 55 21601265 immunoglobulin and vaccines) 56 Antiinfectives (excluding antibiotics 57 1717704 valacyclovir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703063 and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 543291 varicella-zoster immune globulin and vaccines) 5 Antiinfectives (excluding antibiotics 6 908126 Vidarabine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1714277 voriconazole and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724827 Zalcitabine and vaccines) 11 Antiinfectives (excluding antibiotics 12 1708748 Zanamivir and vaccines) 13 Antiinfectives (excluding antibiotics 14 1710612 Zidovudine and vaccines) 15 Antiinfectives (excluding antibiotics 16 21603185 zidovudine, lamivudine and nevirapine and vaccines) 17 Antineoplastic and 18 19010868 abarelixFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1186087 immunomodulating agents 21 Antineoplastic and 22 42900395 immunomodulating agents 23 24 Antineoplastic and 25 40239056 abiraterone immunomodulating agents 26 Antineoplastic and 27 19057483 immunomodulating agents 28 Antineoplastic and 29 1119119 immunomodulating agents 30 Antineoplastic and 31 43525787 ado- emtansine immunomodulating agents 32 Antineoplastic and 33 43533090 immunomodulating agents 34 Antineoplastic and 35 21603910 immunomodulating agents 36 Antineoplastic and 37 40244266 immunomodulating agents 38 Antineoplastic and 39 40253734 alfa-2b immunomodulating agents 40 Antineoplastic and 41 1309770 Aldesleukin immunomodulating agents 42 Antineoplastic and 43 909959 immunomodulating agents 44 Antineoplastic and 45 1312706 immunomodulating agents 46 Antineoplastic and 47 941052 immunomodulating agents 48 Antineoplastic and 49 1368823 immunomodulating agents 50 Antineoplastic and 51 1503057 immunomodulating agents 52 Antineoplastic and 53 904351 immunomodulating agents 54 Antineoplastic and 55 40253109 immunomodulating agents 56 Antineoplastic and 57 19017810 immunomodulating agents 58 Antineoplastic and 59 1381253 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1114375 immunomodulating agents 5 Antineoplastic and 6 1348265 anastrozole immunomodulating agents 7 Antineoplastic and 8 19018070 immunomodulating agents 9 Antineoplastic and 10 44816294 immunomodulating agents 11 Antineoplastic and 12 1333379 immunomodulating agents 13 Antineoplastic and 14 19012585 immunomodulating agents 15 Antineoplastic and 16 42709322 immunomodulating agents 17 Antineoplastic and 18 1314865 AzacitidineFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19014878 Azathioprine immunomodulating agents 21 Antineoplastic and 22 45893268 balugrastim immunomodulating agents 23 24 Antineoplastic and 25 19038440 immunomodulating agents 26 Antineoplastic and 27 40239665 immunomodulating agents 28 Antineoplastic and 29 40236987 immunomodulating agents 30 Antineoplastic and 31 19015523 immunomodulating agents 32 Antineoplastic and 33 1397141 immunomodulating agents 34 Antineoplastic and 35 1389888 immunomodulating agents 36 Antineoplastic and 37 1344381 immunomodulating agents 38 Antineoplastic and 39 1329241 immunomodulating agents 40 Antineoplastic and 41 1336825 immunomodulating agents 42 Antineoplastic and 43 42900401 immunomodulating agents 44 Antineoplastic and 45 40241969 brentuximab vedotin immunomodulating agents 46 Antineoplastic and 47 40253793 briakinumab immunomodulating agents 48 Antineoplastic and 49 19033280 Buserelin immunomodulating agents 50 Antineoplastic and 51 1333357 immunomodulating agents 52 Antineoplastic and 53 40222431 immunomodulating agents 54 Antineoplastic and 55 43012292 immunomodulating agents 56 Antineoplastic and 57 40161669 canakinumab immunomodulating agents 58 Antineoplastic and 59 1337620 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1344905 immunomodulating agents 5 Antineoplastic and 6 21601405 immunomodulating agents 7 Antineoplastic and 8 42873638 immunomodulating agents 9 Antineoplastic and 10 21601438 immunomodulating agents 11 Antineoplastic and 12 1350066 immunomodulating agents 13 Antineoplastic and 14 21603763 catumaxomab immunomodulating agents 15 Antineoplastic and 16 45893501 cepeginterferon alfa-2b immunomodulating agents 17 Antineoplastic and 18 44818466 ceritinibFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 912263 immunomodulating agents 21 Antineoplastic and 22 1315411 immunomodulating agents 23 24 Antineoplastic and 25 1390051 immunomodulating agents 26 Antineoplastic and 27 1397599 immunomodulating agents 28 Antineoplastic and 29 19054825 immunomodulating agents 30 Antineoplastic and 31 19054821 immunomodulating agents 32 Antineoplastic and 33 43534820 cridanimod immunomodulating agents 34 Antineoplastic and 35 40242675 immunomodulating agents 36 Antineoplastic and 37 1310317 Cyclophosphamide immunomodulating agents 38 Antineoplastic and 39 19010482 Cyclosporine immunomodulating agents 40 Antineoplastic and 41 1311078 Cytarabine immunomodulating agents 42 Antineoplastic and 43 43532299 immunomodulating agents 44 Antineoplastic and 45 1311409 immunomodulating agents 46 Antineoplastic and 47 19036892 immunomodulating agents 48 Antineoplastic and 49 1311443 immunomodulating agents 50 Antineoplastic and 51 1358436 immunomodulating agents 52 Antineoplastic and 53 45893271 dasiprotimut-T immunomodulating agents 54 Antineoplastic and 55 1311799 immunomodulating agents 56 Antineoplastic and 57 19024728 immunomodulating agents 58 Antineoplastic and 59 19058410 degarelix immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603721 immunomodulating agents 5 Antineoplastic and 6 19051642 denileukin diftitox immunomodulating agents 7 Antineoplastic and 8 1525866 immunomodulating agents 9 Antineoplastic and 10 46221699 dinutuximab immunomodulating agents 11 Antineoplastic and 12 1315942 immunomodulating agents 13 Antineoplastic and 14 1338512 Doxorubicin immunomodulating agents 15 Antineoplastic and 16 19080458 immunomodulating agents 17 Antineoplastic and 18 19132294 EdrecolomabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 936429 immunomodulating agents 21 Antineoplastic and 22 21603770 immunomodulating agents 23 24 Antineoplastic and 25 42900250 immunomodulating agents 26 Antineoplastic and 27 1344354 immunomodulating agents 28 Antineoplastic and 29 40230712 immunomodulating agents 30 Antineoplastic and 31 1325363 immunomodulating agents 32 Antineoplastic and 33 1349025 immunomodulating agents 34 Antineoplastic and 35 1151789 immunomodulating agents 36 Antineoplastic and 37 19104221 Ethoglucid immunomodulating agents 38 Antineoplastic and 39 1350504 immunomodulating agents 40 Antineoplastic and 41 19011440 immunomodulating agents 42 Antineoplastic and 43 1398399 immunomodulating agents 44 Antineoplastic and 45 1304850 Filgrastim immunomodulating agents 46 Antineoplastic and 47 40226579 immunomodulating agents 48 Antineoplastic and 49 1395557 immunomodulating agents 50 Antineoplastic and 51 955632 immunomodulating agents 52 Antineoplastic and 53 21601443 fluorouracil, combinations immunomodulating agents 54 Antineoplastic and 55 1356461 immunomodulating agents 56 Antineoplastic and 57 19020079 immunomodulating agents 58 Antineoplastic and 59 19065450 fosfestrol immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21601411 immunomodulating agents 5 Antineoplastic and 6 1304044 fulvestrant immunomodulating agents 7 Antineoplastic and 8 1319193 immunomodulating agents 9 Antineoplastic and 10 1314924 immunomodulating agents 11 Antineoplastic and 12 19098566 gemtuzumab immunomodulating agents 13 Antineoplastic and 14 21603822 gestonorone immunomodulating agents 15 Antineoplastic and 16 19041065 immunomodulating agents 17 Antineoplastic and 18 1366310 GoserelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603901 gusperimus immunomodulating agents 21 Antineoplastic and 22 1366773 histrelin immunomodulating agents 23 24 Antineoplastic and 25 1377141 hydroxyurea immunomodulating agents 26 Antineoplastic and 27 44507848 Ibrutinib immunomodulating agents 28 Antineoplastic and 29 19078097 immunomodulating agents 30 Antineoplastic and 31 45776944 immunomodulating agents 32 Antineoplastic and 33 19078187 immunomodulating agents 34 Antineoplastic and 35 1304107 immunomodulating agents 36 Antineoplastic and 37 21603883 immunocyanin immunomodulating agents 38 Antineoplastic and 39 937368 immunomodulating agents 40 Antineoplastic and 41 1379969 Alfa-2a immunomodulating agents 42 Antineoplastic and 43 1380068 -2b immunomodulating agents 44 Antineoplastic and 45 19044394 Interferon Alfa-n1 immunomodulating agents 46 Antineoplastic and 47 1781314 interferon alfacon-1 immunomodulating agents 48 Antineoplastic and 49 722424 Interferon beta-1a immunomodulating agents 50 Antineoplastic and 51 713196 interferon beta-1b immunomodulating agents 52 Antineoplastic and 53 19122123 Interferon Type II immunomodulating agents 54 Antineoplastic and 55 19109079 Interferon-beta immunomodulating agents 56 Antineoplastic and 57 40238188 immunomodulating agents 58 Antineoplastic and 59 1367268 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19025348 immunomodulating agents 5 Antineoplastic and 6 1359548 immunomodulating agents 7 Antineoplastic and 8 1101898 immunomodulating agents 9 Antineoplastic and 10 19026972 immunomodulating agents 11 Antineoplastic and 12 19009705 immunomodulating agents 13 Antineoplastic and 14 21603875 immunomodulating agents 15 Antineoplastic and 16 1315946 letrozole immunomodulating agents 17 Antineoplastic and 18 1351541 LeuprolideFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 44506753 immunomodulating agents 21 Antineoplastic and 22 1391846 immunomodulating agents 23 24 Antineoplastic and 25 21603788 immunomodulating agents 26 Antineoplastic and 27 21601401 immunomodulating agents 28 Antineoplastic and 29 43534811 immunomodulating agents 30 Antineoplastic and 31 988447 immunomodulating agents 32 Antineoplastic and 33 1394337 Mechlorethamine immunomodulating agents 34 Antineoplastic and 35 1301267 immunomodulating agents 36 Antineoplastic and 37 21603920 immunomodulating agents 38 Antineoplastic and 39 1436650 mercaptopurine immunomodulating agents 40 Antineoplastic and 41 1305058 Methotrexate immunomodulating agents 42 Antineoplastic and 43 19025194 methyl 5-aminolevulinate immunomodulating agents 44 Antineoplastic and 45 21603888 immunomodulating agents 46 Antineoplastic and 47 44816310 miltefosine immunomodulating agents 48 Antineoplastic and 49 19125635 immunomodulating agents 50 Antineoplastic and 51 21603794 immunomodulating agents 52 Antineoplastic and 53 1389036 Mitomycin immunomodulating agents 54 Antineoplastic and 55 1309161 immunomodulating agents 56 Antineoplastic and 57 1309188 immunomodulating agents 58 Antineoplastic and 59 19009676 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19051865 Muromonab-CD3 immunomodulating agents 5 Antineoplastic and 6 19012565 immunomodulating agents 7 Antineoplastic and 8 735843 immunomodulating agents 9 Antineoplastic and 10 19002912 immunomodulating agents 11 Antineoplastic and 12 1394023 immunomodulating agents 13 Antineoplastic and 14 1315286 immunomodulating agents 15 Antineoplastic and 16 21601412 immunomodulating agents 17 Antineoplastic and 18 44507676 obinutuzumabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603807 immunomodulating agents 21 Antineoplastic and 22 40167582 ofatumumab immunomodulating agents 23 24 Antineoplastic and 25 45892579 immunomodulating agents 26 Antineoplastic and 27 19069046 omacetaxine mepesuccinate immunomodulating agents 28 Antineoplastic and 29 1318030 immunomodulating agents 30 Antineoplastic and 31 1318011 immunomodulating agents 32 Antineoplastic and 33 1378382 immunomodulating agents 34 Antineoplastic and 35 21603725 paclitaxel poliglumex immunomodulating agents 36 Antineoplastic and 37 19100985 immunomodulating agents 38 Antineoplastic and 39 46221435 immunomodulating agents 40 Antineoplastic and 41 40167554 immunomodulating agents 42 Antineoplastic and 43 581480 pegademase bovine immunomodulating agents 44 Antineoplastic and 45 1326481 immunomodulating agents 46 Antineoplastic and 47 1325608 immunomodulating agents 48 Antineoplastic and 49 1714165 peginterferon alfa-2a immunomodulating agents 50 Antineoplastic and 51 21603870 peginterferon alfa-2a, combinations immunomodulating agents 52 Antineoplastic and 53 1797155 peginterferon alfa-2b immunomodulating agents 54 Antineoplastic and 55 21603869 peginterferon alfa-2b, combinations immunomodulating agents 56 Antineoplastic and 57 45775146 peginterferon beta-1a immunomodulating agents 58 Antineoplastic and 59 1304919 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19031224 immunomodulating agents 5 Antineoplastic and 6 42801287 immunomodulating agents 7 Antineoplastic and 8 19102785 immunomodulating agents 9 Antineoplastic and 10 19046625 immunomodulating agents 11 Antineoplastic and 12 19093366 immunomodulating agents 13 Antineoplastic and 14 45775206 immunomodulating agents 15 Antineoplastic and 16 40253110 immunomodulating agents 17 Antineoplastic and 18 19017581 PlerixaforFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19009165 immunomodulating agents 21 Antineoplastic and 22 21603880 poly I:C immunomodulating agents 23 24 Antineoplastic and 25 21603881 poly ICLC immunomodulating agents 26 Antineoplastic and 27 40253122 polyplatillen immunomodulating agents 28 Antineoplastic and 29 43014237 immunomodulating agents 30 Antineoplastic and 31 43013182 immunomodulating agents 32 Antineoplastic and 33 40166461 immunomodulating agents 34 Antineoplastic and 35 19135793 immunomodulating agents 36 Antineoplastic and 37 1351779 immunomodulating agents 38 Antineoplastic and 39 19038536 immunomodulating agents 40 Antineoplastic and 41 21601413 immunomodulating agents 42 Antineoplastic and 43 42903460 immunomodulating agents 44 Antineoplastic and 45 43534809 immunomodulating agents 46 Antineoplastic and 47 19023450 immunomodulating agents 48 Antineoplastic and 49 1314273 immunomodulating agents 50 Antineoplastic and 51 40168385 immunomodulating agents 52 Antineoplastic and 53 21603876 immunomodulating agents 54 Antineoplastic and 55 40244464 ruxolitinib immunomodulating agents 56 Antineoplastic and 57 1308432 immunomodulating agents 58 Antineoplastic and 59 21603751 immunomodulating agents 60

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1 2 3 Antineoplastic and 4 45892883 immunomodulating agents 5 Antineoplastic and 6 21601409 immunomodulating agents 7 Antineoplastic and 8 44818461 siltuximab immunomodulating agents 9 Antineoplastic and 10 40224095 sipuleucel-T immunomodulating agents 11 Antineoplastic and 12 19034726 immunomodulating agents 13 Antineoplastic and 14 21603808 sitimagene ceradenovec immunomodulating agents 15 Antineoplastic and 16 1363387 immunomodulating agents 17 Antineoplastic and 18 19136210 StreptozocinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1336539 immunomodulating agents 21 Antineoplastic and 22 950637 Tacrolimus immunomodulating agents 23 24 Antineoplastic and 25 1436678 immunomodulating agents 26 Antineoplastic and 27 19071159 TASONERMIN immunomodulating agents 28 Antineoplastic and 29 19056756 immunomodulating agents 30 Antineoplastic and 31 21601444 tegafur, combinations immunomodulating agents 32 Antineoplastic and 33 19011067 immunomodulating agents 34 Antineoplastic and 35 1341149 immunomodulating agents 36 Antineoplastic and 37 19092845 immunomodulating agents 38 Antineoplastic and 39 19136750 immunomodulating agents 40 Antineoplastic and 41 42900584 immunomodulating agents 42 Antineoplastic and 43 19137042 immunomodulating agents 44 Antineoplastic and 45 1437379 Thioguanine immunomodulating agents 46 Antineoplastic and 47 19137385 immunomodulating agents 48 Antineoplastic and 49 19102231 immunomodulating agents 50 Antineoplastic and 51 21603796 tiazofurine immunomodulating agents 52 Antineoplastic and 53 40171288 immunomodulating agents 54 Antineoplastic and 55 42904205 immunomodulating agents 56 Antineoplastic and 57 1378509 immunomodulating agents 58 Antineoplastic and 59 1342346 Toremifene immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603727 immunomodulating agents 5 Antineoplastic and 6 43532497 immunomodulating agents 7 Antineoplastic and 8 1387104 trastuzumab immunomodulating agents 9 Antineoplastic and 10 19042545 immunomodulating agents 11 Antineoplastic and 12 903643 Tretinoin immunomodulating agents 13 Antineoplastic and 14 21601404 immunomodulating agents 15 Antineoplastic and 16 45893469 , combinations immunomodulating agents 17 Antineoplastic and 18 1343039 TriptorelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19101677 immunomodulating agents 21 Antineoplastic and 22 40161532 immunomodulating agents 23 24 Antineoplastic and 25 19012543 immunomodulating agents 26 Antineoplastic and 27 40238052 immunomodulating agents 28 Antineoplastic and 29 45774639 immunomodulating agents 30 Antineoplastic and 31 40241937 immunomodulating agents 32 Antineoplastic and 33 19008264 immunomodulating agents 34 Antineoplastic and 35 1308290 Vincristine immunomodulating agents 36 Antineoplastic and 37 19008336 immunomodulating agents 38 Antineoplastic and 39 21601451 immunomodulating agents 40 Antineoplastic and 41 1343346 immunomodulating agents 42 Antineoplastic and 43 43534805 immunomodulating agents 44 Antineoplastic and 45 42709321 vismodegib immunomodulating agents 46 Antineoplastic and 47 40253798 immunomodulating agents 48 Antineoplastic and 49 1337651 immunomodulating agents 50 Antineoplastic and 51 21603843 vorozole immunomodulating agents 52 Antineoplastic and 53 21603736 immunomodulating agents 54 19037596 Acetylcarnitine Central nervous system stimulants 55 56 19112518 Central nervous system stimulants 57 714785 Central nervous system stimulants 58 19032667 Central nervous system stimulants 59 742185 atomoxetine Central nervous system stimulants 60

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1 2 3 1134439 Caffeine Central nervous system stimulants 4 5 40223464 Citicoline Central nervous system stimulants 6 1311826 Deanol Central nervous system stimulants 7 731533 Central nervous system stimulants 8 719311 Dextroamphetamine Central nervous system stimulants 9 10 21604759 Central nervous system stimulants 11 19061288 Central nervous system stimulants 12 19061392 Central nervous system stimulants 13 21604773 Central nervous system stimulants 14 15 19067036 idebenone Central nervous system stimulants 16 21604777 Central nervous system stimulants 17 709567 Central nervous system stimulants 18 43534829 mebicarFor peer review onlyCentral nervous system stimulants 19 20 19052682 Central nervous system stimulants 21 704053 Central nervous system stimulants 22 705944 Methylphenidate Central nervous system stimulants 23 710650 modafinil Central nervous system stimulants 24 25 21604778 nizofenone Central nervous system stimulants 26 19082891 Central nervous system stimulants 27 727835 Central nervous system stimulants 28 44819159 Central nervous system stimulants 29 30 43534828 PHENIBUT Central nervous system stimulants 31 21604783 Central nervous system stimulants 32 19046654 Piracetam Central nervous system stimulants 33 21604784 Central nervous system stimulants 34 35 19029018 Central nervous system stimulants 36 19096031 propentofylline Central nervous system stimulants 37 19097999 pyrisuccideanol Central nervous system stimulants 38 19060358 Pyrithioxin Central nervous system stimulants 39 40 19095462 vinpocetine Central nervous system stimulants 41 21602495 and Contraceptives 42 40253989 chlormadinone and ethinylestradiol Contraceptives 43 1588000 Contraceptives 44 45 43534785 and ethinylestradiol Contraceptives 46 1519936 Etonogestrel Contraceptives 47 21602483 and ethinylestradiol Contraceptives 48 21602494 gestodene and ethinylestradiol Contraceptives 49 50 1589505 Levonorgestrel Contraceptives 51 19092358 Lynestrenol Contraceptives 52 21602490 lynestrenol and ethinylestradiol Contraceptives 53 21602476 lynestrenol and ethinylestradiol Contraceptives 54 55 1500211 Medroxyprogesterone Contraceptives 56 1300978 Megestrol Contraceptives 57 21602477 megestrol and ethinylestradiol Contraceptives 58 21602489 megestrol and ethinylestradiol Contraceptives 59 60 21602487 and Contraceptives

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1 2 3 1521369 Norethindrone Contraceptives 4 5 19128258 Norgestrienone Contraceptives 6 21602500 Contraceptives 7 21602475 quingestanol and ethinylestradiol Contraceptives 8 40225722 ulipristal Contraceptives 9 10 905151 Alclometasone Corticosteroid 11 930747 amcinonide Corticosteroid 12 1115572 Beclomethasone Corticosteroid 13 920458 Betamethasone Corticosteroid 14 15 939259 Budesonide Corticosteroid 16 998415 Clobetasol Corticosteroid 17 950882 clocortolone Corticosteroid 18 1507705 CortisoneFor peer review onlyCorticosteroid 19 20 917205 Desonide Corticosteroid 21 917336 Desoximetasone Corticosteroid 22 1518254 Dexamethasone Corticosteroid 23 960988 Diflorasone Corticosteroid 24 25 1196514 Corticosteroid 26 19110714 Corticosteroid 27 955252 Fluocinonide Corticosteroid 28 19055344 Fluocortolone Corticosteroid 29 30 955583 Fluorometholone Corticosteroid 31 956266 Flurandrenolide Corticosteroid 32 1149380 fluticasone Corticosteroid 33 966468 Halcinonide Corticosteroid 34 35 949759 halobetasol Corticosteroid 36 975125 Hydrocortisone Corticosteroid 37 992127 Loteprednol Corticosteroid 38 909021 medrysone Corticosteroid 39 40 1506270 Methylprednisolone Corticosteroid 41 905233 Corticosteroid 42 928110 prednicarbate Corticosteroid 43 1550557 prednisolone Corticosteroid 44 45 1551099 Prednisone Corticosteroid 46 977421 rimexolone Corticosteroid 47 903963 Triamcinolone Corticosteroid 48 21601546 and -sparing agents Diuretics 49 50 991382 Amiloride Diuretics 51 1316354 Diuretics 52 21601475 bendroflumethiazide and potassium Diuretics 53 bendroflumethiazide and potassium-sparing 54 21601551 agents Diuretics 55 932745 Bumetanide Diuretics 56 57 21601524 bumetanide and potassium Diuretics 58 21601555 bumetanide and potassium-sparing agents Diuretics 59 21601552 and potassium-sparing agents Diuretics 60

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1 2 3 19019698 Diuretics 4 5 992590 Diuretics 6 21601478 chlorothiazide and potassium Diuretics 7 21601485 chlorothiazide, combinations Diuretics 8 21601506 and potassium Diuretics 9 10 21601548 chlortalidone and potassium-sparing agents Diuretics 11 1395058 Chlorthalidone Diuretics 12 19051444 Diuretics 13 21601495 Diuretics 14 15 21601508 clofenamide and potassium Diuretics 16 19099181 Diuretics 17 21601505 clopamide and potassium Diuretics 18 21601500 clorexoloneFor peer review onlyDiuretics 19 20 21601502 , combinations with psycholeptics Diuretics 21 19010927 Diuretics 22 19010015 Diuretics 23 21601481 cyclopenthiazide and potassium Diuretics 24 25 21601549 cyclopenthiazide and potassium-sparing agents Diuretics 26 19082886 Diuretics 27 21601483 cyclothiazide and potassium Diuretics 28 21601545 and potassium-sparing agents Diuretics 29 30 1309799 Diuretics 31 19103548 Ethacrynic Acid Diuretics 32 21601531 Diuretics 33 21601501 Diuretics 34 35 956874 Furosemide Diuretics 36 21601523 furosemide and potassium Diuretics 37 21601554 furosemide and potassium-sparing agents Diuretics 38 974166 Hydrochlorothiazide Diuretics 39 40 21601477 hydrochlorothiazide and potassium Diuretics 41 21601488 hydrochlorothiazide, combinations Diuretics 42 1376289 Diuretics 43 21601476 hydroflumethiazide and potassium Diuretics 44 45 21601486 hydroflumethiazide, combinations Diuretics 46 978555 Indapamide Diuretics 47 21601473 Diuretics 48 21601547 mebutizide and potassium-sparing agents Diuretics 49 50 19000556 Diuretics 51 21601507 mefruside and potassium Diuretics 52 19003070 Diuretics 53 905273 Diuretics 54 55 21601482 methyclothiazide and potassium Diuretics 56 21601497 Diuretics 57 907013 Diuretics 58 21601550 metolazone and potassium-sparing agents Diuretics 59 60 21601529 Diuretics

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1 2 3 19025498 Diuretics 4 5 948787 Diuretics 6 21601479 polythiazide and potassium Diuretics 7 19081320 Diuretics 8 21601504 quinethazone and potassium Diuretics 9 10 970250 Spironolactone Diuretics 11 19137056 Theobromine Diuretics 12 21601527 Diuretics 13 19036797 Diuretics 14 15 942350 torsemide Diuretics 16 904542 Diuretics 17 904639 Trichlormethiazide Diuretics 18 21601480 trichlormethiazideFor peer and potassium review onlyDiuretics 19 20 21601544 trichlormethiazide and potassium-sparing agents Diuretics 21 19010493 Diuretics 22 1139042 Acetylcysteine Mucolytics 23 19088167 Ambroxol Mucolytics 24 25 19030493 Bromhexine Mucolytics 26 19041843 Carbocysteine Mucolytics 27 21603389 combinations Mucolytics 28 21603387 Mucolytics 29 30 1125443 Dornase Alfa Mucolytics 31 19095266 eprazinone Mucolytics 32 19058933 erdosteine Mucolytics 33 19071861 Mucolytics 34 35 994058 Mannitol Mucolytics 36 1354698 Mesna Mucolytics 37 21603393 Mucolytics 38 19039512 Mucolytics 39 40 21603390 Mucolytics 41 903031 tiopronin Mucolytics 42 1363516 5-Hydroxytryptophan Psychotherapeutic agents 43 19018226 Psychotherapeutic agents 44 45 19029555 Psychotherapeutic agents 46 21604750 Psychotherapeutic agents 47 21604715 Psychotherapeutic agents 48 19032424 amineptin Psychotherapeutic agents 49 50 19057607 Psychotherapeutic agents 51 710062 Amitriptyline Psychotherapeutic agents 52 713109 Psychotherapeutic agents 53 757688 aripiprazole Psychotherapeutic agents 54 55 40164052 Psychotherapeutic agents 56 19016440 Psychotherapeutic agents 57 19058055 Psychotherapeutic agents 58 19039227 Psychotherapeutic agents 59 60 750982 Psychotherapeutic agents

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1 2 3 21604508 Psychotherapeutic agents 4 5 19039883 Psychotherapeutic agents 6 45893485 Psychotherapeutic agents 7 19122262 Psychotherapeutic agents 8 794852 Chlorpromazine Psychotherapeutic agents 9 10 19095002 Psychotherapeutic agents 11 797617 Psychotherapeutic agents 12 798834 Psychotherapeutic agents 13 21604532 Psychotherapeutic agents 14 15 19100363 clothiapine Psychotherapeutic agents 16 800878 Psychotherapeutic agents 17 19051234 Psychotherapeutic agents 18 716968 DesipramineFor peer review onlyPsychotherapeutic agents 19 20 717607 Psychotherapeutic agents 21 19023846 Psychotherapeutic agents 22 21604705 Psychotherapeutic agents 23 21604500 Psychotherapeutic agents 24 25 19037989 Dothiepin Psychotherapeutic agents 26 738156 Doxepin Psychotherapeutic agents 27 739323 Droperidol Psychotherapeutic agents 28 715259 Psychotherapeutic agents 29 30 715939 Escitalopram Psychotherapeutic agents 31 21604717 Psychotherapeutic agents 32 21604524 Psychotherapeutic agents 33 755695 Fluoxetine Psychotherapeutic agents 34 35 19055982 Flupenthixol Psychotherapeutic agents 36 756018 Psychotherapeutic agents 37 19056465 Psychotherapeutic agents 38 751412 Fluvoxamine Psychotherapeutic agents 39 40 21604748 Psychotherapeutic agents 41 766529 Haloperidol Psychotherapeutic agents 42 19017241 Psychotherapeutic agents 43 778268 Imipramine Psychotherapeutic agents 44 45 21604690 imipramine oxide Psychotherapeutic agents 46 19122204 Psychotherapeutic agents 47 21604725 Psychotherapeutic agents 48 21604724 iproniazide Psychotherapeutic agents 49 50 781705 Psychotherapeutic agents 51 43560354 Psychotherapeutic agents 52 21604554 Psychotherapeutic agents 53 19124477 Psychotherapeutic agents 54 55 19091830 Psychotherapeutic agents 56 792263 Psychotherapeutic agents 57 40230761 Psychotherapeutic agents 58 794147 Psychotherapeutic agents 59 60 19072021 Psychotherapeutic agents

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1 2 3 19110751 Psychotherapeutic agents 4 5 703083 Psychotherapeutic agents 6 19005147 Methotrimeprazine Psychotherapeutic agents 7 19072088 metylperon Psychotherapeutic agents 8 19007737 Psychotherapeutic agents 9 10 19080226 Psychotherapeutic agents 11 19072123 Psychotherapeutic agents 12 725131 Psychotherapeutic agents 13 19010652 Psychotherapeutic agents 14 15 709699 Psychotherapeutic agents 16 21604519 Psychotherapeutic agents 17 21604560 Psychotherapeutic agents 18 714684 nefazodoneFor peer review onlyPsychotherapeutic agents 19 20 19127550 Psychotherapeutic agents 21 19128066 Psychotherapeutic agents 22 721724 Psychotherapeutic agents 23 785788 olanzapine Psychotherapeutic agents 24 25 19129635 Psychotherapeutic agents 26 21604739 Psychotherapeutic agents 27 19025922 Psychotherapeutic agents 28 703244 Psychotherapeutic agents 29 30 722031 Psychotherapeutic agents 31 19028044 Psychotherapeutic agents 32 19131663 Psychotherapeutic agents 33 19053565 Psychotherapeutic agents 34 35 733008 Psychotherapeutic agents 36 733896 Psychotherapeutic agents 37 745790 Psychotherapeutic agents 38 19093225 Psychotherapeutic agents 39 40 19133992 pipothiazine Psychotherapeutic agents 41 21604744 Psychotherapeutic agents 42 19052903 Psychotherapeutic agents 43 19115044 Psychotherapeutic agents 44 45 754270 Psychotherapeutic agents 46 766814 quetiapine Psychotherapeutic agents 47 19098514 Psychotherapeutic agents 48 715710 Psychotherapeutic agents 49 50 19084693 Psychotherapeutic agents 51 19035226 Psychotherapeutic agents 52 735979 Risperidone Psychotherapeutic agents 53 766209 Psychotherapeutic agents 54 55 19050633 Psychotherapeutic agents 56 739138 Sertraline Psychotherapeutic agents 57 19136626 Sulpiride Psychotherapeutic agents 58 19100431 Psychotherapeutic agents 59 60 19041817 Psychotherapeutic agents

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1 2 3 19000305 Psychotherapeutic agents 4 5 700299 Psychotherapeutic agents 6 700465 Thiothixene Psychotherapeutic agents 7 19041910 Psychotherapeutic agents 8 19008012 Psychotherapeutic agents 9 10 19100775 Psychotherapeutic agents 11 703470 Psychotherapeutic agents 12 703547 Psychotherapeutic agents 13 704984 Psychotherapeutic agents 14 15 19005101 Psychotherapeutic agents 16 19005104 Psychotherapeutic agents 17 705755 Psychotherapeutic agents 18 19006186 TryptophanFor peer review onlyPsychotherapeutic agents 19 20 743670 Psychotherapeutic agents 21 19043327 Psychotherapeutic agents 22 40234834 Psychotherapeutic agents 23 19008261 Psychotherapeutic agents 24 25 44507700 Psychotherapeutic agents 26 21604710 zimeldine Psychotherapeutic agents 27 712615 Psychotherapeutic agents 28 19102109 Psychotherapeutic agents 29 30 19010886 Psychotherapeutic agents 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 STROBE Statement—Checklist of items that should be included 3 4 Item Location in manuscript where items 5 No Recommendation are reported 6 Title and abstract 1 (a) Indicate the study’s design with a Abstract: Design and setting: 7 commonly used term in the title or the “descriptive drug utilization study” 8 abstract 9 10 (b) Provide in the abstract an informative Abstract 11 and balanced summary of what was done 12 and what was found 13 14 Introduction 15 Background/rationale 2 Explain the scientific background and Introduction 16 rationale for the investigation being 17 reported 18 For peer review only 19 Objectives 3 State specific objectives, including any Introduction: From “Our primary aim 20 prespecified hypotheses was ..” until “ambulatory setting” 21 Methods 22 23 Study design 4 Present key elements of study design early Abstract: Design and setting 24 in the paper Methods: Data sources: “We conducted 25 a drug utilisation study using pediatric 26 27 patient populations…” 28 Setting 5 Describe the setting, locations, and relevant Abstract: Design and setting 29 dates, including periods of recruitment, 30 Methods: Data sources, Data collection 31 exposure, follow-up, and data collection 32 Participants 6 (a) Give the eligibility criteria, and the Abstract: Design and setting, Patients 33 sources and methods of selection of Methods: Data collection 34 participants 35 36 Variables 7 Clearly define all outcomes, exposures, Methods: Data sources, Data collection, 37 predictors, potential confounders, and effect Statistical analysis 38 modifiers. Give diagnostic criteria, if 39 applicable 40 41 Data sources/ 8* For each variable of interest, give sources Methods: Data extraction & Statistical 42 measurement of data and details of methods of assessment analysis 43 (measurement). Describe comparability of 44 assessment methods if there is more than 45 46 one group 47 Bias 9 Describe any efforts to address potential Discussion: Strengths and limitations 48 sources of bias 49 Study size 10 Explain how the study size was arrived at Methods: Data sources, Data collection 50 51 Results: Study population 52 53 Quantitative 11 Explain how quantitative variables were Methods: Statistical analysis 54 variables handled in the analyses. If applicable, 55 describe which groupings were chosen and 56 why 57 58 Statistical methods 12 (a) Describe all statistical methods, Methods: Statistical analysis 59 including those used to control for 60 confounding

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1 2 (b) Describe any methods used to examine Methods: Statistical analysis 3 subgroups and interactions 4 5 (c) Explain how missing data were n/a 6 addressed 7 (d) If applicable, describe analytical Methods: Data collection 8 9 methods taking account of sampling 10 strategy 11 (e) Describe any sensitivity analyses n/a 12 13 Results 14 Participants 13* (a) Report numbers of individuals at each Results: Study population 15 stage of study—eg numbers potentially 16 eligible, examined for eligibility, confirmed 17 18 Foreligible, peer included in thereview study, completing only 19 follow-up, and analysed 20 (b) Give reasons for non-participation at n/a 21 each stage 22 23 (c) Consider use of a flow diagram n/a 24 Descriptive data 14* (a) Give characteristics of study participants Results: Study population, User- and 25 (eg demographic, clinical, social) and prescription prevalence 26 27 information on exposures and potential 28 confounders 29 (b) Indicate number of participants with n/a 30 missing data for each variable of interest 31 32 Outcome data 15* Report numbers of outcome events or Results: (Inpatients) (Ambulatory) user- 33 summary measures and prescription prevalence, Most 34 commonly used drugs by class in an 35 inpatient/ambulatory setting 36 37 Main results 16 (a) Give unadjusted estimates and, if Results 38 applicable, confounder-adjusted estimates Tables & Figures 39 40 and their precision (eg, 95% confidence 41 interval). Make clear which confounders 42 were adjusted for and why they were 43 included 44 45 (b) Report category boundaries when n/a 46 continuous variables were categorized 47 (c) If relevant, consider translating n/a 48 estimates of relative risk into absolute risk 49 50 for a meaningful time period 51 Other analyses 17 Report other analyses done—eg analyses of n/a 52 subgroups and interactions, and sensitivity 53 54 analyses 55 Discussion 56 Key results 18 Summarise key results with reference to Discussion: From “To our 57 58 study objectives knowledge…” until “Australia” 59 Limitations 19 Discuss limitations of the study, taking into Discussion: Strengths and limitations 60 account sources of potential bias or imprecision. Discuss both direction and

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1 2 magnitude of any potential bias 3 Interpretation 20 Give a cautious overall interpretation of Discussion: Comparison with literature, 4 5 results considering objectives, limitations, Implications for Practice and Policy 6 multiplicity of analyses, results from similar 7 studies, and other relevant evidence 8 Generalisability 21 Discuss the generalisability (external Discussion: Implications for Practice 9 10 validity) of the study results and Policy 11 12 Other information 13 14 Funding 22 Give the source of funding and the role of Title Page: Funding Source 15 the funders for the present study and, if 16 applicable, for the original study on which 17 the present article is based 18 For peer review only 19 20 *Give information separately for exposed and unexposed groups. 21 22 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 23 24 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 25 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 26 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 27 available at www.strobe-statement.org. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Application of a common data model (CDM) to rank the pediatric user and prescription prevalence of fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia: A descriptive study.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-032426.R1

Article Type: Original research

Date Submitted by the 17-Oct-2019 Author:

Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Man, Kenneth; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Pratt, Nicole; University of South Australia, Sansom Institute for Health Resarch Park, Rae Woong; Ajou University Cho, Soo-Yeon; Ajou University Li, Yu-Chuan (Jack); Taiwan Medical University, College of Medical Science and Technology Iqbal, Usman; Taipei Medical University, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology Nguyen, Phung-Anh; National Yang Ming University, Institute of Biomedical Informatics Schuemie, Martijn; Janssen Research and Development, Epidemiology Analytics; University of California, Los Angeles, Department of Biostatistics

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Pharmacology and therapeutics, Epidemiology

Keywords: CLINICAL PHARMACOLOGY, EPIDEMIOLOGY, PAEDIATRICS

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1 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 74

1 2 3 Application of a common data model (CDM) to rank the pediatric user and prescription prevalence of 4 5 6 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia: A descriptive 7 8 study. 9 10 11 Authors: Ruth Brauera, PhD, Ian C.K. Wonga,b, PhD, Kenneth Manb, MPH, Nicole Prattc, PhD, 12 13 Rae Woong Parkd, MD, PhD, Soo-Yeon Chod, RN, MPH, Li, Yu-Chuan (Jack) Lie, MD, PhD, 14 15 Usman Iqbale, PhD, Alex Nguyene, PhD, Martijn Schuemief, PhD. 16 For peer review only 17 18 19 20 a b 21 Affiliations: UCL School of Pharmacy, London, United Kingdom; University of Hong Kong, Hong Kong; 22 23 cUniversity of South Australia, Adelaide, Australia; dAjou University School of Medicine, Suwon, South- 24 25 Korea; eTaipei Medical University, Taipei, Taiwan; and fJanssen Research and Development, New Jersey. 26 27 28 29 [email protected]) 30 Corresponding author: Martijn Schuemie ( 31 32 33 34 Funding Source: No funding was secured for this study. 35 36 37 Word count: 2887 38 39 40 41 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 Page 3 of 74 BMJ Open

1 2 3 Abstract 4 5 6 Objective: To measure the pediatric user and prescription prevalence in inpatient and ambulatory 7 8 settings in South Korea, Hong Kong, Taiwan, Japan and Australia by age and gender. A further objective 9 was to list the most commonly used drugs per drug class, per country. 10 11 12 Design and setting: Hospital inpatient and insurance paediatric health care data from the following 13 14 databases were used to conduct this descriptive drug utilization study: (i) the South Korean Ajou 15 16 University School of MedicineFor (AUSOM)peer database; review (ii) the Hong Kong only Clinical Data Analysis and 17 Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s National Health 18 19 Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits Scheme (PBS). 20 21 Country specific data were transformed into the Observational Medical Outcomes Partnership (OMOP) 22 Common Data Model (CDM). 23 24 25 Patients: Follow-up of children (≤18 years) with at least 1 day of observation in any of the respective 26 27 databases started in January 2009 and ended in December 2013. 28 29 30 Main outcome measures: For each drug class we assessed the per-protocol overall user and 31 prescription prevalence rates (per 1000 persons) per country and setting. 32 33 34 Results: Our dynamic study cohort comprised 1,574,524 children (52.9% male). The highest proportion 35 36 of dispensings was recorded in the youngest age category (<2 years) for inpatients (45.1%) with a 37 38 relatively high user prevalence of analgesics and antibiotics. Adrenergics, antihistamines, mucolytics and 39 corticosteroids were used in 10-15% of patients. For ambulatory patients, the highest proportion of 40 41 dispensings was recorded in the middle age category (2-11 years, 67.1%) with antibiotics the most 42 43 dispensed drug overall. 44 45 46 Conclusions: Country-specific drug pediatric utilization patterns were described ranked and compared 47 between four East-Asian countries and Australia. The widespread east-Asian use of mucolytics warrants 48 49 further investigation. 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 4 of 74

1 2 3 Strengths and limitations of this study 4 5 6 7  We conducted the largest Western pacific pediatric drug utiIisation study to date using a 8 9 common data model (CDM) which allowed us to rank the user and prescription prevalence of 10 11 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia. 12 13  Our comprehensive overview of country-specific pharmacological agents used in both an 14 15 16 ambulatory andFor inpatient peer setting, by genderreview and age, included only data of 1,574,524 children and 17 18 identified important differences in drug pediatric utilization patterns. 19 20  Despite the differences in databases in terms of setting and study populations, we believe our 21 22 overview of prescription patterns and rankings is an important step to further investigate and 23 24 25 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. 26 27  Over the counter (OTC) prescribing in individual countries was not captured and we may have 28 29 underestimated the true drug utilization of agents, such as paracetamol and some 30 31 antihistamines. 32 33 34  We collected data until the end of 2013 and acknowledge that, due to the rapid change in 35 36 pediatric licensing of therapeutic agents, some of our findings might be worthwhile replicating 37 38 with more current data. 39 40 41 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 Page 5 of 74 BMJ Open

1 2 3 Introduction 4 5 6 7 An important step to facilitate the rational use of drugs in pediatric populations is to investigate drug 8 9 utilization patterns [1]. Observational data in the form of electronic health records and insurance claims 10 11 data, real life data, have been used successfully to investigate the use of drugs in children[1-3]. 12 13 European studies on pediatric drug utilization patterns, have shown that the most commonly used drugs 14 15 16 in European children Forinclude anti-infective, peer respiratory review and dermatological only drugs and are largely 17 18 prescribed off-label[3]. Whilst drug-specific pediatric drug utilization data from East Asian countries are 19 20 available[4-6], a comprehensive overview of the most commonly drugs prescribed is currently lacking. 21 22 23 24 The Asian Pharmacoepidemiology Network (AsPEN), the first multinational research network in Asia, in 25 26 collaboration with the Observational Medical Outcome Partnership (OMOP) set up an initiative to 27 28 convert domestic databases in Asian countries to a Common Data Model (CDM) to offer a multinational 29 30 research infrastructure to facilitate studies[7 8]. We used this network of observational healthcare 31 32 databases in South Korea, Hong Kong, Taiwan, Japan and Australia to measure and compare the 33 34 35 prevalence of drug prescribing in East Asian and Australian children. Our primary aim was to measure 36 37 the pediatric user and prescription prevalence in inpatient and ambulatory settings in the five 38 39 aforementioned countries by age and gender. A further objective was to list the most commonly used 40 41 drugs per drug class, per country, in both an inpatient and ambulatory setting. 42 43 44 Methods 45 46 47 Data sources 48 49 50 We conducted a drug utilisation study using pediatric patient populations from the following databases: 51 52 53 (i) Ajou University School of Medicine (AUSOM) from South Korea; (ii) the Hong Kong Clinical Data 54 55 Analysis and Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 74

1 2 3 National Health Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits 4 5 6 Scheme (PBS). All data were anonymized to protect patient confidentiality. 7 8 9 All five countries have universal health care systems and none of the databases included information on 10 11 patients using private health care[7]. The South Korean and Hong Kong databases, AUSOM and CDARS, 12 13 collect and archive the electronic health records (EHR) of hospital inpatients. Briefly, AUSOM is an EHR 14 15 database of a Korean teaching hospital providing both secondary and tertiary care, with 1,096 patient 16 For peer review only 17 18 beds and 23 operating rooms with data for over 2,073,120 individuals, collected since 1994. By contrast, 19 20 CDARS contains secondary care data from all public hospitals in Hong Kong and their associated 21 22 ambulatory and primary care clinics since 1995 [9-11]. The database was developed and is maintained 23 24 by the Hong Kong Hospital Authority, a statutory body providing health care services available to all 25 26 Hong Kong residents (over 7 million) and covering about 80% of all hospital admissions. 27 28 29 30 The Japanese, Taiwanese and Australian data were extracted from insurance research databases. The 31 32 Japanese JMDC comprises data from 60 Society-Managed Health Insurances covering workers aged 18 33 34 to 65 and their dependents (children and elderly)[12]. The monthly claims data are derived from claims 35 36 issued by clinics, hospitals and community pharmacies from July 2009 onwards. Australian data consist 37 38 39 of national pharmacy claims data from the Australian Government Department of Human Services 40 41 which provides information of medicines subsidized and dispensed under the Pharmaceutical Benefits 42 43 Scheme. PBS data are collected from pharmacies and private hospitals, and discharge or outpatient 44 45 dispensing from public hospitals, but do not include inpatient public hospital prescriptions. From 46 47 Taiwan, we extracted reimbursement data from the Bureau National Health Insurance (NHI) system, 48 49 50 which has registered all medical claims since 1995. More than 99% of the citizens of Taiwan are enrolled 51 52 in the NHI, which offers mandatory and comprehensive medical care coverage to all Taiwanese 53 54 residents. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 74 BMJ Open

1 2 3 Information on specific indications of drug use was not available in the datasets from Hong Kong, Taiwan 4 5 6 and Japan. Further details of each database have been described elsewhere[13]. 7 8 9 10 11 12 Data collection 13 14 For this retrospective descriptive study we identified children below or equal to the age of 18 with at 15 16 For peer review only 17 least 1 day of observation in any of the respective databases. The follow-up period for all children 18 19 started in January 2009 or the start date of observation, whichever was last. Follow-up ended in 20 21 December 2013, the last date observation or the date a child turned 18, whichever was first. Specifically, 22 23 observation time was defined as: 1) The start of the first visit (inpatient, outpatient or ER) to the end of 24 25 26 the last visit for the Korean AUSOM database; 2) The date of birth until death in the Hong Kong CDARS 27 28 database and 3) The insurance enrollment date in the Japan JMDC, Taiwan NHIRD, and Australian PBS. 29 30 Data were available from the end of 2009 onwards for the Japanese JMDC and until December 2011 for 31 32 the Taiwanese database (NHIRD). We used randomly selected samples from CDARS, NHIRD and PBS as 33 34 35 only ~ 10% of the total data were made available for research. 36 37 38 Data extraction 39 40 41 Data extraction, a population file with information on demographics and dispensing records, was 42 43 performed through a shared analysis program combining R and SQL. This program was distributed to the 44 45 data partners, executed locally against the data in OMOP CDM format, and results were returned to the 46 47 central coordinating site (University of Hong Kong). Both the extraction software and the analysis code 48 49 50 are available as open source: https://github.com/OHDSI/StudyProtocols/tree/master/DrugsInPeds. 51 52 53 Each database's full set of drug codes were mapped to RxNorm concepts using a semi-automated 54 55 process; using known ATC codes for each code, a set of one or more RxNorm ingredients was identified 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 74

1 2 3 based on the OMOP Standardized Vocabularies link between ATC and RxNorm. In case of ambiguity, 4 5 6 manual adjudication was used to select the appropriate RxNorm ingredient. Structured information on 7 8 strength and formulation was used to further link drug codes do RxNorm clinical drugs (e.g. 9 10 'Acetaminohpen 100mg Oral '), although this more granular information was not used in this 11 12 study. 13 14 15 Research ethics approval 16 For peer review only 17 18 This study had been approved by the Institutional Review Board of the University of Hong Kong/Hospital 19 20 21 Authority Hong Kong West Cluster (HKU/HA HKW IRB), reference number: UW 13-504. 22 23 24 Patient and Public Involvement 25 26 27 We did not involve patients or the public in our work. 28 29 30 Statistical analysis 31 32 33 Total follow-up time was calculated for each child, stratified by age group and by calendar year. Age was 34 35 assessed on a day-by-day basis, and grouped according to the guidelines of the International Conference 36 37 of Harmonization (ICH) as < 2 years, 2-11 years, and 12-18 years[14]. Drugs were classified according to 38 39 40 a custom defined drug classification (Supplemental Material 1). This classification was based on 41 42 pharmacological class, and where appropriate aggregated further by indication. For each drug class we 43 44 assessed the overall user and prescription prevalence rates (per 1000 persons) per country and setting 45 46 (inpatient or ambulatory) by counting the number of children using or number of dispensings of a 47 48 49 specific drug (numerator). We used the total person count per database and per setting (inpatient or 50 51 ambulatory) as the denominator to calculate prevalence rates. If a person was observed for at least one 52 53 day in a particular category (e.g. age group) that person was counted in the denominator for that 54 55 category. Over the study period, and within a calendar year, children could contribute to more than one 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 74 BMJ Open

1 2 3 age category. For all 15 different custom drug classes the prevalence per 1000 persons was calculated as 4 5 6 the percentage of the total country specific user prevalence (class specific user prevalence/ total user 7 8 prevalence). Lastly, we identified the five drugs with the highest user prevalence (per 1000 persons) per 9 10 drug class in each country. 11 12 13 14 Results 15 16 Study population For peer review only 17 18 19 20 Our dynamic study cohort comprised 1,574,524 children (52.9 % male). The total number of follow-up 21 22 years was 4,783,549 years, with a mean individual follow-up of 3.0 years. The database that contributed 23 24 most person years to the study was the Japanese JDMC (58 %) (Table 1). Altogether, we recorded close 25 26 to 9 million pediatric inpatient dispensings (8,848,699) and more than 44 million ambulatory 27 28 dispensings (44,652,871). The relative number of dispensings prescribed per age category differed 29 30 31 between the inpatient and ambulatory patient settings, with the highest proportion of dispensings 32 33 recorded in the youngest age category (<2 years) for inpatients (45.1%) and in the middle age category 34 35 (2-11 years) for ambulatory patients (67.1%). 36 37 38 User- and prescription prevalence 39 40 41 The recorded user- and prescription prevalence of all therapeutic agents was lower in the inpatient 42 43 44 population than the ambulatory population (Table 2a & Table 2b). Analgesics (including non-steroidal 45 46 anti-inflammatory drugs [NSAIDs]) had the highest user prevalence in Korea, Hong Kong and Taiwan in 47 48 the inpatient setting, however, antibiotics had the highest prescription prevalence in most countries 49 50 (Hong Kong, Japan and Taiwan). In the ambulatory setting, antibiotics had the highest user prevalence in 51 52 53 all countries, however, the highest prescription prevalence differed across countries. In Japan, the 54 55 highest prescription prevalence was recorded for corticosteroids, while in Taiwan the highest 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 74

1 2 3 prescription prevalence was for antihistamines and lastly, in Australia the highest prevalence was 4 5 6 recorded for antibiotics. 7 8 9 Inpatient user- and prescription prevalence 10 11 12 Overall, the inpatient user prevalence of analgesics and antibiotics was high relative to the user 13 14 prevalence of other agents in all countries (Table 2a). Adrenergics, antihistamines, mucolytics and 15 16 corticosteroids were usedFor in 10-15% peer of patients review while the remaining only categories of medicines were used 17 18 in <5% of patients. The user prevalence of mucolytics in Korea and Japan was high compared the user 19 20 21 prevalence of other agents. Inpatient prescription prevalence for different classes of agents showed 22 23 patterns similar to those seen for the user prevalence. 24 25 26 Most drugs were more commonly used by males compared to females (data not shown). The use of 27 28 contraceptives, antidiabetic, psychotherapeutic, antineoplastic and immunomodulating agents was 29 30 more common in females. 31 32 33 Results stratified by age show that the inpatient use of drugs was highest in the youngest age group (<2 34 35 36 years) in all but four classes (contraceptives, antidiabetic, psychotherapeutic, antineoplastic and 37 38 immunomodulating agents) (Figure 1). 39 40 41 Ambulatory user- and prescription prevalence 42 43 44 The pediatric use of different classes of drugs in an ambulatory setting was measured in Japan, Taiwan 45 46 and Australia (Table 2b). The highest ambulatory user prevalence across all drug classes was country 47 48 49 specific with antibiotics ranked high in Japan (22%) and Australia (46%), followed by corticosteroids 50 51 (20% and 23% respectively). In Taiwan the highest user prevalence of any drug class was measured for 52 53 analgesics (17%), closely followed by antihistamines (16%). The pattern of inpatient prescription 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 74 BMJ Open

1 2 3 prevalence for different classes of agents was similar to the pattern seen for the user prevalence. A very 4 5 6 low prescription prevalence of antiinfectives (not including antibiotics) was measured in all countries. 7 8 9 The ambulatory dispensing of drugs stratified by gender showed fewer differences between males and 10 11 females in all databases (Figure 2). In contrast to the gender difference seen in an inpatient setting, the 12 13 ambulatory use of antibiotic agents, antihistamines and corticosteroids was higher in females. 14 15 16 The user prevalence byFor age showed peer a very different review pattern when onlycompared to inpatient use: The use of 17 18 most drugs, by class, was highest in the middle age category (2-11 years) in Japan and Australia (data 19 20 21 not shown). For Taiwan, the highest use for many drug classes was measured in the youngest age 22 23 category. The use of contraceptives, antidiabetic, psychotherapeutic, antineoplastic and 24 25 immunomodulating agents was highest in the oldest age group across all three databases. 26 27 28 Most commonly used drugs by class in an inpatient setting 29 30 31 Paracetamol was the most prevalent analgesic used in all countries, however, the prevalence of 32 33 paracetamol users differed across countries with Hong Kong and Japan using mostly paracetamol while 34 35 36 Korea and Taiwan had a greater spread of analgesic product use (Table 3a). Phenobarbital was the most 37 38 prescribed antiepileptic agent in three countries and the second most prescribed antiepileptic agent in 39 40 Taiwan. Chlorpheniramine was one of the most used antihistamines in all countries with the exception 41 42 of Japan. 43 44 45 Differences in the most used pediatric drugs in an inpatient setting were seen for drugs with a high user 46 47 48 prevalence overall, such as antibiotic and adrenergic agents. An outlying pattern of the user prevalence 49 50 for specific agents was seen in South Korea: The most used antibiotic (ceftriaxone) and adrenergic agent 51 52 (formoterol) in Korea were not among the five drugs with the highest inpatient user prevalence in any of 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 74

1 2 3 the other East Asian countries. Furthermore, the most used mucolytic (bromhexine) and corticosteroid 4 5 6 (dexamethasone) in Korea were less frequently used in other countries. 7 8 9 Most commonly used drugs by class in an ambulatory setting 10 11 12 As in the inpatient setting, the most commonly used analgesic in an ambulatory setting in Japan, Taiwan 13 14 and Australia was paracetamol (Table 3b). Overall, more similarities in the most commonly used drugs 15 16 per custom defined drugFor class werepeer seen between review Japan and Taiwan. only For antibiotic agents, the use of 17 18 amoxicillin, cephalexin and erythoromicin was very similar in Taiwan and Australia. For other drug 19 20 21 classes there was less overlap. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 Page 13 of 74 BMJ Open

1 2 3 Discussion 4 5 6 To our knowledge, this is the first comprehensive overview of pediatric drug use in Korea, Hong Kong, 7 8 Japan, Taiwan and Australia. This study has shown a high inpatient user prevalence of analgesics and 9 10 antibiotics relative to the user prevalence of other drug classes. The highest ambulatory user prevalence 11 12 across all drug classes was country specific with antibiotics and corticosteroids ranked high in Japan and 13 14 Australia. In Taiwan, the user prevalence of analgesics was highest followed by antihistamines. 15 16 For peer review only 17 Mucolytics were amongst the most frequently used drugs in Korea, Japan and Taiwan, but not in Hong 18 19 Kong and Australia. For pediatric inpatients, medication use was highest in males and the lowest age 20 21 category (<2 years), whilst for outpatients gender differences were less pronounced and medication use 22 23 was highest in 2-11 year olds in Japan and Australia. 24 25 26 Comparison with literature 27 28 29 30 Whilst we used a custom therapeutic classification and not ATC classification, the most commonly used 31 32 drugs in every class were compared to those as reported by Sturkenboom in 2005[3]. Overall, the choice 33 34 of specific pediatric therapeutic agents differed widely between the aforementioned three European 35 36 countries and the East Asian countries in our study. Exceptions were similarities in the use of amoxicillin, 37 38 39 salbutamol and paracetamol. The inpatient study results (Tables 2a & 3a) were compared to results of a 40 41 study by Rashed et al. (2015), who reported on the drug utilization patterns of children admitted to a 42 43 pediatric ward in the UK, Germany, Australia, Hong Kong and Malaysia[2]. As in our study, antibacterials 44 45 and analgesics were the two most used therapeutic groups in all five countries. 46 47 National Korean outpatient data on pediatric polypharmacy show that in pediatric users of two or more 48 49 50 drugs (younger than 12 years), respiratory agents are most often prescribed, followed by drugs to treat 51 52 , central nervous system agents and antibiotics[5]. Whilst our study was not directly comparable 53 54 as we had information on Korean inpatient dispensing only, our Taiwanese outpatient data showed a 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 74

1 2 3 high ambulatory use of analgesics, antihistamines, whilst Australian and Japanese data showed a high 4 5 6 ambulatory use of antibiotics and corticosteroids. 7 8 9 Implications for Practice and Policy: Pediatric licensing of drugs in the Western Pacific region 10 11 12 National agencies responsible for regulating therapeutic goods often base their regulations on 13 14 international guidelines, especially for new drug licensing[15 16]. For instance, in Korea it is not 15 16 obligatory to carry outFor clinical trialspeer for pediatrics review and to develop pediatriconly drugs at present, whilst 17 18 various support policies are being developed in recognition of the need for the development and 19 20 21 provision of information on pediatric drugs (personal communication, S. Cho, 2017). Out of the five 22 23 countries included in this study, Japan is the only country with a specific pediatric working group within 24 25 the Pharmaceuticals and Medical Devices Agency[17]. 26 27 28 Results of the current study suggest that the extent to which international pediatric prescribing 29 30 guidelines affect local prescribing practices differs from country to country. For instance, our study, in 31 32 33 line with other studies,shows the widespread of mucolytics in children in Korea, Japan and Taiwan[6]. 34 35 This is a finding of note as in 2010 several European drug agencies withdrew the licenses for 36 37 carbocysteine and acetylcysteine for children younger than two years of age because their use was 38 39 associated with worsening of respiratory tract infections[18]. More recently, the European Medicines 40 41 42 Agency (EMA) published a revised assessment report on products containing ambroxol and bromhexine 43 44 in which the use of these products in children below <2 years of age is discouraged[19]. Our study 45 46 showed that the use of mucolytics was very high in the youngest age group in all countries but Hong 47 48 Kong and Australia. 49 50 51 Another drug that is contraindicated for use in children in some European countries is 52 53 tulobuterol. This drug, a β2-agonist, is licensed in seven countries worldwide for childhood asthma[20 54 55 21]. In 2010, the European Medicines Agency refused a paediatric investigation plan for tulobuterol and 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 74 BMJ Open

1 2 3 granted a waiver (restricting potential use to patients >18 years) as tulobuterol was considered likely to 4 5 6 be ineffective or unsafe in the pediatric population[22]. Yet, in this study tulobuterol was the most used 7 8 adrenergic agent in an outpatient setting in Japan with 74% of all tulobuterol prescribed as patches 9 10 (hokunalin tape) and the remaining 26% prescribed as a liquid (oral). 11 12 A further finding of note was the relatively common ambulatory use of dihydrocodeine in Japan 13 14 and codeine in Taiwan and Australia. Both codeine and dihydrocodeine are morphine derivatives and 15 16 For peer review only 17 are contraindicated for use in children younger than 12 in Europe since 2013[23]. This is mainly due to 18 19 the unpredictable metabolism of codeine to morphine[24]. At the time of data collection (2009-2012) 20 21 Australia already had prescribing guidelines in place in which it was recommended to restrict the use of 22 23 codeine in children under 12. 24 25 26 Lastly, we found that sulfamethoxazole is still one of the most used antibiotic agents in Taiwan. 27 28 In many European countries, including the UK, the importance of the sulfonamides has decreased as a 29 30 result of increasing bacterial resistance and their replacement by antibacterials which are generally 31 32 more active and less toxic[25]. 33 34 35 36 37 Strengths and limitations 38 39 We conducted the largest Western pacific pediatric drug utiIisation study to date. Data extraction was 40 41 performed through a shared analysis program and a standardized analysis process was applied to all 42 43 44 databases. Using a common data model (CDM), and CDM vocabulary concept identifiers, we were able 45 46 to use standardised drug codes across countries which allowed us to rank the user and prescription 47 48 prevalence of fifteen different drug classes in five different countries. We found some important 49 50 similarities and differences in country specific drug utilization patterns between Korea, Hong Kong, 51 52 53 Japan, Taiwan and Australia. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 74

1 2 3 It is important to highlight that our study did not aim to directly compare the drug prevalence 4 5 6 rates between the countries in this study, rather we aimed to provide a comprehensive overview of the 7 8 country-specific pharmacological agents used in both an ambulatory and inpatient setting by gender and 9 10 age. Differences in user and prescription prevalence patterns between the five countries in our study 11 12 may reflect differences in the underlying prevalence of diseases, differences in physician prescribing 13 14 behavior and differences in medicine availability and data capture. Like other drug utilization studies 15 16 For peer review only 17 using electronic health records, we could not distinguish between these. Additionally, as medical 18 19 indications were not available in all data sets we were unable to report the reasons for prescriptions. 20 21 we acknowledge that this limits the clinical interpretation of our data. Formularies were different across 22 23 countries as well, particularly with regard to which medicines were subsidized in the data and for which 24 25 26 indication. It is also worth noting that we did not distinguish between formulations and we acknowledge 27 28 that this limits the clinical interpretation of our data. Lastly, the five databases captured different source 29 30 populations. 31 32 Despite the differences in databases in terms of size, setting and study populations, we believe 33 34 35 our overview of prescription patterns and rankings is an important step to further investigate and 36 37 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. Standardizing 38 39 medication use across countries will help when implementing adverse event monitoring programs 40 41 across the region. 42 43 44 Over the counter (OTC) prescribing in individual countries was not captured and we may have 45 46 underestimated the true drug utilization of agents, such as paracetamol and some antihistamines. OTC 47 48 prescribing is most likely to have affected any ambulatory drug utilization estimates. 49 50 Future studies could be conducted using the current dataset in OMOP CDM format to capture any 51 52 53 changes in pediatric drug dispensing over time. We collected data until the end of 2013 and 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 74 BMJ Open

1 2 3 acknowledge that, due to the rapid change in pediatric licensing of therapeutic agents, some of our 4 5 6 findings might be worthwhile replicating with more current data. 7 8 9 10 Conclusion 11 12 13 Country-specific drug pediatric utilization patterns were described ranked and compared between four 14 15 East-Asian countries and Australia.The widespread east-Asian use of mucolytics and the use of 16 For peer review only 17 18 tulobuterol in Japan warrants further investigation. 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 18 of 74

1 2 3 4 5 6 Acknowledgments: The analysis is based in part on work from the Observational Health Sciences and 7 8 Informatics collaborative (OHDSI). OHDSI (http://ohdsi.org) is a multi-stakeholder, interdisciplinary 9 10 collaborative to create open-source solutions that bring out the value of observational health data 11 12 through large-scale analytics. 13 14 15 16 For peer review only 17 18 Financial Disclosure: Dr. Schuemie is an employee of Janssen Research & Development. None of the 19 20 remaining authors have financial relationships relevant to this article to disclose. 21 22 23 24 Potential Conflicts of Interest: The authors have no conflicts of interest relevant to this article to 25 26 disclose. 27 28 29 30 31 32 Author’s contribution: MS and ICKW designed the study. MS wrote the protocol for this study and was 33 34 responsible for the statistical programming. RB wrote the first draft of the manuscript. All authors ran 35 36 country specific analyses, contributed original data and provided comments. 37 38 39 40 41 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 Page 19 of 74 BMJ Open

References 1 2 3 1. Wong IC, Murray ML. The potential of UK clinical databases in enhancing paediatric medication research. Br J Clin 4 Pharmacol 2005;59(6):750-5. doi: 10.1111/j.1365-2125.2005.02450.x [published Online First: 2005/06/14] 5 6 2. Rashed AN, Wong IC, Wilton L, et al. Drug Utilisation Patterns in Children Admitted to a Paediatric General Medical 7 Ward in Five Countries. Drugs - real world outcomes 2015;2(4):397-410. doi: 10.1007/s40801-015-0049-y 8 3. Sturkenboom MC, Verhamme KM, Nicolosi A, et al. Drug use in children: cohort study in three European countries. 9 Bmj 2008;337:a2245. doi: 10.1136/bmj.a2245 10 4. Chua KL, Soh SE, Ma S, et al. Pediatric asthma mortality and hospitalization trends across Asia pacific: relationship with 11 asthma drug utilization patterns. World Organ J 2009;2(5):77-82. doi: 10.1097/WOX.0b013e3181a7c288 12 [published Online First: 2009/05/01] 13 5. Jeon SM, Park S, Rhie SJ, et al. Prescribing patterns of polypharmacy in Korean pediatric patients. PLoS One 14 15 2019;14(10):e0222781. doi: 10.1371/journal.pone.0222781 [published Online First: 2019/10/02] 16 6. Cheng CL, Kao Yang YH, LiuFor CC, et al. Apeer retrospective review study on the usage only of cough and cold in viral 17 respiratory tract infections in Taiwanese children. Pharmacoepidemiol Drug Saf 2014;23(1):36-42. doi: 18 10.1002/pds.3460 [published Online First: 2013/05/29] 19 7. Lai EC, Ryan P, Zhang Y, et al. Applying a common data model to Asian databases for multinational 20 pharmacoepidemiologic studies: opportunities and challenges. Clin Epidemiol 2018;10:875-85. doi: 21 10.2147/CLEP.S149961 [published Online First: 2018/08/14] 22 8. As PENc, Andersen M, Bergman U, et al. The Asian Pharmacoepidemiology Network (AsPEN): promoting multi- 23 national collaboration for pharmacoepidemiologic research in Asia. Pharmacoepidemiol Drug Saf 24 25 2013;22(7):700-4. doi: 10.1002/pds.3439 [published Online First: 2013/05/09] 26 9. Chan EW, Lau WC, Leung WK, et al. Prevention of Dabigatran-Related Gastrointestinal Bleeding With Gastroprotective 27 Agents: A Population-Based Study. Gastroenterology 2015;149(3):586-95 e3. doi: 10.1053/j.gastro.2015.05.002 28 [published Online First: 2015/05/12] 29 10. Chui CS, Man KK, Cheng CL, et al. An investigation of the potential association between retinal detachment and oral 30 fluoroquinolones: a self-controlled case series study. The Journal of antimicrobial chemotherapy 31 2014;69(9):2563-7. doi: 10.1093/jac/dku145 [published Online First: 2014/05/17] 32 11. Man KK, Chan EW, Coghill D, et al. Methylphenidate and the risk of trauma. Pediatrics 2015;135(1):40-8. doi: 33 34 10.1542/peds.2014-1738 [published Online First: 2014/12/17] 35 12. Tanaka S, Seto K, Kawakami K. Pharmacoepidemiology in Japan: medical databases and research achievements. 36 Journal of Pharmaceutical Health Care and Sciences 2015;1(1):16. doi: 10.1186/s40780-015-0016-5 37 13. Lai EC, Man KK, Chaiyakunapruk N, et al. Brief Report: Databases in the Asia-Pacific Region: The Potential for a 38 Distributed Network Approach. Epidemiology 2015;26(6):815-20. doi: 10.1097/EDE.0000000000000325 39 [published Online First: 2015/07/02] 40 14. Rose K, Stötter H. ICH E 11: clinical investigation of medicinal products in the paediatric population. In: Rose K, JN 41 vdA, eds. Guide to paediatric clinical research. Basel: KArger 2007:33-37. 42 43 15. Woo Y, Kim HE, Chung S, et al. Pediatric medication error reports in Korea adverse event reporting system database, 44 1989-2012: comparing with adult reports. Journal of Korean medical science 2015;30(4):371-7. doi: 45 10.3346/jkms.2015.30.4.371 46 16. Taiwan Food and Drugs Administration. 2016 Taiwan Food and Drug Administration Annual Report. [updated 47 October 2016. Available from: http://www.fda.gov.tw/upload/ebook/AnnuaReport/2016. 48 17. Sato J. Global Pediatric Development: We Are Making Progress. PMDA Perspective.: Japanese Pharmaceuticals and 49 Medical Devices Agency (PMDA), 2014. 50 18. Mallet P, Mourdi N, Dubus JC, et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine 51 and carbocysteine systemic use in paediatric patients: a national survey. PLoS One 2011;6(7):e22792. doi: 52 53 10.1371/journal.pone.0022792 54 19. European Medicines Agency (EMA). Revised assessment report: Ambroxol and bromhexine containing medicinal 55 products. 10 September 2015. [Available from: 56 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ambroxol_and_bromhexine_ 57 31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500184106.pdf 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 74

20. Schmiedl S, Fischer R, Ibanez L, et al. Utilisation and off-label prescriptions of respiratory drugs in children. PLoS One 1 2014;9(9):e105110. doi: 10.1371/journal.pone.0105110 2 3 21. Arakawa H, Hamasaki Y, Kohno Y, et al. Japanese guidelines for childhood asthma 2017. Allergology international : 4 official journal of the Japanese Society of Allergology 2017 doi: 10.1016/j.alit.2016.11.003 5 22. European Medicines Agency (EMA). Opinion of the Paediatric Committee on the refusal of a Paediatric Investigation 6 Plan and on the granting of a product-specific waiver. 6 July 2010. [cited 2017 February 27]. Available from: 7 http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500095327.pdf. 8 23. European Medicines Agency (EMA). Assessment report: Codeine containing medicinal products for the treatment of 9 cough and/or cold in paediatric patients. 12 March 2015. [Available from: 10 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Codeine_cough_or_cold_in_c 11 hildren/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500186522.pdf. 12 13 24. Ciszkowski C, Madadi P, Phillips MS, et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. The 14 New England journal of medicine 2009;361(8):827-8. doi: 10.1056/NEJMc0904266 15 25. British National Formulary (BNF). CLARITHROMYCIN [updated 30-03-2017. Available from: 16 https://www.evidence.nhs.uk/formulary/bnf/current/5-infections/51-antibacterial-drugs/515-For peer review only 17 macrolides/clarithromycin. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 Page 21 of 74 BMJ Open

Tables and Figures 1 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 22 of 74 Table 1. Patient characteristics, person years and number of prescription by age and calendar year 1 Korea (AUSOM) Hong Kong (CDARS)* Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 2 (n = 220,076) (n = 18,634) (n = 913,006) (n = 235,214) (n = 187,594) 3 Total number of person years 259,750 71,502 3,006,825 630,051 774,420 4 Gender (number of children/ 5 6 number of person years[%]) 7 Female 98,921/ 8,389/ 433,918/ 113,179/ 87,129/ 8 115,868 (44.61) 31,433 (43.96) 1,459,304 (48.53) 301,824 (47.90) 360,099 (46.50) 9 Male 121,155/ 9,656/ 479,088/ 122,035/ 100,465/ 10 143,882 (55.39) 36,875 (51.57) 1,547,521 (51.47) 328,226 (52.10) 414,322 (53.50) 11 Age (number of children/ 12 number of person years [%]) For peer review only 13 <2 years 69,121/ 5,758/ 175,070/ 31,659/ 62,021/ 14 15 32,909 (12.7) 7,937 (11.1) 304,672 (10.1) 42,445 (6.7) 86,181 (11.1) 16 2-11 years 122,177/ 11,120/ 448,008/ 133,727/ 138,714/ 17 152,352 (58.7) 34,767 (48.6) 1,613,909 (53.7) 305,543 (48.5) 462,755 (59.8) 18 12-18 years 60,230/ 9,458/ 348,343/ 131,969/ 86,051/ 19 74,489 (28.7) 28,798 (40.3) 1,088,244 (36.2) 282,063 (44.8) 225,484 (29.1) 20 Calendar year (number of children/ 21 number of person years [%]) 22 2009 109,462/ 14,797/ 519,973/ 228,059/ 165,735/ 23 72,472 (27.9) 14,148 (19.8) 311,734 (10.4) 216,660 (34.4) 149,157 (19.3) 24 25 2010 101,055/ 14,843/ 573,486/ 221,661/ 168,702/ 26 66,090 (25.4) 14,147 (19.8) 644,681 (21.4) 211,666 (33.6) 152,689 (19.7) 27 2011 93,416/ 15,001/ 590,384/ 208,643/ 171,233/ 28 57,515 (22.1) 14,274 (20.0) 665,955 (22.2) 201,725 (32.0) 155,597 (20.1) 29 2012 83,504/ 15,215/ 594,331/ 172,842/ 30 44,161 (17.1) 14,459 (20.2) 686,775 (22.8) 158,117 (20.4) 31 2013 51,575/ 15,182/ 589,192/ 173,286/ 32 19,512 (7.5) 14,475 (20.2) 697,680 (23.2) 158,861 (20.5) 33 34 Number of drugs dispensed 35 (inpatient) 36 Total 3,126,567 48,166 5,311,981 361,985 - 37 <2 years, n (%) 1,354,036 (43.3) 17,816 (37.0) 2,523,959 (47.5) 92,518 (25.6) - 38 2-11 years, n (%) 1,158,851 (37.1) 12,852 (26.7) 1,980,742 (37.3) 156,401 (43.2) - 39 40 12-18 years, n (%) 613,680 (19.6) 17,498 (36.3) 807,280 (15.2) 113,066 (31.2) - 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 23 of 74 BMJ Open

Number of drugs dispensed 1 (ambulatory) 2 3 Total - 19,511,710 23,520,356 1,620,805 4 <2 years, n (%) - 1,346,903 (6.9) 2,880,951 (12.2) 187,486 (11.5) 5 2-11 years, n (%) - 14,036,081 (71.9) 14,984,130 (63.7) 950,984 (58.7) 6 12-18 years, n (%) - 5,655,275 (24.0) 482,335 (29.8) 7 4,128,726 (21.2) 8 9 *For 589 children in CDARS gender was not recorded at admission 10 11 12 For peer review only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 24 of 74 Table 2a. User prevalence & prescription prevalence and in an inpatient setting by therapeutic level: Prevalence per 1000 persons Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 Class* User Prescription User Prescription User Prescription User Prescription 2 prevalence prevalence prevalence prevalence prevalence prevalence prevalence prevalence 3 (%)** (%)*** (%)** (%)*** (%)** (%)*** (%)** (%)*** 4 Analgesics (inc. NSAIDs) 109 (23) 1269 (23) 131 (36) 314 (19) 31 (19) 380 (24) 43 (25) 195 (23) 5 6 Antibiotics 107 (22) 1141 (20) 91 (25) 634 (37) 43 (26) 496 (31) 37 (21) 233 (27) 7 8 Adrenergics 65 (14) 520 (9) 31 (9) 101 (6) 23 (14) 161 (10) 23 (13) 110 (13) 9 10 Antihistamines 53 (11) 520 (9) 55 (15) 136 (8) 11 (7) 48 (3) 23 (13) 77 (9) 11 12 Mucolytics 53 (11) For614 (11) peer4 (1) review7 (0) 22 (13) only168 (11) 19 (11) 69 (8) 13 14 Corticosteroids 45 (9) 425 (8) 21 (6) 89 (5) 15 (9) 89 (6) 18 (10) 72 (8) 15 16 Antiinfectives (excluding 9 (2) 130 (2) 14 (4) 48 (3) 2 (1) 28 (2) 2 (1) 15 (2) 17 antibiotics and vaccines) 18 Antiepileptics 8 (2) 431 (8) 3 (1) 36 (2) 2 (1) 27 (2) 2 (1) 23 (3) 19 20 Diuretics 8 (2) 170 (3) 3 (1) 39 (2) 2 (1) 42 (3) 2 (1) 14 (2) 21 22 Anticlotting and 7 (1) 188 (3) 1 (0) 25 (1) 12 (7) 99 (6) 2 (1) 8 (1) 23 antifibrinolytic agents 24 Antidiabetic drugs 4 (1) 19 (0) 0 (0) 7 (0) 1 (1) 4 (0) 1 (1) 5 (1) 25 26 Psychotherapeutic agents 2 (0) 65 (1) 3 (1) 138 (8) 2 (1) 17 (1) 1 (1) 14 (2) 27 28 Antineoplastic and 2 (0) 100 (2) 1 (0) 61 (4) 1 (1) 26 (2) 0 (0) 14 (2) 29 immunomodulating 30 agents 31 Central nervous system 1 (0) 20 (0) 2 (1) 62 (4) 0 (0) 2 (0) 0 (0) 3 (0) 32 stimulants 33 Contraceptives 0 (0) 2 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 34 35 Total 473 (100%) 5614 (100%) 360 (100%) 1697 (100%) 167 (100%) 1587 (100%) 173 (100%) 852 (100%) 36 37 38 *custom classification, see Supplemental Material 1 39 **For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific user prevalence (class 40 specific user prevalence/ total user prevalence) 41 *** For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific prescription 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 74 BMJ Open

prevalence (class specific prescription prevalence/ total prescription prevalence) 1 2 Table 2b. User prevalence & prescription prevalence and in an ambulatory setting by therapeutic level (prevalence per 1000 persons) 3 Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 4 5 Class* User prevalence Prescription User prevalence Prescription User prevalence Prescription 6 (%)** prevalence (%)** prevalence (%)** prevalence 7 (%)*** (%)*** (%)*** 8 Antibiotics 440 (22) 882 (25) 796 (14) 2010 (8) 679 (46) 918 (52) 9 10 Corticosteroids 401 (20) 954 (27) 701 (13) 1352 (6) 348 (23) 281 (16) 11 12 Analgesics (inc. NSAIDs) For333 (16) peer428 (12) review933 (17) only5889 (24) 96 (6) 61 (3) 13 14 Adrenergics 242 (12) 405 (11) 814 (15) 4666 (19) 184 (12) 193 (11) 15 16 Antihistamines 261 (13) 415 (12) 883 (16) 6246 (26) 3 (0) 1 (0) 17 18 Mucolytics 240 (12) 353 (10) 756 (14) 3053 (13) 0 (0) 0 (0) 19 Antiinfectives (excluding antibiotics 20 91 (4) 60 (2) 490 (9) 842 (3) 72 (5) 25 (1) 21 and vaccines) 22 Contraceptives 1 (0) 1 (0) 23 (0) 17 (0) 34 (2) 27 (2) 23 24 Psychotherapeutic agents 2 (0) 7 (0) 23 (0) 41 (0) 33 (2) 86 (5) 25 26 Central nervous system stimulants 3 (0) 5 (0) 20 (0) 65 (0) 25 (2) 117 (7) 27 Antineoplastic and 28 4 (0) 7 (0) 9 (0) 15 (0) 1 (0) 3 (0) immunomodulating agents 29 30 Antiepileptics 2 (0) 5 (0) 15 (0) 44 (0) 6 (0) 41 (2) 31 32 Anticlotting and antifibrinolytic agents 3 (0) 2 (0) 13 (0) 10 (0) 1 (0) 2 (0) 33 34 Diuretics 0 (0) 1 (0) 4 (0) 5 (0) 2 (0) 2 (0) 35 36 Antidiabetic drugs 0 (0) 1 (0) 2 (0) 8 (0) 3 (0) 5 (0) 37 38 Total 2023 (100%) 3526 (100%) 5482 (100%) 24263 (100%) 1487 (100%) 1762 (100%) 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 26 of 74

*custom classification, see Supplemental Material 1 1 2 **For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific user prevalence (class specific user 3 prevalence/ total user prevalence) 4 *** For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific prescription prevalence (class specific 5 prescription prevalence/ total prescription prevalence) 6 7 8 9 10 11 12 For peer review only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 27 of 74 BMJ Open

Table 3a. Most commonly used drugs per custom defined drug class, per country, in an inpatient setting 1 2 Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 3 Drug name Number Drug name Number Drug name Number Drug name Number per 4 per 1000 per 1000 per 1000 1000 users 5 users users users 6 Antibiotics Ceftriaxone 27.02 Amoxicillin 34.08 Cefazolin 10.09 Cefazolin 15.17 7 Roxithromycin 19.03 Gentamicin Sulfate 18.09 Ampicillin 9.2 Amoxicillin 10.9 8 9 Cefotaxime 17.11 Penicillin G 14.33 Sulbactam 5.56 Gentamicin Sulfate 8.79 10 Ofloxacin 16.84 Cefuroxime 12.72 Clarithromycin 5.25 Ampicillin 7 11 Clarithromycin 10.9 Ampicillin 12.4 Cefcapene 4.61 Cephalexin 6.64 12 Analgesics (inc. Paracetamol For50.94 peerParacetamol review127.67 Paracetamol only 19.32 Paracetamol 30.17 13 14 NSAIDs) Ibuprofen 50.45 Tramadol 4.99 Remifentanil 7.34 Diclofenac 17.94 15 Tramadol 28.9 Ibuprofen 4.78 Flurbiprofen 5.2 Ibuprofen 15.07 16 Fentanyl 26.85 Diclofenac 1.66 Loxoprofen 4.39 Meperidine 5.21 17 Ketorolac 19.11 Aspirin 1.29 Pentazocine 3.91 Ketorolac 4.81 18 19 Adrenergics Formoterol 27.63 Salbutamol 22.81 Tulobuterol 10.32 Terbutaline 8.09 20 Epinephrine 26.85 Pseudoephedrine 6.01 Procaterol 8.12 Pseudoephedrine 7.79 21 Phenylephrine 14.97 Propranolol 1.02 Salbutamol 7.51 Procaterol 7.5 22 Salbutamol 14.64 Terbutaline 0.97 Epinephrine 4.62 Fenoterol 4.97 23 24 Pseudoephedrine 6.12 Phenylephrine 0.59 Ephedrine 1.8 Salbutamol 4.74 25 Antihistamines Chlorpheniramine 51.7 Chlorpheniramine 38.37 Cyproheptadine 5.23 Cyproheptadine 14.26 26 Ketotifen 4.02 Diphenhydramine 19.59 Epinastine 1.24 Chlorpheniramine 4.4 27 Levocetirizine 1.85 Triprolidine 6.01 Ketotifen 1.12 Diphenhydramine 3.01 28 29 Ebastine 1.23 Promethazine 2.36 Diphenhydramine 1 Brompheniramine 1.94 30 Fexofenadine 1 Cetirizine 0.8 Mequitazine 0.77 Cetirizine 1.91 31 Mucolytics Bromhexine 39.3 Bromhexine 2.09 Carbocysteine 18.93 Acetylcysteine 11.04 32 Acetylcysteine 24.28 Acetylcysteine 1.02 Ambroxol 8.23 Ambroxol 7.18 33 34 Mannitol 4.7 Carbocysteine 0.48 Bromhexine 4.6 Bromhexine 3.32 35 Erdosteine 3.54 Mesna 0.27 Acetylcysteine 0.21 Mannitol 1.16 36 Carbocysteine 0.69 - - Eprazinone 0.17 Carbocysteine 0.22 37 Corticosteroids Dexamethasone 23.48 Prednisolone 9.34 prednisolone 4.09 Prednisolone 4.92 38 39 Budesonide 15.45 Hydrocortisone 7.89 Methylprednisolone 3.95 Hydrocortisone 4.61 40 Prednisolone 12.11 Beclomethasone 3.6 Dexamethasone 3.36 Dexamethasone 4.4 41 Hydrocortisone 10.15 Dexamethasone 2.9 Hydrocortisone 3.17 Triamcinolone 4.13 42 Prednicarbate 7.74 Budesonide 1.29 Betamethasone 1.95 Methylprednisolone 3.61 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 28 of 74

Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 2 3 Antiinfectives Oseltamivir 3.27 Hep.B hyp. globulin 4.35 Oseltamivir 0.5 Lysozyme 0.62 4 Acyclovir 2.53 Oseltamivir 2.84 lysozyme 0.31 Nystatin 0.54 5 Fluconazole 1.3 Acyclovir 2.15 palivizumab 0.26 Fluconazole 0.37 6 Palivizumab 0.55 Clotrimazole 2.09 Acyclovir 0.24 Clotrimazole 0.29 7 Itraconazole 0.49 Nystatin 1.82 Fluconazole 0.2 Acyclovir 0.24 8 9 Anticlotting and Heparin 5.98 Heparin 0.91 Heparin 11.5 Heparin 1.33 10 antifibrinolytic Antithrombin III 1.59 Dipyridamole 0.32 Dipyridamole 0.28 Streptokinase 0.19 11 agents Streptokinase 0.6 Urokinase 0.27 Warfarin 0.25 Urokinase 0.11 12 Urokinase For0.54 peerWarfarin review0.16 Antithrombin only III 0.24 Dipyridamole 0.1 13 14 Enoxaparin 0.1 Enoxaparin 0.11 Urokinase 0.07 Warfarin 0.06 15 Antiepileptics Phenobarbital 3.64 Phenobarbital 1.18 Phenobarbital 0.95 Phenytoin 0.66 16 Levetiracetam 2.58 Phenytoin 0.7 Carbamazepine 0.63 Phenobarbital 0.59 17 Lamotrigine 2.41 Carbamazepine 0.64 Zonisamide 0.15 Clonazepam 0.51 18 19 Topiramate 1.38 Levetiracetam 0.59 Levetiracetam 0.14 Oxcarbazepine 0.23 20 Fosphenytoin 0.8 Topiramate 0.32 Clonazepam 0.14 Topiramate 0.19 21 Diuretics Furosemide 6.54 Furosemide 2.41 Furosemide 1.78 Furosemide 1.58 22 Spironolactone 1.32 Spironolactone 1.45 Spironolactone 0.87 Spironolactone 0.17 23 24 Theobromine 1.2 Hydrochlorothiazide 0.43 Trichlormethiazide 0.06 Bumetanide 0.03 25 Hydrochlorothiazide 0.08 - Hydrochlorothiazide 0.02 Trichlormethiazide 0.02 26 - - Torsemide 0.02 Amiloride 0.01 27 Psychotherapeutic Haloperidol 0.58 Risperidone 1.34 Droperidol 0.79 Haloperidol 0.34 28 agents 29 Risperidone 0.52 Haloperidol 1.02 Chlorpromazine 0.37 Risperidone 0.2 30 Quetiapine 0.42 Fluoxetine 0.75 Risperidone 0.26 Quetiapine 0.13 31 Escitalopram 0.3 Olanzapine 0.48 olanzapine 0.11 Aripiprazole 0.09 32 Fluoxetine 0.28 Sertraline 0.43 Haloperidol 0.1 Sulpiride 0.08 33 34 Antineoplastic & Filgrastim 0.68 Vincristine 0.43 Methotrexate 0.16 Methotrexate 0.2 35 immunomodulating Methotrexate 0.5 Doxorubicin 0.38 Vincristine 0.14 Cytarabine 0.16 36 agents Cyclophosphamide 0.45 Methotrexate 0.32 Cyclophosphamide 0.14 Filgrastim 0.16 37 Vincristine 0.35 Cyclophosphamide 0.32 Tacrolimus 0.13 Vincristine 0.14 38 39 Cyclosporine 0.34 Cytarabine 0.32 Cyclosporine 0.13 Cyclophosphamide 0.14 40 Central nervous Caffeine 0.66 Caffeine 1.4 Caffeine 0.1 Piracetam 0.27 41 system stimulants Methylphenidate 0.23 Methylphenidate 0.8 Atomoxetine 0.03 Methylphenidate 0.08 42 Acetylcarnitine 0.05 Tomoxetine 0.11 Methylphenidate 0.02 atomoxetine <0.01 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 74 BMJ Open

Drug class Korea (AUSOM) Hong Japan (JMDC) Taiwan Drug Korea (AUSOM) Hong Kong 1 Kong (NHIRD) class (CDARS) 2 3 (CDARS) 4 Antidiabetic drugs Regular Insulin 3.24 Metformin 0.27 Regular Insulin 0.5 Regular Insulin 0.54 5 Insulin Detemir 0.32 Insulin Detemir 0.11 Insulin Glargine 0.06 Insulin Glargine 0.09 6 Insulin Glargine 0.12 Gliclazide 0.11 Insulin Lispro 0.04 Metformin 0.05 7 Metformin 0.06 - Metformin 0.01 Insulin Detemir 0.04 8 9 Insuline Glulisine 0.05 - Insuline Glulisine 0.01 Glimepiride 0.01 10 Contraceptives Megestrol 0.16 Levonorgestrel 0.16 Norethindrone <0.01 Medroxyprogeste 0.02 11 Medroxyprogeste 0.04 Medroxyprogeste 0.05 Medroxyprogeste <0.01 Megestrol 0.01 12 - For peerNorethindrone review0.05 - only - 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 30 of 74

Table 3b. Most commonly used drugs per custom defined drug class, per country, in an ambulatory setting 1 2 Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 3 Drug name Number Drug name Number Drug name Number 4 per 1000 per per 1000 5 users 1000 users 6 users 7 Antibiotics Clarithromycin 112.34 Amoxicillin 443.86 Amoxicillin 506.88 8 9 Gentamicin 109.87 Cephalexin 276.72 Cephalexin 279.23 10 Cefcapene 84.12 Sulfamethoxazole 217.87 Chloramphenicol 148.45 11 Gentamicin Sulfate 73.38 Erythromycin 170.63 Erythromycin 147.04 12 Ofloxacin 72.45 Clindamycin 168.23 Cefaclor 116.35 13 14 Corticosteroids Betamethasone 232.34 Betamethasone 353.29 Prednisolone 165.53 15 Dexamethasone 154.65 Dexamethasone 285.17 Hydrocortisone 83.38 16 HydrocortisoneFor peer64.61 reviewTriamcinolone only198.38 fluticasone 71.28 17 Prednisolone 60.3 Prednisolone 194.59 Betamethasone 65.42 18 19 Fluorometholone 57.76 Fluorometholone 180.39 Dexamethasone 63.29 20 Analgesics (inc. Paracetamol 253.67 Paracetamol 879.68 Paracetamol 72.78 21 NSAIDs) Loxoprofen 63.76 Diclofenac 679.67 Codeine 27.87 22 Salicylamide 42.91 Ibuprofen 615.18 Ibuprofen 9.71 23 24 Dihydrocodeine 34.9 Codeine 194.02 Oxycodone 6.08 25 Ketoprofen 31.47 Naproxen 101.18 Diclofenac 4.85 26 Antihistamines Cyproheptadine 75.51 Dexchlorpheniramine 461.81 Cyproheptadine 3.11 27 Ketotifen 57.63 Cyproheptadine 442.32 Promethazine 0.07 28 29 Olopatadine 48.02 Cetirizine 381.81 - - 30 Clemastine 46.31 Mequitazine 338.95 - - 31 Mequitazine 35.14 Chlorpheniramine 309.08 - - 32 Adrenergics Tulobuterol 103.78 Pseudoephedrine 728.27 Salbutamol 164.14 33 34 Epinephrine 86.05 Fenoterol 301.3 Salmeterol 32.61 35 Procaterol 70.65 Procaterol 279.84 Clonidine 9.54 36 Salbutamol 57.82 Tretoquinol 209.47 Epinephrine 4.15 37 Phenylephrine 9.87 Terbutaline 177.29 Terbutaline 3.04 38 39 Mucolytics Carbocysteine 175.47 Ambroxol 546.33 Dornase Alfa 0.19 40 Ambroxol 78.67 Bromhexine 335.46 Mannitol 0.01 41 Bromhexine 49.24 Eprazinone 274.49 Acetylcysteine 0.01 42 Eprazinone 8.95 Acetylcysteine 265.77 Mesna 0.01 43 44 Acetylcysteine 8.46 Carbocysteine 197.11 - - 45 Antiinfectives Oseltamivir 41.17 Lysozyme 377.54 Nystatin 63.5 46 Lysozyme 25.34 Oseltamivir 73.71 Acyclovir 1.78 47 Acyclovir 14.65 Econazole 44.27 Terbinafine 1.43 48 49 Vidarabine 6.63 Clotrimazole 29.53 Amphotericin B 1.41 50 Valacyclovir 5.05 Ketoconazole 29 Ketoconazole 1.4 51 Psychotherapeutic Risperidone 0.72 Sulpiride 7.64 Fluoxetine 9 52 agents Sulpiride 0.37 Imipramine 3.24 Risperidone 6.59 53 54 Imipramine 0.32 Doxepin 2.27 Sertraline 5.8 55 Aripiprazole 0.32 Fluoxetine 2.12 Escitalopram 4.3 56 Fluvoxamine 0.27 Risperidone 2.06 Amitriptyline 3.4 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 74 BMJ Open

Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 1 2 Contraceptives Norethindrone 0.48 Norethindrone 15.18 Levonorgestrel 26.22 3 Medroxyprogesterone 0.29 Medroxyprogesterone 9.53 Etonogestrel 7.82 4 - - Lynestrenol 0.09 Medroxyprogesterone 4.81 5 - - Megestrol <0.01 Norethindrone 3.73 6 7 - - - - Megestrol 0.01 8 Central nervous Caffeine 2.11 Methylphenidate 13.54 Methylphenidate 21.24 9 system stimulants Methylphenidate 0.68 Piracetam 3.22 Dextroamphetamine 6.09 10 Atomoxetine 0.32 Caffeine 3.2 Atomoxetine 3.28 11 12 Modafinil 0.01 Atomoxetine 1.36 Modafinil 0.02 13 Citicoline 0.01 Modafinil 0.02 - - 14 Antineoplastic and Tacrolimus 3.44 Tretinoin 6.81 Methotrexate 0.52 15 immunomodulating Cyclosporine 0.26 Tacrolimus 0.93 Azathioprine 0.29 16 agents For peer review only 17 Leuprolide 0.21 Methotrexate 0.38 Mercaptopurine 0.2 18 Methotrexate 0.09 Azathioprine 0.29 Cyclosporine 0.16 19 Vincristine 0.08 Leuprolide 0.15 Tacrolimus 0.15 20 Antiepileptics Phenobarbital 1.19 Phenobarbital 9.4 Carbamazepine 2.51 21 22 Carbamazepine 0.63 Clonazepam 2.56 Lamotrigine 1.47 23 Zonisamide 0.15 Oxcarbazepine 0.99 Levetiracetam 1.18 24 Clonazepam 0.15 Carbamazepine 0.99 Topiramate 1.09 25 Levetiracetam 0.13 Topiramate 0.98 Phenytoin 0.41 26 27 Anticlotting and Heparin 2.66 Streptokinase 9.55 Warfarin 0.42 28 antifibrinolytic Dipyridamole 0.12 Dipyridamole 1.82 Enoxaparin 0.27 29 agents Warfarin 0.11 Heparin 0.94 Clopidogrel 0.14 30 Beraprost 0.04 Epoprostenol 0.16 Dipyridamole 0.02 31 32 Ticlopidine 0.02 Warfarin 0.12 Dalteparin 0.01 33 Diuretics Furosemide 0.42 Furosemide 1.78 Furosemide 0.82 34 Spironolactone 0.27 Spironolactone 1.52 Spironolactone 0.51 35 Trichlormethiazide 0.02 Hydrochlorothiazide 0.49 Hydrochlorothiazide 0.51 36 37 Hydrochlorothiazide 0 Trichlormethiazide 0.4 Indapamide 0.12 38 Torsemide 0 Bumetanide 0.06 Amiloride 0.03 39 Antidiabetic drugs Regular Insulin, 0.09 Metformin 0.76 Metformin 1.46 40 Human 41 Insulin Glargine 0.07 Gliclazide 0.49 Insulin Glargine 0.98 42 43 Insulin Lispro 0.04 Regular Insulin, 0.36 Regular Insulin, 0.79 44 Human Human 45 Metformin 0.01 Tolbutamide 0.26 Insulin Detemir 0.64 46 Voglibose 0.01 Acarbose 0.25 Insulin Lispro 0.22 47 48 *custom classification, see Supplemental Material 1 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 32 of 74

Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 1 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 Page 33 of 74 BMJ Open

1 2 3 4 5 6 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 Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 33 34 35 36 37 38 39 40 41 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 34 of 74

1 2 3 4 5 6 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 34 35 36 37 38 39 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 40 41 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 Page 35 of 74 BMJ Open

1 2 3 Concept ID Name Class 4 5 1319998 Acebutolol Adrenergics 6 1154343 Albuterol Adrenergics 7 930021 alfuzosin Adrenergics 8 919986 apraclonidine Adrenergics 9 10 1111220 arformoterol Adrenergics 11 1314002 Atenolol Adrenergics 12 19034275 bambuterol Adrenergics 13 1322081 Betaxolol Adrenergics 14 15 1338005 Bisoprolol Adrenergics 16 915542 brimonidine Adrenergics 17 21603320 carbuterol Adrenergics 18 950370 CarteololFor peer review onlyAdrenergics 19 20 1346823 carvedilol Adrenergics 21 19097824 Clenbuterol Adrenergics 22 1398937 Clonidine Adrenergics 23 19086622 dapiprazole Adrenergics 24 25 19061088 Dexmedetomidine Adrenergics 26 990009 Dipivefrin Adrenergics 27 1337720 Dobutamine Adrenergics 28 1363053 Doxazosin Adrenergics 29 30 1143374 Ephedrine Adrenergics 31 1343916 Epinephrine Adrenergics 32 19063575 esmolol Adrenergics 33 19053979 Fenoterol Adrenergics 34 35 1196677 formoterol Adrenergics 36 1366237 Guanabenz Adrenergics 37 1344965 Guanfacine Adrenergics 38 19068969 Hexoprenaline Adrenergics 39 40 1181809 Isoetharine Adrenergics 41 21603309 isoprenaline, combinations Adrenergics 42 1183554 Isoproterenol Adrenergics 43 1386957 Labetalol Adrenergics 44 45 1192218 Levalbuterol Adrenergics 46 932815 Levobunolol Adrenergics 47 1123995 metaproterenol Adrenergics 48 19009365 methoxyphenamine Adrenergics 49 50 1305447 Methyldopa Adrenergics 51 905531 Metipranolol Adrenergics 52 1307046 Metoprolol Adrenergics 53 1308368 Midodrine Adrenergics 54 55 42873636 mirabegron Adrenergics 56 1313200 Nadolol Adrenergics 57 21603310 orciprenaline, combinations Adrenergics 58 19026274 p-Hydroxyamphetamine Adrenergics 59 60 1327978 Penbutolol Adrenergics

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1 2 3 1335301 Phenoxybenzamine Adrenergics 4 5 1335539 Phentolamine Adrenergics 6 1135766 Phenylephrine Adrenergics 7 1345858 Pindolol Adrenergics 8 1125449 pirbuterol Adrenergics 9 10 1350489 Prazosin Adrenergics 11 19028950 Procaterol Adrenergics 12 1353766 Propranolol Adrenergics 13 1154332 Pseudoephedrine Adrenergics 14 15 19035396 reproterol Adrenergics 16 1137529 salmeterol Adrenergics 17 19012925 silodosin Adrenergics 18 924566 tamsulosinFor peer review onlyAdrenergics 19 20 1341238 Terazosin Adrenergics 21 1236744 Terbutaline Adrenergics 22 21603325 terbutaline, combinations Adrenergics 23 902427 Timolol Adrenergics 24 25 778474 tizanidine Adrenergics 26 21603319 tretoquinol Adrenergics 27 19043191 tulobuterol Adrenergics 28 43532539 vilanterol Adrenergics 29 30 19029393 aceclofenac Analgesics (inc. NSAIDs) 31 19029398 acemetacin Analgesics (inc. NSAIDs) 32 1125315 Acetaminophen Analgesics (inc. NSAIDs) 33 21603946 alclofenac Analgesics (inc. NSAIDs) 34 35 19059528 Alfentanil Analgesics (inc. NSAIDs) 36 19018431 alminoprofen Analgesics (inc. NSAIDs) 37 1103552 almotriptan Analgesics (inc. NSAIDs) 38 19018432 aloxiprin Analgesics (inc. NSAIDs) 39 aminophenazone, combinations excl. 40 21604337 psycholeptics Analgesics (inc. NSAIDs) 41 aminophenazone, combinations with 42 21604341 psycholeptics Analgesics (inc. NSAIDs) 43 44 19125628 Aminopyrine Analgesics (inc. NSAIDs) 45 1036059 Antipyrine Analgesics (inc. NSAIDs) 46 19136654 Apazone Analgesics (inc. NSAIDs) 47 1112807 Aspirin Analgesics (inc. NSAIDs) 48 49 40254364 avocado and soyabean oil, unsaponifiables Analgesics (inc. NSAIDs) 50 19016435 benorilate Analgesics (inc. NSAIDs) 51 21603972 benoxaprofen Analgesics (inc. NSAIDs) 52 19019620 Benzydamine Analgesics (inc. NSAIDs) 53 54 21604279 bezitramide Analgesics (inc. NSAIDs) 55 1139179 bromfenac Analgesics (inc. NSAIDs) 56 21604346 bucetin Analgesics (inc. NSAIDs) 57 21604350 bucetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 58 59 21604353 bucetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 60 19032724 Bufexamac Analgesics (inc. NSAIDs)

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1 2 3 19039703 bumadizone Analgesics (inc. NSAIDs) 4 5 1133201 Buprenorphine Analgesics (inc. NSAIDs) 6 1133732 Butorphanol Analgesics (inc. NSAIDs) 7 21604363 cannabinoids Analgesics (inc. NSAIDs) 8 21604318 carbasalate calcium Analgesics (inc. NSAIDs) 9 carbasalate calcium combinations excl. 10 21604324 psycholeptics Analgesics (inc. NSAIDs) 11 12 1118084 celecoxib Analgesics (inc. NSAIDs) 13 1395573 Chondroitin Sulfates Analgesics (inc. NSAIDs) 14 19018512 clofezone Analgesics (inc. NSAIDs) 15 1201620 Codeine Analgesics (inc. NSAIDs) 16 17 21604268 codeine, combinations with psycholeptics Analgesics (inc. NSAIDs) 18 21603980 dexibuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 19056874 Dexketoprofen Analgesics (inc. NSAIDs) 20 19021940 Dextromoramide Analgesics (inc. NSAIDs) 21 dextropropoxyphene, combinations with 22 21604282 psycholeptics Analgesics (inc. NSAIDs) 23 24 19088393 dezocine Analgesics (inc. NSAIDs) 25 19088915 diacetylrhein Analgesics (inc. NSAIDs) 26 21604262 DIAMORPHINE Analgesics (inc. NSAIDs) 27 1124300 Diclofenac Analgesics (inc. NSAIDs) 28 29 21603952 difenpiramide Analgesics (inc. NSAIDs) 30 1126128 Diflunisal Analgesics (inc. NSAIDs) 31 1189596 dihydrocodeine Analgesics (inc. NSAIDs) 32 1126557 Dihydroergotamine Analgesics (inc. NSAIDs) 33 34 21604370 dihydroergotamine, combinations Analgesics (inc. NSAIDs) 35 21604313 dipyrocetyl Analgesics (inc. NSAIDs) 36 21604323 dipyrocetyl, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 37 21604328 dipyrocetyl, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 39 19056645 droxicam Analgesics (inc. NSAIDs) 40 1189697 eletriptan Analgesics (inc. NSAIDs) 41 1145379 Ergotamine Analgesics (inc. NSAIDs) 42 21604372 ergotamine, combinations with psycholeptics Analgesics (inc. NSAIDs) 43 44 19059506 ethenzamide Analgesics (inc. NSAIDs) 45 21604322 ethenzamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 46 21604327 ethenzamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 47 1195492 Etodolac Analgesics (inc. NSAIDs) 48 49 19011355 etoricoxib Analgesics (inc. NSAIDs) 50 19095703 fenbufen Analgesics (inc. NSAIDs) 51 1153928 Fenoprofen Analgesics (inc. NSAIDs) 52 1154029 Fentanyl Analgesics (inc. NSAIDs) 53 54 21603950 fentiazac Analgesics (inc. NSAIDs) 55 19135796 Feprazone Analgesics (inc. NSAIDs) 56 21604014 feprazone, combinations Analgesics (inc. NSAIDs) 57 19054931 floctafenine Analgesics (inc. NSAIDs) 58 59 19110711 Flufenamic Acid Analgesics (inc. NSAIDs) 60 21604374 flumedroxone Analgesics (inc. NSAIDs)

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1 2 3 21603981 flunoxaprofen Analgesics (inc. NSAIDs) 4 5 19064698 flupirtine Analgesics (inc. NSAIDs) 6 1156378 Flurbiprofen Analgesics (inc. NSAIDs) 7 19113015 fonazine Analgesics (inc. NSAIDs) 8 1189458 frovatriptan Analgesics (inc. NSAIDs) 9 10 21604356 glafenine Analgesics (inc. NSAIDs) 11 1360332 Glucosamine Analgesics (inc. NSAIDs) 12 21604004 glucosaminoglycan polysulfate Analgesics (inc. NSAIDs) 13 21604317 guacetisal Analgesics (inc. NSAIDs) 14 15 1174888 Hydrocodone Analgesics (inc. NSAIDs) 16 1126658 Hydromorphone Analgesics (inc. NSAIDs) 17 21604295 hydromorphone and antispasmodics Analgesics (inc. NSAIDs) 18 1177480 IbuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 21603979 ibuproxam Analgesics (inc. NSAIDs) 21 19069104 imidazole-2-hydroxybenzoate Analgesics (inc. NSAIDs) 22 21603958 indometacin, combinations Analgesics (inc. NSAIDs) 23 1178663 Indomethacin Analgesics (inc. NSAIDs) 24 25 21603976 indoprofen Analgesics (inc. NSAIDs) 26 19113032 iprazochrome Analgesics (inc. NSAIDs) 27 19069191 kebuzone Analgesics (inc. NSAIDs) 28 21604270 ketobemidone Analgesics (inc. NSAIDs) 29 30 21604293 ketobemidone and antispasmodics Analgesics (inc. NSAIDs) 31 1185922 Ketoprofen Analgesics (inc. NSAIDs) 32 21603985 ketoprofen, combinations Analgesics (inc. NSAIDs) 33 1136980 Ketorolac Analgesics (inc. NSAIDs) 34 35 1189766 Levorphanol Analgesics (inc. NSAIDs) 36 19071933 lonazolac Analgesics (inc. NSAIDs) 37 19049709 lornoxicam Analgesics (inc. NSAIDs) 38 19071936 loxoprofen Analgesics (inc. NSAIDs) 39 40 21603997 lumiracoxib Analgesics (inc. NSAIDs) 41 19125097 Meclofenamic Acid Analgesics (inc. NSAIDs) 42 19125195 Mefenamic Acid Analgesics (inc. NSAIDs) 43 1150345 meloxicam Analgesics (inc. NSAIDs) 44 45 40254075 meloxicam, combinations Analgesics (inc. NSAIDs) 46 1102527 Meperidine Analgesics (inc. NSAIDs) 47 19003010 Meptazinol Analgesics (inc. NSAIDs) 48 metamizole sodium, combinations excl. 49 21604336 psycholeptics Analgesics (inc. NSAIDs) 50 metamizole sodium, combinations with 51 21604340 psycholeptics Analgesics (inc. NSAIDs) 52 1103640 Methadone Analgesics (inc. NSAIDs) 53 54 21604280 methadone, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 55 19005257 Methoxyflurane Analgesics (inc. NSAIDs) 56 1106740 Methysergide Analgesics (inc. NSAIDs) 57 19072129 mofebutazone Analgesics (inc. NSAIDs) 58 59 19072152 morniflumate Analgesics (inc. NSAIDs) 60 1110410 Morphine Analgesics (inc. NSAIDs)

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1 2 3 21604292 morphine and antispasmodics Analgesics (inc. NSAIDs) 4 5 19056115 MORPHOLINE SALICYLATE Analgesics (inc. NSAIDs) 6 1113648 nabumetone Analgesics (inc. NSAIDs) 7 1114122 Nalbuphine Analgesics (inc. NSAIDs) 8 40254094 naproxcinod Analgesics (inc. NSAIDs) 9 10 1115008 Naproxen Analgesics (inc. NSAIDs) 11 40254098 naproxen and misoprostol Analgesics (inc. NSAIDs) 12 1118117 naratriptan Analgesics (inc. NSAIDs) 13 19015602 Nefopam Analgesics (inc. NSAIDs) 14 15 909795 nepafenac Analgesics (inc. NSAIDs) 16 21604259 nicomorphine Analgesics (inc. NSAIDs) 17 21604334 nifenazone Analgesics (inc. NSAIDs) 18 19019023 NiflumicFor Acid peer review onlyAnalgesics (inc. NSAIDs) 19 20 19069425 nimesulide Analgesics (inc. NSAIDs) 21 923829 Opium Analgesics (inc. NSAIDs) 22 19082874 orgotein Analgesics (inc. NSAIDs) 23 19003691 oxaceprol Analgesics (inc. NSAIDs) 24 25 21603953 oxametacin Analgesics (inc. NSAIDs) 26 1118045 oxaprozin Analgesics (inc. NSAIDs) 27 19082880 oxetorone Analgesics (inc. NSAIDs) 28 1124957 Oxycodone Analgesics (inc. NSAIDs) 29 30 1125765 Oxymorphone Analgesics (inc. NSAIDs) 31 19025925 Oxyphenbutazone Analgesics (inc. NSAIDs) 32 19129648 Papaveretum Analgesics (inc. NSAIDs) 33 19003570 parecoxib Analgesics (inc. NSAIDs) 34 35 1130585 Pentazocine Analgesics (inc. NSAIDs) 36 21604294 pethidine and antispasmodics Analgesics (inc. NSAIDs) 37 21604274 pethidine, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 19033710 Phenacetin Analgesics (inc. NSAIDs) 39 40 21604349 phenacetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 41 21604352 phenacetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 42 19132884 Phenazocine Analgesics (inc. NSAIDs) 43 21604335 phenazone, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 44 45 21604339 phenazone, combinations with psycholeptics Analgesics (inc. NSAIDs) 46 1135710 Phenylbutazone Analgesics (inc. NSAIDs) 47 19134009 Pirinitramide Analgesics (inc. NSAIDs) 48 1146810 Piroxicam Analgesics (inc. NSAIDs) 49 50 21603974 pirprofen Analgesics (inc. NSAIDs) 51 19047076 Pizotyline Analgesics (inc. NSAIDs) 52 19029327 proglumetacin Analgesics (inc. NSAIDs) 53 21604347 propacetamol Analgesics (inc. NSAIDs) 54 55 1153664 Propoxyphene Analgesics (inc. NSAIDs) 56 19029322 propyphenazone Analgesics (inc. NSAIDs) 57 propyphenazone, combinations excl. 58 21604338 psycholeptics Analgesics (inc. NSAIDs) 59 propyphenazone, combinations with 60 21604342 psycholeptics Analgesics (inc. NSAIDs)

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1 2 3 21604005 proquazone Analgesics (inc. NSAIDs) 4 5 19016749 remifentanil Analgesics (inc. NSAIDs) 6 21604355 rimazolium Analgesics (inc. NSAIDs) 7 1154077 rizatriptan Analgesics (inc. NSAIDs) 8 1189754 rofecoxib Analgesics (inc. NSAIDs) 9 10 1164108 salicylamide Analgesics (inc. NSAIDs) 11 21604321 salicylamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 12 21604326 salicylamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 13 1137460 Salsalate Analgesics (inc. NSAIDs) 14 15 19078219 Sufentanil Analgesics (inc. NSAIDs) 16 1236607 Sulindac Analgesics (inc. NSAIDs) 17 1140643 Sumatriptan Analgesics (inc. NSAIDs) 18 1036636 SuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 19026459 tapentadol Analgesics (inc. NSAIDs) 21 21604011 tenidap Analgesics (inc. NSAIDs) 22 19041220 tenoxicam Analgesics (inc. NSAIDs) 23 19002431 Tilidine Analgesics (inc. NSAIDs) 24 25 19042155 tolfenamic acid Analgesics (inc. NSAIDs) 26 1102917 Tolmetin Analgesics (inc. NSAIDs) 27 1103314 Tramadol Analgesics (inc. NSAIDs) 28 1103374 valdecoxib Analgesics (inc. NSAIDs) 29 30 21604358 viminol Analgesics (inc. NSAIDs) 31 19005061 ziconotide Analgesics (inc. NSAIDs) 32 1116031 zolmitriptan Analgesics (inc. NSAIDs) 33 19102108 zomepirac Analgesics (inc. NSAIDs) 34 35 19123877 Amdinocillin Antibiotics 36 19088223 Amdinocillin Pivoxil Antibiotics 37 1790868 Amikacin Antibiotics 38 1713332 Amoxicillin Antibiotics 39 40 1717327 Ampicillin Antibiotics 41 21602839 ampicillin, combinations Antibiotics 42 40255264 aspoxicillin Antibiotics 43 19018516 azidocillin Antibiotics 44 45 1734104 Azithromycin Antibiotics 46 45893479 azithromycin, fluconazole and secnidazole Antibiotics 47 19015123 Azlocillin Antibiotics 48 1715117 Aztreonam Antibiotics 49 50 1734205 bacampicillin Antibiotics 51 915175 Bacitracin Antibiotics 52 40255908 bekanamycin Antibiotics 53 21602924 biapenem Antibiotics 54 55 19018742 brodimoprim Antibiotics 56 1740546 Carbenicillin Antibiotics 57 40255589 carumonam Antibiotics 58 21602879 cefacetrile Antibiotics 59 60 1768849 Cefaclor Antibiotics

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1 2 3 1769535 Cefadroxil Antibiotics 4 5 19070174 Cefamandole Antibiotics 6 19070680 Cefatrizine Antibiotics 7 21602875 cefazedone Antibiotics 8 1771162 Cefazolin Antibiotics 9 10 40255561 cefbuperazone Antibiotics 11 21602911 cefcapene Antibiotics 12 1796458 cefdinir Antibiotics 13 1747005 cefditoren Antibiotics 14 15 1748975 cefepime Antibiotics 16 45893466 cefepime and amikacin Antibiotics 17 19028241 cefetamet Antibiotics 18 1796435 CefiximeFor peer review onlyAntibiotics 19 20 21602899 cefmenoxime Antibiotics 21 19072255 Cefmetazole Antibiotics 22 40255560 cefminox Antibiotics 23 19028286 cefodizime Antibiotics 24 25 19072857 Cefonicid Antibiotics 26 1773402 Cefoperazone Antibiotics 27 21602913 cefoperazone, combinations Antibiotics 28 19028288 ceforanide Antibiotics 29 30 1774470 Cefotaxime Antibiotics 31 45893191 cefotaxime, combinations Antibiotics 32 1774932 Cefotetan Antibiotics 33 19051271 Cefotiam Antibiotics 34 35 1775741 Cefoxitin Antibiotics 36 21602917 cefozopran Antibiotics 37 21602905 cefpiramide Antibiotics 38 19001904 cefpirome Antibiotics 39 40 1749008 cefpodoxime Antibiotics 41 1738366 cefprozil Antibiotics 42 21602880 cefroxadine Antibiotics 43 19051345 Cefsulodin Antibiotics 44 45 40230597 ceftaroline Antibiotics 46 1776684 Ceftazidime Antibiotics 47 21602881 ceftezole Antibiotics 48 1749083 ceftibuten Antibiotics 49 50 1777254 Ceftizoxime Antibiotics 51 21602928 ceftobiprole medocaril Antibiotics 52 45892599 ceftolozane Antibiotics 53 1777806 Ceftriaxone Antibiotics 54 55 21602912 ceftriaxone, combinations Antibiotics 56 1778162 Cefuroxime Antibiotics 57 21603039 cefuroxime and metronidazole Antibiotics 58 1786621 Cephalexin Antibiotics 59 60 19052683 Cephaloridine Antibiotics

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1 2 3 19086759 Cephalothin Antibiotics 4 5 19086790 Cephapirin Antibiotics 6 1786842 Cephradine Antibiotics 7 990069 Chloramphenicol Antibiotics 8 19095043 Chlortetracycline Antibiotics 9 10 997496 Cinoxacin Antibiotics 11 1797513 Ciprofloxacin Antibiotics 12 45893269 ciprofloxacin and metronidazole Antibiotics 13 45893270 ciprofloxacin and ornidazole Antibiotics 14 15 45893513 ciprofloxacin and tinidazole Antibiotics 16 1750500 Clarithromycin Antibiotics 17 997881 Clindamycin Antibiotics 18 19047240 clofoctolFor peer review onlyAntibiotics 19 20 21602847 clometocillin Antibiotics 21 19047265 clomocycline Antibiotics 22 1800835 Cloxacillin Antibiotics 23 1701677 colistimethate Antibiotics 24 25 901845 Colistin Antibiotics 26 21602811 combinations of tetracyclines Antibiotics 27 45774861 dalbavancin Antibiotics 28 1789517 dalfopristin Antibiotics 29 30 1786617 Daptomycin Antibiotics 31 1714527 Demeclocycline Antibiotics 32 19023508 Dibekacin Antibiotics 33 1724666 Dicloxacillin Antibiotics 34 35 1790024 dirithromycin Antibiotics 36 1713905 doripenem Antibiotics 37 1738521 Doxycycline Antibiotics 38 1743222 Enoxacin Antibiotics 39 40 21602826 epicillin Antibiotics 41 1717963 ertapenem Antibiotics 42 1746940 Erythromycin Antibiotics 43 43534793 faropenem Antibiotics 44 45 40239985 fidaxomicin Antibiotics 46 19050750 Fleroxacin Antibiotics 47 40255562 flomoxef Antibiotics 48 19054936 Floxacillin Antibiotics 49 50 19064329 flumequine Antibiotics 51 21602982 flurithromycin Antibiotics 52 956653 Fosfomycin Antibiotics 53 45893495 furazidin Antibiotics 54 55 21603026 garenoxacin Antibiotics 56 1789276 gatifloxacin Antibiotics 57 1716721 gemifloxacin Antibiotics 58 45892419 Gentamicin Antibiotics 59 60 919345 Gentamicin Sulfate (USP) Antibiotics

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1 2 3 1747032 grepafloxacin Antibiotics 4 5 19101402 habekacin Antibiotics 6 19069006 hetacillin Antibiotics 7 21602933 iclaprim Antibiotics 8 1778262 Imipenem Antibiotics 9 10 21603004 isepamicin Antibiotics 11 19123240 Josamycin Antibiotics 12 1784749 Kanamycin Antibiotics 13 1742253 Levofloxacin Antibiotics 14 15 43534794 levofloxacin and ornidazole Antibiotics 16 1790692 Lincomycin Antibiotics 17 1736887 linezolid Antibiotics 18 1707800 lomefloxacinFor peer review onlyAntibiotics 19 20 1708100 loracarbef Antibiotics 21 19092353 Lymecycline Antibiotics 22 992716 Mafenide Antibiotics 23 19008870 mandelic acid Antibiotics 24 25 1709170 meropenem Antibiotics 26 19003644 Methacycline Antibiotics 27 19072054 methampicillin Antibiotics 28 904356 Methenamine Antibiotics 29 30 1707164 Metronidazole Antibiotics 31 19007701 Mezlocillin Antibiotics 32 19072122 midecamycin Antibiotics 33 1708880 Minocycline Antibiotics 34 35 19009138 Miocamycin Antibiotics 36 19126622 Moxalactam Antibiotics 37 1716903 moxifloxacin Antibiotics 38 951511 Mupirocin Antibiotics 39 40 1713930 Nafcillin Antibiotics 41 915981 Neomycin Antibiotics 42 19017585 Netilmicin Antibiotics 43 21603059 nifurtoinol Antibiotics 44 45 920293 Nitrofurantoin Antibiotics 46 45893503 nitrofurantoin, combinations Antibiotics 47 19015464 nitroxoline Antibiotics 48 1721543 Norfloxacin Antibiotics 49 50 45893468 norfloxacin and tinidazole Antibiotics 51 923081 Ofloxacin Antibiotics 52 45893194 ofloxacin and ornidazole Antibiotics 53 19023254 Oleandomycin Antibiotics 54 55 45776147 oritavancin Antibiotics 56 19024197 Ornidazole Antibiotics 57 1724703 Oxacillin Antibiotics 58 19129642 Oxolinic Acid Antibiotics 59 60 925952 Oxytetracycline Antibiotics

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1 2 3 21602926 panipenem and betamipron Antibiotics 4 5 21603025 pazufloxacin Antibiotics 6 19027679 Pefloxacin Antibiotics 7 21602846 penamecillin Antibiotics 8 19126544 Penicillin Antibiotics 9 10 1728416 Penicillin G Antibiotics 11 1729720 Penicillin V Antibiotics 12 penicillins, combinations with other 13 21603037 antibacterials Antibiotics 14 21602808 penimepicycline Antibiotics 15 19088795 phenethicillin Antibiotics 16 17 1746114 Piperacillin Antibiotics 18 21603030 piromidicFor acid peer review onlyAntibiotics 19 19047071 Pivampicillin Antibiotics 20 948582 Antibiotics 21 22 19125201 Pristinamycin Antibiotics 23 19096054 propicillin Antibiotics 24 21603024 prulifloxacin Antibiotics 25 1789515 quinupristin Antibiotics 26 27 991003 retapamulin Antibiotics 28 21603003 ribostamycin Antibiotics 29 1763204 Rifampin Antibiotics 30 19136008 Rifamycins Antibiotics 31 32 1735947 rifaximin Antibiotics 33 21602980 rokitamycin Antibiotics 34 19136024 Rolitetracycline Antibiotics 35 19036545 rosoxacin Antibiotics 36 37 19063874 Roxithromycin Antibiotics 38 21603017 rufloxacin Antibiotics 39 966956 silver sulfadiazine Antibiotics 40 19136044 Sisomicin Antibiotics 41 42 40256175 sitafloxacin Antibiotics 43 1733765 sparfloxacin Antibiotics 44 1701651 Spectinomycin Antibiotics 45 19070251 Spiramycin Antibiotics 46 47 21603040 spiramycin and metronidazole Antibiotics 48 21602993 streptoduocin Antibiotics 49 1836191 Streptomycin Antibiotics 50 1836241 Sulbactam Antibiotics 51 52 19000817 Sulbenicillin Antibiotics 53 1036252 Sulfacetamide Antibiotics 54 1836391 Sulfadiazine Antibiotics 55 21602966 sulfadiazine and tetroxoprim Antibiotics 56 57 21602962 sulfadiazine and trimethoprim Antibiotics 58 19000818 Sulfadimethoxine Antibiotics 59 21602965 sulfadimidine and trimethoprim Antibiotics 60

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1 2 3 19136423 Sulfalene Antibiotics 4 5 21602958 sulfamazone Antibiotics 6 19136426 Sulfamerazine Antibiotics 7 21602967 sulfamerazine and trimethoprim Antibiotics 8 19136429 Sulfamethazine Antibiotics 9 10 1036425 Sulfamethizole Antibiotics 11 1836430 Sulfamethoxazole Antibiotics 12 19000820 Sulfamethoxypyridazine Antibiotics 13 21602952 sulfametomidine Antibiotics 14 15 21602953 sulfametoxydiazine Antibiotics 16 21602963 sulfametrole and trimethoprim Antibiotics 17 19136481 Sulfamoxole Antibiotics 18 21602964 sulfamoxoleFor and peer trimethoprim review onlyAntibiotics 19 20 1036475 Sulfanilamide Antibiotics 21 21602955 sulfaperin Antibiotics 22 21602957 sulfaphenazole Antibiotics 23 19136493 Sulfapyridine Antibiotics 24 25 1036487 sulfathiazole Antibiotics 26 21602942 sulfathiourea Antibiotics 27 19000821 Sulfisomidine Antibiotics 28 1836503 Sulfisoxazole Antibiotics 29 30 19040627 sultamicillin Antibiotics 31 19002077 Talampicillin Antibiotics 32 1741122 tazobactam Antibiotics 33 45775686 tedizolid Antibiotics 34 35 19078399 Teicoplanin Antibiotics 36 40166675 telavancin Antibiotics 37 1702911 telithromycin Antibiotics 38 19041153 temafloxacin Antibiotics 39 40 19100438 temocillin Antibiotics 41 1836948 42 45893484 tetracycline and oleandomycin Antibiotics 43 19137362 Thiamphenicol Antibiotics 44 45 21602817 thiamphenicol, combinations Antibiotics 46 1702364 Ticarcillin Antibiotics 47 1742432 tigecycline Antibiotics 48 1702559 Tinidazole Antibiotics 49 50 902722 Tobramycin Antibiotics 51 1705674 Trimethoprim Antibiotics 52 19006043 Troleandomycin Antibiotics 53 1712549 trovafloxacin Antibiotics 54 55 1707687 Vancomycin Antibiotics 56 19102105 xibornol Antibiotics 57 19047423 abciximab Anticlotting and antifibrinolytic 58 19024063 Acenocoumarol Anticlotting and antifibrinolytic 59 60

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1 2 3 acetylsalicylic acid, combinations with proton 4 40252642 pump inhibitors Anticlotting and antifibrinolytic 5 1347450 alteplase Anticlotting and antifibrinolytic 6 7 19024544 Ancrod Anticlotting and antifibrinolytic 8 19044890 Anistreplase Anticlotting and antifibrinolytic 9 1436169 Antithrombin III Anticlotting and antifibrinolytic 10 43013024 apixaban Anticlotting and antifibrinolytic 11 12 1322207 argatroban Anticlotting and antifibrinolytic 13 19069137 bemiparin Anticlotting and antifibrinolytic 14 21601002 beraprost Anticlotting and antifibrinolytic 15 19084670 bivalirudin Anticlotting and antifibrinolytic 16 17 21601012 brinase Anticlotting and antifibrinolytic 18 46275677 cangrelorFor peer review onlyAnticlotting and antifibrinolytic 19 1350310 cilostazol Anticlotting and antifibrinolytic 20 1322184 clopidogrel Anticlotting and antifibrinolytic 21 22 21600987 cloricromen Anticlotting and antifibrinolytic 23 21600969 clorindione Anticlotting and antifibrinolytic 24 40228152 dabigatran etexilate Anticlotting and antifibrinolytic 25 1301065 Dalteparin Anticlotting and antifibrinolytic 26 27 19026343 danaparoid Anticlotting and antifibrinolytic 28 42898933 defibrotide Anticlotting and antifibrinolytic 29 21601029 dermatan sulfate Anticlotting and antifibrinolytic 30 19011712 desirudin Anticlotting and antifibrinolytic 31 32 1325124 Dicumarol Anticlotting and antifibrinolytic 33 21600970 diphenadione Anticlotting and antifibrinolytic 34 1331270 Dipyridamole Anticlotting and antifibrinolytic 35 21600986 ditazole Anticlotting and antifibrinolytic 36 37 1731597 drotrecogin alfa Anticlotting and antifibrinolytic 38 1301025 Enoxaparin Anticlotting and antifibrinolytic 39 1354118 Epoprostenol Anticlotting and antifibrinolytic 40 1322199 eptifibatide Anticlotting and antifibrinolytic 41 42 21600968 ethyl biscoumacetate Anticlotting and antifibrinolytic 43 19113013 fluindione Anticlotting and antifibrinolytic 44 1315865 fondaparinux Anticlotting and antifibrinolytic 45 1367571 Heparin Anticlotting and antifibrinolytic 46 47 21600984 heparin, combinations Anticlotting and antifibrinolytic 48 19069107 indobufen Anticlotting and antifibrinolytic 49 19092139 lepirudin Anticlotting and antifibrinolytic 50 21601023 melagatran Anticlotting and antifibrinolytic 51 52 19001014 Nadroparin Anticlotting and antifibrinolytic 53 19008276 parnaparin Anticlotting and antifibrinolytic 54 19033934 Phenindione Anticlotting and antifibrinolytic 55 19035344 Phenprocoumon Anticlotting and antifibrinolytic 56 57 21600988 picotamide Anticlotting and antifibrinolytic 58 954696 Plasmin Anticlotting and antifibrinolytic 59 40163718 prasugrel Anticlotting and antifibrinolytic 60

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1 2 3 42801108 Protein C Anticlotting and antifibrinolytic 4 5 19024191 Reteplase Anticlotting and antifibrinolytic 6 19129274 reviparin Anticlotting and antifibrinolytic 7 40241331 rivaroxaban Anticlotting and antifibrinolytic 8 21601014 saruplase Anticlotting and antifibrinolytic 9 10 19136187 Streptokinase Anticlotting and antifibrinolytic 11 21600982 sulodexide Anticlotting and antifibrinolytic 12 19098548 Tenecteplase Anticlotting and antifibrinolytic 13 40241186 Ticagrelor Anticlotting and antifibrinolytic 14 15 1302398 Ticlopidine Anticlotting and antifibrinolytic 16 1308473 tinzaparin Anticlotting and antifibrinolytic 17 19018364 tioclomarol Anticlotting and antifibrinolytic 18 19017067 tirofibanFor peer review onlyAnticlotting and antifibrinolytic 19 20 19042778 triflusal Anticlotting and antifibrinolytic 21 1307515 Urokinase Anticlotting and antifibrinolytic 22 44818499 vorapaxar Anticlotting and antifibrinolytic 23 1310149 Warfarin Anticlotting and antifibrinolytic 24 25 21601024 ximelagatran Anticlotting and antifibrinolytic 26 1529331 Acarbose Antidiabetic drugs 27 1530014 Acetohexamide Antidiabetic drugs 28 44816332 albiglutide Antidiabetic drugs 29 30 43013884 alogliptin Antidiabetic drugs 31 19035533 benfluorex Antidiabetic drugs 32 21600748 buformin Antidiabetic drugs 33 43526465 canagliflozin Antidiabetic drugs 34 35 19033498 Carbutamide Antidiabetic drugs 36 1594973 Chlorpropamide Antidiabetic drugs 37 21600734 combinations Antidiabetic drugs 38 44785829 dapagliflozin Antidiabetic drugs 39 40 45774751 empagliflozin Antidiabetic drugs 41 1583722 exenatide Antidiabetic drugs 42 43534752 gemigliptin Antidiabetic drugs 43 19001409 glibornuride Antidiabetic drugs 44 45 19059796 Gliclazide Antidiabetic drugs 46 1597756 glimepiride Antidiabetic drugs 47 1560171 Glipizide Antidiabetic drugs 48 19097821 gliquidone Antidiabetic drugs 49 50 21600760 glisoxepide Antidiabetic drugs 51 1559684 Glyburide Antidiabetic drugs 52 19001441 glymidine Antidiabetic drugs 53 1000979 guar gum Antidiabetic drugs 54 55 21600730 insulin (beef) Antidiabetic drugs 56 43534747 insulin degludec Antidiabetic drugs 57 44819155 insulin degludec and insulin aspart Antidiabetic drugs 58 1516976 insulin detemir Antidiabetic drugs 59 60 1502905 Insulin Glargine Antidiabetic drugs

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1 2 3 1550023 Insulin Lispro Antidiabetic drugs 4 5 1544838 Insulin, Glulisine, Human Antidiabetic drugs 6 42899447 Insulin, Pork Antidiabetic drugs 7 40239216 Linagliptin Antidiabetic drugs 8 45893517 linagliptin and empagliflozin Antidiabetic drugs 9 10 40170911 liraglutide Antidiabetic drugs 11 44506754 Lixisenatide Antidiabetic drugs 12 21600759 metahexamide Antidiabetic drugs 13 1503297 Metformin Antidiabetic drugs 14 15 45893467 metformin and acarbose Antidiabetic drugs 16 45893267 metformin and canagliflozin Antidiabetic drugs 17 43534751 metformin and dapagliflozin Antidiabetic drugs 18 45893491 metforminFor and peer gemigliptin review onlyAntidiabetic drugs 19 20 21600773 metformin and vildagliptin Antidiabetic drugs 21 1510202 miglitol Antidiabetic drugs 22 21600796 mitiglinide Antidiabetic drugs 23 1502826 nateglinide Antidiabetic drugs 24 25 19033909 Phenformin Antidiabetic drugs 26 21600766 phenformin and sulfonamides Antidiabetic drugs 27 1525215 pioglitazone Antidiabetic drugs 28 43534748 pioglitazone and sitagliptin Antidiabetic drugs 29 30 1517998 Pramlintide Antidiabetic drugs 31 1596977 Regular Insulin, Human Antidiabetic drugs 32 1516766 repaglinide Antidiabetic drugs 33 1547504 rosiglitazone Antidiabetic drugs 34 35 40166035 saxagliptin Antidiabetic drugs 36 1580747 sitagliptin Antidiabetic drugs 37 1502809 Tolazamide Antidiabetic drugs 38 1502855 Tolbutamide Antidiabetic drugs 39 40 19042191 tolrestat Antidiabetic drugs 41 1515249 troglitazone Antidiabetic drugs 42 19122137 vildagliptin Antidiabetic drugs 43 21600778 voglibose Antidiabetic drugs 44 45 19112534 barbexaclone Antiepileptics 46 19018520 Beclamide Antiepileptics 47 740275 Carbamazepine Antiepileptics 48 798874 Clonazepam Antiepileptics 49 50 19054995 dipropylacetamide Antiepileptics 51 44507780 eslicarbazepine Antiepileptics 52 750119 Ethosuximide Antiepileptics 53 750146 Ethotoin Antiepileptics 54 55 40239995 ezogabine Antiepileptics 56 795661 felbamate Antiepileptics 57 713192 fosphenytoin Antiepileptics 58 797399 gabapentin Antiepileptics 59 60 19087394 lacosamide Antiepileptics

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1 2 3 705103 lamotrigine Antiepileptics 4 5 711584 Levetiracetam Antiepileptics 6 702661 Mephenytoin Antiepileptics 7 702685 Mephobarbital Antiepileptics 8 19004254 metharbital Antiepileptics 9 10 759401 methsuximide Antiepileptics 11 718122 oxcarbazepine Antiepileptics 12 19021932 paramethadione Antiepileptics 13 42904177 perampanel Antiepileptics 14 15 19023286 phenacemide Antiepileptics 16 734275 Phenobarbital Antiepileptics 17 19023842 phensuximide Antiepileptics 18 740910 PhenytoinFor peer review onlyAntiepileptics 19 20 734354 pregabalin Antiepileptics 21 751347 Primidone Antiepileptics 22 19095776 progabide Antiepileptics 23 19006586 rufinamide Antiepileptics 24 25 19000921 sulthiame Antiepileptics 26 715458 tiagabine Antiepileptics 27 742267 topiramate Antiepileptics 28 19005629 Trimethadione Antiepileptics 29 30 19010963 Valproic Acid Antiepileptics 31 19020002 Vigabatrin Antiepileptics 32 744798 zonisamide Antiepileptics 33 1140123 acrivastine Antihistamines 34 35 951237 Antazoline Antihistamines 36 1150770 Astemizole Antihistamines 37 1133993 azatadine Antihistamines 38 934075 azelastine Antihistamines 39 40 19034280 bamipine Antihistamines 41 40166571 bepotastine Antihistamines 42 40256760 bilastine Antihistamines 43 1139216 bromodiphenhydramine Antihistamines 44 45 1130863 Brompheniramine Antihistamines 46 21603466 brompheniramine, combinations Antihistamines 47 19081195 buclizine Antihistamines 48 21603499 buclizine, combinations Antihistamines 49 50 1141018 carbinoxamine Antihistamines 51 1149196 Cetirizine Antihistamines 52 990413 chlorcyclizine Antihistamines 53 19049437 chloropyramine Antihistamines 54 55 21603478 chloropyramine, combinations Antihistamines 56 1192710 Chlorpheniramine Antihistamines 57 19049707 chlorphenoxamine Antihistamines 58 21603456 chlorphenoxamine, combinations Antihistamines 59 60 1197677 Clemastine Antihistamines

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1 2 3 21603455 clemastine, combinations Antihistamines 4 5 909358 Cyclizine Antihistamines 6 21603500 cyclizine, combinations Antihistamines 7 1110727 Cyproheptadine Antihistamines 8 21603516 deptropine Antihistamines 9 10 1103006 desloratadine Antihistamines 11 1188052 dexbrompheniramine Antihistamines 12 21603469 dexbrompheniramine, combinations Antihistamines 13 1188114 dexchlorpheniramine Antihistamines 14 15 21603467 dexchlorpheniramine, combinations Antihistamines 16 19028947 Dimethindene Antihistamines 17 1129625 Diphenhydramine Antihistamines 18 21603454 diphenhydramine,For peer combinations review onlyAntihistamines 19 20 19090000 diphenylpyraline Antihistamines 21 21603457 diphenylpyraline, combinations Antihistamines 22 738818 Doxylamine Antihistamines 23 40254475 doxylamine, combinations Antihistamines 24 25 19092433 ebastine Antihistamines 26 903893 emedastine Antihistamines 27 943634 epinastine Antihistamines 28 1153428 fexofenadine Antihistamines 29 30 21603472 histapyrrodine Antihistamines 31 21603477 histapyrrodine, combinations Antihistamines 32 21603484 hydroxyethylpromethazine Antihistamines 33 21603490 hydroxyethylpromethazine, combinations Antihistamines 34 35 19003593 isothipendyl Antihistamines 36 986117 Ketotifen Antihistamines 37 1136422 levocetirizine Antihistamines 38 1107830 Loratadine Antihistamines 39 40 19008999 mebhydroline Antihistamines 41 994341 Meclizine Antihistamines 42 21603501 meclozine, combinations Antihistamines 43 19009145 mequitazine Antihistamines 44 45 19004158 Methapyrilene Antihistamines 46 19009250 methdilazine Antihistamines 47 19086100 mizolastine Antihistamines 48 915855 olopatadine Antihistamines 49 50 19071314 oxatomide Antihistamines 51 21603487 oxomemazine Antihistamines 52 1123534 phenindamine Antihistamines 53 933952 Pheniramine Antihistamines 54 55 19093165 pimethixene Antihistamines 56 1153013 Promethazine Antihistamines 57 21603489 promethazine, combinations Antihistamines 58 1159811 Pyrilamine Antihistamines 59 60 21603510 pyrrobutamine Antihistamines

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1 2 3 21603529 pyrrobutamine, combinations Antihistamines 4 5 43534851 quifenadine Antihistamines 6 21603527 rupatadine Antihistamines 7 43534852 sequifenadine Antihistamines 8 21603465 talastine Antihistamines 9 10 1150836 Terfenadine Antihistamines 11 21603506 thenalidine Antihistamines 12 21603528 thenalidine, combinations Antihistamines 13 21603485 thiazinam Antihistamines 14 15 1037358 Thiethylperazine Antihistamines 16 43012162 thonzylamine Antihistamines 17 19005570 Trimeprazine Antihistamines 18 942799 trimethobenzamideFor peer review onlyAntihistamines 19 20 1105853 Tripelennamine Antihistamines 21 1105889 Triprolidine Antihistamines 22 19101651 tritoqualine Antihistamines 23 Antiinfectives (excluding antibiotics 24 1736971 abacavir and vaccines) 25 Antiinfectives (excluding antibiotics 26 1703687 Acyclovir and vaccines) 27 Antiinfectives (excluding antibiotics 28 21603125 aldesulfone sodium and vaccines) 29 Antiinfectives (excluding antibiotics 30 1726228 aminosalicylic acid and vaccines) 31 Antiinfectives (excluding antibiotics 32 1717240 Amphotericin B and vaccines) 33 Antiinfectives (excluding antibiotics 34 1789428 Amprenavir and vaccines) 35 Antiinfectives (excluding antibiotics 36 19026450 anidulafungin and vaccines) 37 Antiinfectives (excluding antibiotics 38 19063179 Antifungal Agents and vaccines) 39 Antiinfectives (excluding antibiotics 40 46233931 asunaprevir and vaccines) 41 Antiinfectives (excluding antibiotics 42 1727223 Atazanavir and vaccines) 43 44 Antiinfectives (excluding antibiotics 45 43012518 bedaquiline and vaccines) 46 Antiinfectives (excluding antibiotics 47 40238770 boceprevir and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601251 botulinum antitoxin and vaccines) 50 Antiinfectives (excluding antibiotics 51 19122130 brivudine and vaccines) 52 Antiinfectives (excluding antibiotics 53 958396 butenafine and vaccines) 54 Antiinfectives (excluding antibiotics 55 939784 butoconazole and vaccines) 56 Antiinfectives (excluding antibiotics 57 21603094 calcium aminosalicylate and vaccines) 58 Antiinfectives (excluding antibiotics 59 1718054 Caspofungin and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1745072 Cidofovir and vaccines) 5 Antiinfectives (excluding antibiotics 6 21603171 clevudine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1798476 Clofazimine and vaccines) 9 Antiinfectives (excluding antibiotics 10 1000632 Clotrimazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 586491 cytomegalovirus immune globulin and vaccines) 13 Antiinfectives (excluding antibiotics 14 46221696 daclatasvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1711759 Dapsone and vaccines) 17 Antiinfectives (excluding antibiotics 18 1756831 darunavirFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 45893458 darunavir and cobicistat and vaccines) 21 Antiinfectives (excluding antibiotics 22 44819157 delamanid and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 1747157 Delavirdine and vaccines) 26 Antiinfectives (excluding antibiotics 27 1724869 Didanosine and vaccines) 28 Antiinfectives (excluding antibiotics 29 19031041 Diphtheria Antitoxin and vaccines) 30 Antiinfectives (excluding antibiotics 31 43560385 dolutegravir and vaccines) 32 Antiinfectives (excluding antibiotics 33 940864 Econazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1738135 efavirenz and vaccines) 36 Antiinfectives (excluding antibiotics 37 45775080 efinaconazole and vaccines) 38 Antiinfectives (excluding antibiotics 39 42874212 elvitegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 1703069 emtricitabine and vaccines) 42 Antiinfectives (excluding antibiotics 43 21601270 encephalitis, tick borne immunoglobulin and vaccines) 44 Antiinfectives (excluding antibiotics 45 1717002 enfuvirtide and vaccines) 46 Antiinfectives (excluding antibiotics 47 1711246 entecavir and vaccines) 48 Antiinfectives (excluding antibiotics 49 1749301 Ethambutol and vaccines) 50 Antiinfectives (excluding antibiotics 51 21603117 ethambutol and isoniazid and vaccines) 52 Antiinfectives (excluding antibiotics 53 1750074 Ethionamide and vaccines) 54 Antiinfectives (excluding antibiotics 55 1758536 etravirine and vaccines) 56 Antiinfectives (excluding antibiotics 57 45893487 faldaprevir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703603 famciclovir and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1754994 Fluconazole and vaccines) 5 Antiinfectives (excluding antibiotics 6 1755112 Flucytosine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1736829 fosamprenavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724700 Foscarnet and vaccines) 11 Antiinfectives (excluding antibiotics 12 21603147 fosfonet and vaccines) 13 Antiinfectives (excluding antibiotics 14 1757803 Ganciclovir and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601252 gas-gangrene sera and vaccines) 17 Antiinfectives (excluding antibiotics 18 21601269 hepatitisFor A immunoglobulin peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 501343 immune globulin and vaccines) 21 Antiinfectives (excluding antibiotics 22 19078156 Idoxuridine and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 1711523 Indinavir and vaccines) 26 Antiinfectives (excluding antibiotics 27 19083285 Inosine Pranobex and vaccines) 28 Antiinfectives (excluding antibiotics 29 1782521 isoniazid and vaccines) 30 Antiinfectives (excluding antibiotics 31 1703653 Itraconazole and vaccines) 32 Antiinfectives (excluding antibiotics 33 985708 Ketoconazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1704183 Lamivudine and vaccines) 36 Antiinfectives (excluding antibiotics 37 45893193 lamivudine and tenofovir disoproxil and vaccines) 38 Antiinfectives (excluding antibiotics 39 45893478 lamivudine, abacavir and dolutegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 43534799 lamivudine, tenofovir disoproxil and efavirenz and vaccines) 42 Antiinfectives (excluding antibiotics 43 44507693 luliconazole and vaccines) 44 Antiinfectives (excluding antibiotics 45 43532424 lysozyme and vaccines) 46 Antiinfectives (excluding antibiotics 47 1787101 maraviroc and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601244 maribavir and vaccines) 50 Antiinfectives (excluding antibiotics 51 21601272 measles immunoglobulin and vaccines) 52 Antiinfectives (excluding antibiotics 53 21603129 metisazone and vaccines) 54 Antiinfectives (excluding antibiotics 55 19018013 micafungin and vaccines) 56 Antiinfectives (excluding antibiotics 57 907879 Miconazole and vaccines) 58 Antiinfectives (excluding antibiotics 59 21603113 morinamide and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 19010924 moroxydine and vaccines) 5 Antiinfectives (excluding antibiotics 6 40252180 motavizumab and vaccines) 7 Antiinfectives (excluding antibiotics 8 21601273 mumps immunoglobulin and vaccines) 9 Antiinfectives (excluding antibiotics 10 914053 naftifine and vaccines) 11 Antiinfectives (excluding antibiotics 12 21601277 nebacumab and vaccines) 13 Antiinfectives (excluding antibiotics 14 1715472 Nelfinavir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1769389 Nevirapine and vaccines) 17 Antiinfectives (excluding antibiotics 18 922570 NystatinFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 1799139 Oseltamivir and vaccines) 21 Antiinfectives (excluding antibiotics 22 918222 oxiconazole and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 537647 palivizumab and vaccines) 26 Antiinfectives (excluding antibiotics 27 981654 penciclovir and vaccines) 28 Antiinfectives (excluding antibiotics 29 21601271 pertussis immunoglobulin and vaccines) 30 Antiinfectives (excluding antibiotics 31 21603192 pleconaril and vaccines) 32 Antiinfectives (excluding antibiotics 33 1704139 posaconazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 19135812 Prothionamide and vaccines) 36 Antiinfectives (excluding antibiotics 37 1759455 Pyrazinamide and vaccines) 38 Antiinfectives (excluding antibiotics 39 19135830 rabies immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 1712889 raltegravir and vaccines) 42 Antiinfectives (excluding antibiotics 43 43013193 raxibacumab and vaccines) 44 Antiinfectives (excluding antibiotics 45 535714 Rho(D) Immune Globulin and vaccines) 46 Antiinfectives (excluding antibiotics 47 1762711 Ribavirin and vaccines) 48 Antiinfectives (excluding antibiotics 49 1777417 Rifabutin and vaccines) 50 rifampicin, pyrazinamide, ethambutol and Antiinfectives (excluding antibiotics 51 21603120 isoniazid and vaccines) 52 Antiinfectives (excluding antibiotics 53 19035924 rifamycin SV and vaccines) 54 Antiinfectives (excluding antibiotics 55 19035953 rifapentine and vaccines) 56 Antiinfectives (excluding antibiotics 57 40238930 Rilpivirine and vaccines) 58 Antiinfectives (excluding antibiotics 59 1763339 Rimantadine and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1748921 Ritonavir and vaccines) 5 Antiinfectives (excluding antibiotics 6 21601264 rubella immunoglobulin and vaccines) 7 Antiinfectives (excluding antibiotics 8 1746244 Saquinavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 939134 sertaconazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 44785086 simeprevir and vaccines) 13 Antiinfectives (excluding antibiotics 14 44785094 sofosbuvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601266 staphylococcus immunoglobulin and vaccines) 17 Antiinfectives (excluding antibiotics 18 1781406 StavudineFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 21603187 stavudine, lamivudine and nevirapine and vaccines) 21 Antiinfectives (excluding antibiotics 22 940535 sulconazole and vaccines) 23 24 Antiinfectives (excluding antibiotics 25 45776537 tavaborole and vaccines) 26 Antiinfectives (excluding antibiotics 27 40239330 telaprevir and vaccines) 28 Antiinfectives (excluding antibiotics 29 1758392 telbivudine and vaccines) 30 Antiinfectives (excluding antibiotics 31 1710281 tenofovir disoproxil and vaccines) 32 Antiinfectives (excluding antibiotics 33 1741309 terbinafine and vaccines) 34 Antiinfectives (excluding antibiotics 35 941472 terconazole and vaccines) 36 Antiinfectives (excluding antibiotics 37 19078424 terizidone and vaccines) 38 Antiinfectives (excluding antibiotics 39 561401 Tetanus immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 45893523 thioacetazone and vaccines) 42 Antiinfectives (excluding antibiotics 43 21603118 thioacetazone and isoniazid and vaccines) 44 Antiinfectives (excluding antibiotics 45 21603107 tiocarlide and vaccines) 46 Antiinfectives (excluding antibiotics 47 942028 tioconazole and vaccines) 48 Antiinfectives (excluding antibiotics 49 1736999 tipranavir and vaccines) 50 Antiinfectives (excluding antibiotics 51 19101679 tromantadine and vaccines) 52 Antiinfectives (excluding antibiotics 53 45893141 umifenovir and vaccines) 54 Antiinfectives (excluding antibiotics 55 21601265 vaccinia immunoglobulin and vaccines) 56 Antiinfectives (excluding antibiotics 57 1717704 valacyclovir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703063 valganciclovir and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 543291 varicella-zoster immune globulin and vaccines) 5 Antiinfectives (excluding antibiotics 6 908126 Vidarabine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1714277 voriconazole and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724827 Zalcitabine and vaccines) 11 Antiinfectives (excluding antibiotics 12 1708748 Zanamivir and vaccines) 13 Antiinfectives (excluding antibiotics 14 1710612 Zidovudine and vaccines) 15 Antiinfectives (excluding antibiotics 16 21603185 zidovudine, lamivudine and nevirapine and vaccines) 17 Antineoplastic and 18 19010868 abarelixFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1186087 abatacept immunomodulating agents 21 Antineoplastic and 22 42900395 abetimus immunomodulating agents 23 24 Antineoplastic and 25 40239056 abiraterone immunomodulating agents 26 Antineoplastic and 27 19057483 Aclarubicin immunomodulating agents 28 Antineoplastic and 29 1119119 adalimumab immunomodulating agents 30 Antineoplastic and 31 43525787 ado- immunomodulating agents 32 Antineoplastic and 33 43533090 Afatinib immunomodulating agents 34 Antineoplastic and 35 21603910 afelimomab immunomodulating agents 36 Antineoplastic and 37 40244266 aflibercept immunomodulating agents 38 Antineoplastic and 39 40253734 albinterferon alfa-2b immunomodulating agents 40 Antineoplastic and 41 1309770 Aldesleukin immunomodulating agents 42 Antineoplastic and 43 909959 alefacept immunomodulating agents 44 Antineoplastic and 45 1312706 alemtuzumab immunomodulating agents 46 Antineoplastic and 47 941052 alitretinoin immunomodulating agents 48 Antineoplastic and 49 1368823 Altretamine immunomodulating agents 50 Antineoplastic and 51 1503057 Aminoglutethimide immunomodulating agents 52 Antineoplastic and 53 904351 Aminolevulinic Acid immunomodulating agents 54 Antineoplastic and 55 40253109 amrubicin immunomodulating agents 56 Antineoplastic and 57 19017810 Amsacrine immunomodulating agents 58 Antineoplastic and 59 1381253 anagrelide immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1114375 anakinra immunomodulating agents 5 Antineoplastic and 6 1348265 anastrozole immunomodulating agents 7 Antineoplastic and 8 19018070 ancestim immunomodulating agents 9 Antineoplastic and 10 44816294 apremilast immunomodulating agents 11 Antineoplastic and 12 1333379 arsenic trioxide immunomodulating agents 13 Antineoplastic and 14 19012585 ASPARAGINASE immunomodulating agents 15 Antineoplastic and 16 42709322 axitinib immunomodulating agents 17 Antineoplastic and 18 1314865 AzacitidineFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19014878 Azathioprine immunomodulating agents 21 Antineoplastic and 22 45893268 balugrastim immunomodulating agents 23 24 Antineoplastic and 25 19038440 basiliximab immunomodulating agents 26 Antineoplastic and 27 40239665 belatacept immunomodulating agents 28 Antineoplastic and 29 40236987 belimumab immunomodulating agents 30 Antineoplastic and 31 19015523 bendamustine immunomodulating agents 32 Antineoplastic and 33 1397141 bevacizumab immunomodulating agents 34 Antineoplastic and 35 1389888 bexarotene immunomodulating agents 36 Antineoplastic and 37 1344381 bicalutamide immunomodulating agents 38 Antineoplastic and 39 1329241 Bleomycin immunomodulating agents 40 Antineoplastic and 41 1336825 bortezomib immunomodulating agents 42 Antineoplastic and 43 42900401 bosutinib immunomodulating agents 44 Antineoplastic and 45 40241969 brentuximab vedotin immunomodulating agents 46 Antineoplastic and 47 40253793 briakinumab immunomodulating agents 48 Antineoplastic and 49 19033280 Buserelin immunomodulating agents 50 Antineoplastic and 51 1333357 Busulfan immunomodulating agents 52 Antineoplastic and 53 40222431 cabazitaxel immunomodulating agents 54 Antineoplastic and 55 43012292 cabozantinib immunomodulating agents 56 Antineoplastic and 57 40161669 canakinumab immunomodulating agents 58 Antineoplastic and 59 1337620 capecitabine immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1344905 Carboplatin immunomodulating agents 5 Antineoplastic and 6 21601405 carboquone immunomodulating agents 7 Antineoplastic and 8 42873638 carfilzomib immunomodulating agents 9 Antineoplastic and 10 21601438 carmofur immunomodulating agents 11 Antineoplastic and 12 1350066 Carmustine immunomodulating agents 13 Antineoplastic and 14 21603763 catumaxomab immunomodulating agents 15 Antineoplastic and 16 45893501 cepeginterferon alfa-2b immunomodulating agents 17 Antineoplastic and 18 44818466 ceritinibFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 912263 certolizumab pegol immunomodulating agents 21 Antineoplastic and 22 1315411 cetuximab immunomodulating agents 23 24 Antineoplastic and 25 1390051 Chlorambucil immunomodulating agents 26 Antineoplastic and 27 1397599 Cisplatin immunomodulating agents 28 Antineoplastic and 29 19054825 Cladribine immunomodulating agents 30 Antineoplastic and 31 19054821 clofarabine immunomodulating agents 32 Antineoplastic and 33 43534820 cridanimod immunomodulating agents 34 Antineoplastic and 35 40242675 crizotinib immunomodulating agents 36 Antineoplastic and 37 1310317 Cyclophosphamide immunomodulating agents 38 Antineoplastic and 39 19010482 Cyclosporine immunomodulating agents 40 Antineoplastic and 41 1311078 Cytarabine immunomodulating agents 42 Antineoplastic and 43 43532299 dabrafenib immunomodulating agents 44 Antineoplastic and 45 1311409 Dacarbazine immunomodulating agents 46 Antineoplastic and 47 19036892 Daclizumab immunomodulating agents 48 Antineoplastic and 49 1311443 Dactinomycin immunomodulating agents 50 Antineoplastic and 51 1358436 dasatinib immunomodulating agents 52 Antineoplastic and 53 45893271 dasiprotimut-T immunomodulating agents 54 Antineoplastic and 55 1311799 Daunorubicin immunomodulating agents 56 Antineoplastic and 57 19024728 decitabine immunomodulating agents 58 Antineoplastic and 59 19058410 degarelix immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603721 demecolcine immunomodulating agents 5 Antineoplastic and 6 19051642 denileukin diftitox immunomodulating agents 7 Antineoplastic and 8 1525866 Diethylstilbestrol immunomodulating agents 9 Antineoplastic and 10 46221699 dinutuximab immunomodulating agents 11 Antineoplastic and 12 1315942 docetaxel immunomodulating agents 13 Antineoplastic and 14 1338512 Doxorubicin immunomodulating agents 15 Antineoplastic and 16 19080458 eculizumab immunomodulating agents 17 Antineoplastic and 18 19132294 EdrecolomabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 936429 efalizumab immunomodulating agents 21 Antineoplastic and 22 21603770 efaproxiral immunomodulating agents 23 24 Antineoplastic and 25 42900250 enzalutamide immunomodulating agents 26 Antineoplastic and 27 1344354 Epirubicin immunomodulating agents 28 Antineoplastic and 29 40230712 eribulin immunomodulating agents 30 Antineoplastic and 31 1325363 erlotinib immunomodulating agents 32 Antineoplastic and 33 1349025 Estramustine immunomodulating agents 34 Antineoplastic and 35 1151789 Etanercept immunomodulating agents 36 Antineoplastic and 37 19104221 Ethoglucid immunomodulating agents 38 Antineoplastic and 39 1350504 Etoposide immunomodulating agents 40 Antineoplastic and 41 19011440 everolimus immunomodulating agents 42 Antineoplastic and 43 1398399 exemestane immunomodulating agents 44 Antineoplastic and 45 1304850 Filgrastim immunomodulating agents 46 Antineoplastic and 47 40226579 fingolimod immunomodulating agents 48 Antineoplastic and 49 1395557 fludarabine immunomodulating agents 50 Antineoplastic and 51 955632 Fluorouracil immunomodulating agents 52 Antineoplastic and 53 21601443 fluorouracil, combinations immunomodulating agents 54 Antineoplastic and 55 1356461 Flutamide immunomodulating agents 56 Antineoplastic and 57 19020079 formestane immunomodulating agents 58 Antineoplastic and 59 19065450 fosfestrol immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21601411 fotemustine immunomodulating agents 5 Antineoplastic and 6 1304044 fulvestrant immunomodulating agents 7 Antineoplastic and 8 1319193 gefitinib immunomodulating agents 9 Antineoplastic and 10 1314924 gemcitabine immunomodulating agents 11 Antineoplastic and 12 19098566 gemtuzumab immunomodulating agents 13 Antineoplastic and 14 21603822 gestonorone immunomodulating agents 15 Antineoplastic and 16 19041065 golimumab immunomodulating agents 17 Antineoplastic and 18 1366310 GoserelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603901 gusperimus immunomodulating agents 21 Antineoplastic and 22 1366773 histrelin immunomodulating agents 23 24 Antineoplastic and 25 1377141 hydroxyurea immunomodulating agents 26 Antineoplastic and 27 44507848 Ibrutinib immunomodulating agents 28 Antineoplastic and 29 19078097 Idarubicin immunomodulating agents 30 Antineoplastic and 31 45776944 idelalisib immunomodulating agents 32 Antineoplastic and 33 19078187 Ifosfamide immunomodulating agents 34 Antineoplastic and 35 1304107 imatinib immunomodulating agents 36 Antineoplastic and 37 21603883 immunocyanin immunomodulating agents 38 Antineoplastic and 39 937368 infliximab immunomodulating agents 40 Antineoplastic and 41 1379969 Interferon Alfa-2a immunomodulating agents 42 Antineoplastic and 43 1380068 Interferon Alfa-2b immunomodulating agents 44 Antineoplastic and 45 19044394 Interferon Alfa-n1 immunomodulating agents 46 Antineoplastic and 47 1781314 interferon alfacon-1 immunomodulating agents 48 Antineoplastic and 49 722424 Interferon beta-1a immunomodulating agents 50 Antineoplastic and 51 713196 interferon beta-1b immunomodulating agents 52 Antineoplastic and 53 19122123 Interferon Type II immunomodulating agents 54 Antineoplastic and 55 19109079 Interferon-beta immunomodulating agents 56 Antineoplastic and 57 40238188 ipilimumab immunomodulating agents 58 Antineoplastic and 59 1367268 irinotecan immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19025348 ixabepilone immunomodulating agents 5 Antineoplastic and 6 1359548 lapatinib immunomodulating agents 7 Antineoplastic and 8 1101898 leflunomide immunomodulating agents 9 Antineoplastic and 10 19026972 lenalidomide immunomodulating agents 11 Antineoplastic and 12 19009705 lenograstim immunomodulating agents 13 Antineoplastic and 14 21603875 lentinan immunomodulating agents 15 Antineoplastic and 16 1315946 letrozole immunomodulating agents 17 Antineoplastic and 18 1351541 LeuprolideFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 44506753 lipegfilgrastim immunomodulating agents 21 Antineoplastic and 22 1391846 Lomustine immunomodulating agents 23 24 Antineoplastic and 25 21603788 lonidamine immunomodulating agents 26 Antineoplastic and 27 21601401 mannosulfan immunomodulating agents 28 Antineoplastic and 29 43534811 masitinib immunomodulating agents 30 Antineoplastic and 31 988447 Masoprocol immunomodulating agents 32 Antineoplastic and 33 1394337 Mechlorethamine immunomodulating agents 34 Antineoplastic and 35 1301267 Melphalan immunomodulating agents 36 Antineoplastic and 37 21603920 mepolizumab immunomodulating agents 38 Antineoplastic and 39 1436650 mercaptopurine immunomodulating agents 40 Antineoplastic and 41 1305058 Methotrexate immunomodulating agents 42 Antineoplastic and 43 19025194 methyl 5-aminolevulinate immunomodulating agents 44 Antineoplastic and 45 21603888 mifamurtide immunomodulating agents 46 Antineoplastic and 47 44816310 miltefosine immunomodulating agents 48 Antineoplastic and 49 19125635 Mitobronitol immunomodulating agents 50 Antineoplastic and 51 21603794 mitoguazone immunomodulating agents 52 Antineoplastic and 53 1389036 Mitomycin immunomodulating agents 54 Antineoplastic and 55 1309161 Mitotane immunomodulating agents 56 Antineoplastic and 57 1309188 Mitoxantrone immunomodulating agents 58 Antineoplastic and 59 19009676 molgramostim immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19051865 Muromonab-CD3 immunomodulating agents 5 Antineoplastic and 6 19012565 Mycophenolic Acid immunomodulating agents 7 Antineoplastic and 8 735843 natalizumab immunomodulating agents 9 Antineoplastic and 10 19002912 nelarabine immunomodulating agents 11 Antineoplastic and 12 1394023 nilotinib immunomodulating agents 13 Antineoplastic and 14 1315286 nilutamide immunomodulating agents 15 Antineoplastic and 16 21601412 nimustine immunomodulating agents 17 Antineoplastic and 18 44507676 obinutuzumabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603807 oblimersen immunomodulating agents 21 Antineoplastic and 22 40167582 ofatumumab immunomodulating agents 23 24 Antineoplastic and 25 45892579 olaparib immunomodulating agents 26 Antineoplastic and 27 19069046 omacetaxine mepesuccinate immunomodulating agents 28 Antineoplastic and 29 1318030 Oprelvekin immunomodulating agents 30 Antineoplastic and 31 1318011 oxaliplatin immunomodulating agents 32 Antineoplastic and 33 1378382 Paclitaxel immunomodulating agents 34 Antineoplastic and 35 21603725 paclitaxel poliglumex immunomodulating agents 36 Antineoplastic and 37 19100985 panitumumab immunomodulating agents 38 Antineoplastic and 39 46221435 panobinostat immunomodulating agents 40 Antineoplastic and 41 40167554 pazopanib immunomodulating agents 42 Antineoplastic and 43 581480 pegademase bovine immunomodulating agents 44 Antineoplastic and 45 1326481 pegaspargase immunomodulating agents 46 Antineoplastic and 47 1325608 pegfilgrastim immunomodulating agents 48 Antineoplastic and 49 1714165 peginterferon alfa-2a immunomodulating agents 50 Antineoplastic and 51 21603870 peginterferon alfa-2a, combinations immunomodulating agents 52 Antineoplastic and 53 1797155 peginterferon alfa-2b immunomodulating agents 54 Antineoplastic and 55 21603869 peginterferon alfa-2b, combinations immunomodulating agents 56 Antineoplastic and 57 45775146 peginterferon beta-1a immunomodulating agents 58 Antineoplastic and 59 1304919 pemetrexed immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19031224 Pentostatin immunomodulating agents 5 Antineoplastic and 6 42801287 pertuzumab immunomodulating agents 7 Antineoplastic and 8 19102785 pidotimod immunomodulating agents 9 Antineoplastic and 10 19046625 Pipobroman immunomodulating agents 11 Antineoplastic and 12 19093366 Pirarubicin immunomodulating agents 13 Antineoplastic and 14 45775206 pirfenidone immunomodulating agents 15 Antineoplastic and 16 40253110 pixantrone immunomodulating agents 17 Antineoplastic and 18 19017581 PlerixaforFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19009165 Plicamycin immunomodulating agents 21 Antineoplastic and 22 21603880 poly I:C immunomodulating agents 23 24 Antineoplastic and 25 21603881 poly ICLC immunomodulating agents 26 Antineoplastic and 27 40253122 polyplatillen immunomodulating agents 28 Antineoplastic and 29 43014237 pomalidomide immunomodulating agents 30 Antineoplastic and 31 43013182 ponatinib immunomodulating agents 32 Antineoplastic and 33 40166461 Pralatrexate immunomodulating agents 34 Antineoplastic and 35 19135793 Prednimustine immunomodulating agents 36 Antineoplastic and 37 1351779 Procarbazine immunomodulating agents 38 Antineoplastic and 39 19038536 raltitrexed immunomodulating agents 40 Antineoplastic and 41 21601413 ranimustine immunomodulating agents 42 Antineoplastic and 43 42903460 regorafenib immunomodulating agents 44 Antineoplastic and 45 43534809 ridaforolimus immunomodulating agents 46 Antineoplastic and 47 19023450 rilonacept immunomodulating agents 48 Antineoplastic and 49 1314273 rituximab immunomodulating agents 50 Antineoplastic and 51 40168385 romidepsin immunomodulating agents 52 Antineoplastic and 53 21603876 roquinimex immunomodulating agents 54 Antineoplastic and 55 40244464 ruxolitinib immunomodulating agents 56 Antineoplastic and 57 1308432 sargramostim immunomodulating agents 58 Antineoplastic and 59 21603751 satraplatin immunomodulating agents 60

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1 2 3 Antineoplastic and 4 45892883 secukinumab immunomodulating agents 5 Antineoplastic and 6 21601409 semustine immunomodulating agents 7 Antineoplastic and 8 44818461 siltuximab immunomodulating agents 9 Antineoplastic and 10 40224095 sipuleucel-T immunomodulating agents 11 Antineoplastic and 12 19034726 Sirolimus immunomodulating agents 13 Antineoplastic and 14 21603808 sitimagene ceradenovec immunomodulating agents 15 Antineoplastic and 16 1363387 sorafenib immunomodulating agents 17 Antineoplastic and 18 19136210 StreptozocinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1336539 sunitinib immunomodulating agents 21 Antineoplastic and 22 950637 Tacrolimus immunomodulating agents 23 24 Antineoplastic and 25 1436678 Tamoxifen immunomodulating agents 26 Antineoplastic and 27 19071159 TASONERMIN immunomodulating agents 28 Antineoplastic and 29 19056756 Tegafur immunomodulating agents 30 Antineoplastic and 31 21601444 tegafur, combinations immunomodulating agents 32 Antineoplastic and 33 19011067 temoporfin immunomodulating agents 34 Antineoplastic and 35 1341149 temozolomide immunomodulating agents 36 Antineoplastic and 37 19092845 temsirolimus immunomodulating agents 38 Antineoplastic and 39 19136750 Teniposide immunomodulating agents 40 Antineoplastic and 41 42900584 teriflunomide immunomodulating agents 42 Antineoplastic and 43 19137042 Thalidomide immunomodulating agents 44 Antineoplastic and 45 1437379 Thioguanine immunomodulating agents 46 Antineoplastic and 47 19137385 Thiotepa immunomodulating agents 48 Antineoplastic and 49 19102231 Thymopentin immunomodulating agents 50 Antineoplastic and 51 21603796 tiazofurine immunomodulating agents 52 Antineoplastic and 53 40171288 tocilizumab immunomodulating agents 54 Antineoplastic and 55 42904205 tofacitinib immunomodulating agents 56 Antineoplastic and 57 1378509 Topotecan immunomodulating agents 58 Antineoplastic and 59 1342346 Toremifene immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603727 trabectedin immunomodulating agents 5 Antineoplastic and 6 43532497 trametinib immunomodulating agents 7 Antineoplastic and 8 1387104 trastuzumab immunomodulating agents 9 Antineoplastic and 10 19042545 treosulfan immunomodulating agents 11 Antineoplastic and 12 903643 Tretinoin immunomodulating agents 13 Antineoplastic and 14 21601404 triaziquone immunomodulating agents 15 Antineoplastic and 16 45893469 trifluridine, combinations immunomodulating agents 17 Antineoplastic and 18 1343039 TriptorelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19101677 trofosfamide immunomodulating agents 21 Antineoplastic and 22 40161532 ustekinumab immunomodulating agents 23 24 Antineoplastic and 25 19012543 valrubicin immunomodulating agents 26 Antineoplastic and 27 40238052 Vandetanib immunomodulating agents 28 Antineoplastic and 29 45774639 vedolizumab immunomodulating agents 30 Antineoplastic and 31 40241937 Vemurafenib immunomodulating agents 32 Antineoplastic and 33 19008264 Vinblastine immunomodulating agents 34 Antineoplastic and 35 1308290 Vincristine immunomodulating agents 36 Antineoplastic and 37 19008336 Vindesine immunomodulating agents 38 Antineoplastic and 39 21601451 vinflunine immunomodulating agents 40 Antineoplastic and 41 1343346 vinorelbine immunomodulating agents 42 Antineoplastic and 43 43534805 vintafolide immunomodulating agents 44 Antineoplastic and 45 42709321 vismodegib immunomodulating agents 46 Antineoplastic and 47 40253798 voclosporin immunomodulating agents 48 Antineoplastic and 49 1337651 Vorinostat immunomodulating agents 50 Antineoplastic and 51 21603843 vorozole immunomodulating agents 52 Antineoplastic and 53 21603736 zorubicin immunomodulating agents 54 19037596 Acetylcarnitine Central nervous system stimulants 55 56 19112518 adrafinil Central nervous system stimulants 57 714785 Amphetamine Central nervous system stimulants 58 19032667 aniracetam Central nervous system stimulants 59 742185 atomoxetine Central nervous system stimulants 60

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1 2 3 1134439 Caffeine Central nervous system stimulants 4 5 40223464 Citicoline Central nervous system stimulants 6 1311826 Deanol Central nervous system stimulants 7 731533 dexmethylphenidate Central nervous system stimulants 8 719311 Dextroamphetamine Central nervous system stimulants 9 10 21604759 fencamfamin Central nervous system stimulants 11 19061288 fenethylline Central nervous system stimulants 12 19061392 fenozolone Central nervous system stimulants 13 21604773 fipexide Central nervous system stimulants 14 15 19067036 idebenone Central nervous system stimulants 16 21604777 linopirdine Central nervous system stimulants 17 709567 Lisdexamfetamine Central nervous system stimulants 18 43534829 mebicarFor peer review onlyCentral nervous system stimulants 19 20 19052682 Meclofenoxate Central nervous system stimulants 21 704053 Methamphetamine Central nervous system stimulants 22 705944 Methylphenidate Central nervous system stimulants 23 710650 modafinil Central nervous system stimulants 24 25 21604778 nizofenone Central nervous system stimulants 26 19082891 oxiracetam Central nervous system stimulants 27 727835 Pemoline Central nervous system stimulants 28 44819159 phenibut Central nervous system stimulants 29 30 43534828 PHENIBUT Central nervous system stimulants 31 21604783 pipradrol Central nervous system stimulants 32 19046654 Piracetam Central nervous system stimulants 33 21604784 pramiracetam Central nervous system stimulants 34 35 19029018 prolintane Central nervous system stimulants 36 19096031 propentofylline Central nervous system stimulants 37 19097999 pyrisuccideanol Central nervous system stimulants 38 19060358 Pyrithioxin Central nervous system stimulants 39 40 19095462 vinpocetine Central nervous system stimulants 41 21602495 chlormadinone and ethinylestradiol Contraceptives 42 40253989 chlormadinone and ethinylestradiol Contraceptives 43 1588000 Desogestrel Contraceptives 44 45 43534785 dienogest and ethinylestradiol Contraceptives 46 1519936 Etonogestrel Contraceptives 47 21602483 gestodene and ethinylestradiol Contraceptives 48 21602494 gestodene and ethinylestradiol Contraceptives 49 50 1589505 Levonorgestrel Contraceptives 51 19092358 Lynestrenol Contraceptives 52 21602490 lynestrenol and ethinylestradiol Contraceptives 53 21602476 lynestrenol and ethinylestradiol Contraceptives 54 55 1500211 Medroxyprogesterone Contraceptives 56 1300978 Megestrol Contraceptives 57 21602477 megestrol and ethinylestradiol Contraceptives 58 21602489 megestrol and ethinylestradiol Contraceptives 59 60 21602487 nomegestrol and estradiol Contraceptives

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1 2 3 1521369 Norethindrone Contraceptives 4 5 19128258 Norgestrienone Contraceptives 6 21602500 quingestanol Contraceptives 7 21602475 quingestanol and ethinylestradiol Contraceptives 8 40225722 ulipristal Contraceptives 9 10 905151 Alclometasone Corticosteroid 11 930747 amcinonide Corticosteroid 12 1115572 Beclomethasone Corticosteroid 13 920458 Betamethasone Corticosteroid 14 15 939259 Budesonide Corticosteroid 16 998415 Clobetasol Corticosteroid 17 950882 clocortolone Corticosteroid 18 1507705 CortisoneFor peer review onlyCorticosteroid 19 20 917205 Desonide Corticosteroid 21 917336 Desoximetasone Corticosteroid 22 1518254 Dexamethasone Corticosteroid 23 960988 Diflorasone Corticosteroid 24 25 1196514 flunisolide Corticosteroid 26 19110714 Fluocinolone Acetonide Corticosteroid 27 955252 Fluocinonide Corticosteroid 28 19055344 Fluocortolone Corticosteroid 29 30 955583 Fluorometholone Corticosteroid 31 956266 Flurandrenolide Corticosteroid 32 1149380 fluticasone Corticosteroid 33 966468 Halcinonide Corticosteroid 34 35 949759 halobetasol Corticosteroid 36 975125 Hydrocortisone Corticosteroid 37 992127 Loteprednol Corticosteroid 38 909021 medrysone Corticosteroid 39 40 1506270 Methylprednisolone Corticosteroid 41 905233 Mometasone Corticosteroid 42 928110 prednicarbate Corticosteroid 43 1550557 prednisolone Corticosteroid 44 45 1551099 Prednisone Corticosteroid 46 977421 rimexolone Corticosteroid 47 903963 Triamcinolone Corticosteroid 48 21601546 altizide and potassium-sparing agents Diuretics 49 50 991382 Amiloride Diuretics 51 1316354 Bendroflumethiazide Diuretics 52 21601475 bendroflumethiazide and potassium Diuretics 53 bendroflumethiazide and potassium-sparing 54 21601551 agents Diuretics 55 932745 Bumetanide Diuretics 56 57 21601524 bumetanide and potassium Diuretics 58 21601555 bumetanide and potassium-sparing agents Diuretics 59 21601552 butizide and potassium-sparing agents Diuretics 60

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1 2 3 19019698 Canrenone Diuretics 4 5 992590 Chlorothiazide Diuretics 6 21601478 chlorothiazide and potassium Diuretics 7 21601485 chlorothiazide, combinations Diuretics 8 21601506 chlortalidone and potassium Diuretics 9 10 21601548 chlortalidone and potassium-sparing agents Diuretics 11 1395058 Chlorthalidone Diuretics 12 19051444 cicletanine Diuretics 13 21601495 clofenamide Diuretics 14 15 21601508 clofenamide and potassium Diuretics 16 19099181 Clopamide Diuretics 17 21601505 clopamide and potassium Diuretics 18 21601500 clorexoloneFor peer review onlyDiuretics 19 20 21601502 clorexolone, combinations with psycholeptics Diuretics 21 19010927 conivaptan Diuretics 22 19010015 Cyclopenthiazide Diuretics 23 21601481 cyclopenthiazide and potassium Diuretics 24 25 21601549 cyclopenthiazide and potassium-sparing agents Diuretics 26 19082886 cyclothiazide Diuretics 27 21601483 cyclothiazide and potassium Diuretics 28 21601545 epitizide and potassium-sparing agents Diuretics 29 30 1309799 eplerenone Diuretics 31 19103548 Ethacrynic Acid Diuretics 32 21601531 etozolin Diuretics 33 21601501 fenquizone Diuretics 34 35 956874 Furosemide Diuretics 36 21601523 furosemide and potassium Diuretics 37 21601554 furosemide and potassium-sparing agents Diuretics 38 974166 Hydrochlorothiazide Diuretics 39 40 21601477 hydrochlorothiazide and potassium Diuretics 41 21601488 hydrochlorothiazide, combinations Diuretics 42 1376289 Hydroflumethiazide Diuretics 43 21601476 hydroflumethiazide and potassium Diuretics 44 45 21601486 hydroflumethiazide, combinations Diuretics 46 978555 Indapamide Diuretics 47 21601473 mebutizide Diuretics 48 21601547 mebutizide and potassium-sparing agents Diuretics 49 50 19000556 Mefruside Diuretics 51 21601507 mefruside and potassium Diuretics 52 19003070 Mersalyl Diuretics 53 905273 Methyclothiazide Diuretics 54 55 21601482 methyclothiazide and potassium Diuretics 56 21601497 meticrane Diuretics 57 907013 Metolazone Diuretics 58 21601550 metolazone and potassium-sparing agents Diuretics 59 60 21601529 muzolimine Diuretics

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1 2 3 19025498 piretanide Diuretics 4 5 948787 Polythiazide Diuretics 6 21601479 polythiazide and potassium Diuretics 7 19081320 quinethazone Diuretics 8 21601504 quinethazone and potassium Diuretics 9 10 970250 Spironolactone Diuretics 11 19137056 Theobromine Diuretics 12 21601527 tienilic acid Diuretics 13 19036797 tolvaptan Diuretics 14 15 942350 torsemide Diuretics 16 904542 Triamterene Diuretics 17 904639 Trichlormethiazide Diuretics 18 21601480 trichlormethiazideFor peer and potassium review onlyDiuretics 19 20 21601544 trichlormethiazide and potassium-sparing agents Diuretics 21 19010493 Xipamide Diuretics 22 1139042 Acetylcysteine Mucolytics 23 19088167 Ambroxol Mucolytics 24 25 19030493 Bromhexine Mucolytics 26 19041843 Carbocysteine Mucolytics 27 21603389 combinations Mucolytics 28 21603387 domiodol Mucolytics 29 30 1125443 Dornase Alfa Mucolytics 31 19095266 eprazinone Mucolytics 32 19058933 erdosteine Mucolytics 33 19071861 letosteine Mucolytics 34 35 994058 Mannitol Mucolytics 36 1354698 Mesna Mucolytics 37 21603393 neltenexine Mucolytics 38 19039512 sobrerol Mucolytics 39 40 21603390 stepronin Mucolytics 41 903031 tiopronin Mucolytics 42 1363516 5-Hydroxytryptophan Psychotherapeutic agents 43 19018226 Acepromazine Psychotherapeutic agents 44 45 19029555 acetophenazine Psychotherapeutic agents 46 21604750 agomelatine Psychotherapeutic agents 47 21604715 alaproclate Psychotherapeutic agents 48 19032424 amineptin Psychotherapeutic agents 49 50 19057607 Amisulpride Psychotherapeutic agents 51 710062 Amitriptyline Psychotherapeutic agents 52 713109 Amoxapine Psychotherapeutic agents 53 757688 aripiprazole Psychotherapeutic agents 54 55 40164052 Asenapine Psychotherapeutic agents 56 19016440 Benperidol Psychotherapeutic agents 57 19058055 bifemelane Psychotherapeutic agents 58 19039227 bromperidol Psychotherapeutic agents 59 60 750982 Bupropion Psychotherapeutic agents

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1 2 3 21604508 butaperazine Psychotherapeutic agents 4 5 19039883 butriptyline Psychotherapeutic agents 6 45893485 cariprazine Psychotherapeutic agents 7 19122262 chlorproethazine Psychotherapeutic agents 8 794852 Chlorpromazine Psychotherapeutic agents 9 10 19095002 Chlorprothixene Psychotherapeutic agents 11 797617 Citalopram Psychotherapeutic agents 12 798834 Clomipramine Psychotherapeutic agents 13 21604532 clopenthixol Psychotherapeutic agents 14 15 19100363 clothiapine Psychotherapeutic agents 16 800878 Clozapine Psychotherapeutic agents 17 19051234 cyamemazine Psychotherapeutic agents 18 716968 DesipramineFor peer review onlyPsychotherapeutic agents 19 20 717607 Desvenlafaxine Psychotherapeutic agents 21 19023846 dibenzepin Psychotherapeutic agents 22 21604705 dimetacrine Psychotherapeutic agents 23 21604500 dixyrazine Psychotherapeutic agents 24 25 19037989 Dothiepin Psychotherapeutic agents 26 738156 Doxepin Psychotherapeutic agents 27 739323 Droperidol Psychotherapeutic agents 28 715259 duloxetine Psychotherapeutic agents 29 30 715939 Escitalopram Psychotherapeutic agents 31 21604717 etoperidone Psychotherapeutic agents 32 21604524 fluanisone Psychotherapeutic agents 33 755695 Fluoxetine Psychotherapeutic agents 34 35 19055982 Flupenthixol Psychotherapeutic agents 36 756018 Fluphenazine Psychotherapeutic agents 37 19056465 Fluspirilene Psychotherapeutic agents 38 751412 Fluvoxamine Psychotherapeutic agents 39 40 21604748 gepirone Psychotherapeutic agents 41 766529 Haloperidol Psychotherapeutic agents 42 19017241 iloperidone Psychotherapeutic agents 43 778268 Imipramine Psychotherapeutic agents 44 45 21604690 imipramine oxide Psychotherapeutic agents 46 19122204 Iprindole Psychotherapeutic agents 47 21604725 iproclozide Psychotherapeutic agents 48 21604724 iproniazide Psychotherapeutic agents 49 50 781705 Isocarboxazid Psychotherapeutic agents 51 43560354 levomilnacipran Psychotherapeutic agents 52 21604554 levosulpiride Psychotherapeutic agents 53 19124477 Lithium Psychotherapeutic agents 54 55 19091830 Lofepramine Psychotherapeutic agents 56 792263 Loxapine Psychotherapeutic agents 57 40230761 lurasidone Psychotherapeutic agents 58 794147 Maprotiline Psychotherapeutic agents 59 60 19072021 medifoxamine Psychotherapeutic agents

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1 2 3 19110751 MELITRACEN Psychotherapeutic agents 4 5 703083 Mesoridazine Psychotherapeutic agents 6 19005147 Methotrimeprazine Psychotherapeutic agents 7 19072088 metylperon Psychotherapeutic agents 8 19007737 Mianserin Psychotherapeutic agents 9 10 19080226 milnacipran Psychotherapeutic agents 11 19072123 minaprine Psychotherapeutic agents 12 725131 Mirtazapine Psychotherapeutic agents 13 19010652 Moclobemide Psychotherapeutic agents 14 15 709699 Molindone Psychotherapeutic agents 16 21604519 moperone Psychotherapeutic agents 17 21604560 mosapramine Psychotherapeutic agents 18 714684 nefazodoneFor peer review onlyPsychotherapeutic agents 19 20 19127550 Nialamide Psychotherapeutic agents 21 19128066 Nomifensine Psychotherapeutic agents 22 721724 Nortriptyline Psychotherapeutic agents 23 785788 olanzapine Psychotherapeutic agents 24 25 19129635 Opipramol Psychotherapeutic agents 26 21604739 oxaflozane Psychotherapeutic agents 27 19025922 oxypertine Psychotherapeutic agents 28 703244 paliperidone Psychotherapeutic agents 29 30 722031 Paroxetine Psychotherapeutic agents 31 19028044 Penfluridol Psychotherapeutic agents 32 19131663 Perazine Psychotherapeutic agents 33 19053565 periciazine Psychotherapeutic agents 34 35 733008 Perphenazine Psychotherapeutic agents 36 733896 Phenelzine Psychotherapeutic agents 37 745790 Pimozide Psychotherapeutic agents 38 19093225 pipamperone Psychotherapeutic agents 39 40 19133992 pipothiazine Psychotherapeutic agents 41 21604744 pivagabine Psychotherapeutic agents 42 19052903 Promazine Psychotherapeutic agents 43 19115044 prothipendyl Psychotherapeutic agents 44 45 754270 Protriptyline Psychotherapeutic agents 46 766814 quetiapine Psychotherapeutic agents 47 19098514 quinupramine Psychotherapeutic agents 48 715710 rasagiline Psychotherapeutic agents 49 50 19084693 reboxetine Psychotherapeutic agents 51 19035226 Remoxipride Psychotherapeutic agents 52 735979 Risperidone Psychotherapeutic agents 53 766209 Selegiline Psychotherapeutic agents 54 55 19050633 sertindole Psychotherapeutic agents 56 739138 Sertraline Psychotherapeutic agents 57 19136626 Sulpiride Psychotherapeutic agents 58 19100431 sultopride Psychotherapeutic agents 59 60 19041817 thiopropazate Psychotherapeutic agents

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1 2 3 19000305 thioproperazine Psychotherapeutic agents 4 5 700299 Thioridazine Psychotherapeutic agents 6 700465 Thiothixene Psychotherapeutic agents 7 19041910 tianeptine Psychotherapeutic agents 8 19008012 Tiapride Psychotherapeutic agents 9 10 19100775 toloxatone Psychotherapeutic agents 11 703470 Tranylcypromine Psychotherapeutic agents 12 703547 Trazodone Psychotherapeutic agents 13 704984 Trifluoperazine Psychotherapeutic agents 14 15 19005101 Trifluperidol Psychotherapeutic agents 16 19005104 Triflupromazine Psychotherapeutic agents 17 705755 Trimipramine Psychotherapeutic agents 18 19006186 TryptophanFor peer review onlyPsychotherapeutic agents 19 20 743670 venlafaxine Psychotherapeutic agents 21 19043327 veralipride Psychotherapeutic agents 22 40234834 vilazodone Psychotherapeutic agents 23 19008261 Viloxazine Psychotherapeutic agents 24 25 44507700 vortioxetine Psychotherapeutic agents 26 21604710 zimeldine Psychotherapeutic agents 27 712615 ziprasidone Psychotherapeutic agents 28 19102109 zotepine Psychotherapeutic agents 29 30 19010886 Zuclopenthixol Psychotherapeutic agents 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 STROBE Statement—Checklist of items that should be included 3 4 Item Location in manuscript where items 5 No Recommendation are reported 6 Title and abstract 1 (a) Indicate the study’s design with a Abstract: Design and setting: 7 commonly used term in the title or the “descriptive drug utilization study” 8 abstract 9 10 (b) Provide in the abstract an informative Abstract 11 and balanced summary of what was done 12 and what was found 13 14 Introduction 15 Background/rationale 2 Explain the scientific background and Introduction 16 rationale for the investigation being 17 reported 18 For peer review only 19 Objectives 3 State specific objectives, including any Introduction: From “Our primary aim 20 prespecified hypotheses was ..” until “ambulatory setting” 21 Methods 22 23 Study design 4 Present key elements of study design early Abstract: Design and setting 24 in the paper Methods: Data sources: “We conducted 25 a drug utilisation study using pediatric 26 27 patient populations…” 28 Setting 5 Describe the setting, locations, and relevant Abstract: Design and setting 29 dates, including periods of recruitment, 30 Methods: Data sources, Data collection 31 exposure, follow-up, and data collection 32 Participants 6 (a) Give the eligibility criteria, and the Abstract: Design and setting, Patients 33 sources and methods of selection of Methods: Data collection 34 participants 35 36 Variables 7 Clearly define all outcomes, exposures, Methods: Data sources, Data collection, 37 predictors, potential confounders, and effect Statistical analysis 38 modifiers. Give diagnostic criteria, if 39 applicable 40 41 Data sources/ 8* For each variable of interest, give sources Methods: Data extraction & Statistical 42 measurement of data and details of methods of assessment analysis 43 (measurement). Describe comparability of 44 assessment methods if there is more than 45 46 one group 47 Bias 9 Describe any efforts to address potential Discussion: Strengths and limitations 48 sources of bias 49 Study size 10 Explain how the study size was arrived at Methods: Data sources, Data collection 50 51 Results: Study population 52 53 Quantitative 11 Explain how quantitative variables were Methods: Statistical analysis 54 variables handled in the analyses. If applicable, 55 describe which groupings were chosen and 56 why 57 58 Statistical methods 12 (a) Describe all statistical methods, Methods: Statistical analysis 59 including those used to control for 60 confounding

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1 2 (b) Describe any methods used to examine Methods: Statistical analysis 3 subgroups and interactions 4 5 (c) Explain how missing data were n/a 6 addressed 7 (d) If applicable, describe analytical Methods: Data collection 8 9 methods taking account of sampling 10 strategy 11 (e) Describe any sensitivity analyses n/a 12 13 Results 14 Participants 13* (a) Report numbers of individuals at each Results: Study population 15 stage of study—eg numbers potentially 16 eligible, examined for eligibility, confirmed 17 18 Foreligible, peer included in thereview study, completing only 19 follow-up, and analysed 20 (b) Give reasons for non-participation at n/a 21 each stage 22 23 (c) Consider use of a flow diagram n/a 24 Descriptive data 14* (a) Give characteristics of study participants Results: Study population, User- and 25 (eg demographic, clinical, social) and prescription prevalence 26 27 information on exposures and potential 28 confounders 29 (b) Indicate number of participants with n/a 30 missing data for each variable of interest 31 32 Outcome data 15* Report numbers of outcome events or Results: (Inpatients) (Ambulatory) user- 33 summary measures and prescription prevalence, Most 34 commonly used drugs by class in an 35 inpatient/ambulatory setting 36 37 Main results 16 (a) Give unadjusted estimates and, if Results 38 applicable, confounder-adjusted estimates Tables & Figures 39 40 and their precision (eg, 95% confidence 41 interval). Make clear which confounders 42 were adjusted for and why they were 43 included 44 45 (b) Report category boundaries when n/a 46 continuous variables were categorized 47 (c) If relevant, consider translating n/a 48 estimates of relative risk into absolute risk 49 50 for a meaningful time period 51 Other analyses 17 Report other analyses done—eg analyses of n/a 52 subgroups and interactions, and sensitivity 53 54 analyses 55 Discussion 56 Key results 18 Summarise key results with reference to Discussion: From “To our 57 58 study objectives knowledge…” until “Australia” 59 Limitations 19 Discuss limitations of the study, taking into Discussion: Strengths and limitations 60 account sources of potential bias or imprecision. Discuss both direction and

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1 2 magnitude of any potential bias 3 Interpretation 20 Give a cautious overall interpretation of Discussion: Comparison with literature, 4 5 results considering objectives, limitations, Implications for Practice and Policy 6 multiplicity of analyses, results from similar 7 studies, and other relevant evidence 8 Generalisability 21 Discuss the generalisability (external Discussion: Implications for Practice 9 10 validity) of the study results and Policy 11 12 Other information 13 14 Funding 22 Give the source of funding and the role of Title Page: Funding Source 15 the funders for the present study and, if 16 applicable, for the original study on which 17 the present article is based 18 For peer review only 19 20 *Give information separately for exposed and unexposed groups. 21 22 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 23 24 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 25 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 26 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 27 available at www.strobe-statement.org. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Application of a common data model (CDM) to rank the pediatric user and prescription prevalence of fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia: An observational, descriptive study.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-032426.R2

Article Type: Original research

Date Submitted by the 03-Dec-2019 Author:

Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Man, Kenneth; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy Pratt, Nicole; University of South Australia, Sansom Institute for Health Resarch Park, Rea Woong; Ajou University Cho, Soo-Yeon; Ajou University Li, Yu-Chuan (Jack); Taiwan Medical University, College of Medical Science and Technology Iqbal, Usman; Taipei Medical University, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology Nguyen, Phung-Anh; National Yang Ming University, Institute of Biomedical Informatics Schuemie, Martijn; Janssen Research and Development, Epidemiology Analytics; University of California, Los Angeles, Department of Biostatistics

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Pharmacology and therapeutics, Epidemiology

Keywords: CLINICAL PHARMACOLOGY, EPIDEMIOLOGY, PAEDIATRICS

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1 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 76

1 2 3 Application of a common data model (CDM) to rank the pediatric user and prescription prevalence of 4 5 6 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia: An observational, 7 8 descriptive study. 9 10 11 Authors: Ruth Brauera, PhD, Ian C.K. Wonga,b, PhD, Kenneth Manb, MPH, Nicole Prattc, PhD, 12 13 Rae Woong Parkd, MD, PhD, Soo-Yeon Chod, RN, MPH, Li, Yu-Chuan (Jack) Lie, MD, PhD, 14 15 Usman Iqbale, PhD, Alex Nguyene, PhD, Martijn Schuemief, PhD. 16 For peer review only 17 18 19 20 a b 21 Affiliations: UCL School of Pharmacy, London, United Kingdom; University of Hong Kong, Hong Kong; 22 23 cUniversity of South Australia, Adelaide, Australia; dAjou University School of Medicine, Suwon, South- 24 25 Korea; eTaipei Medical University, Taipei, Taiwan; and fJanssen Research and Development, New Jersey. 26 27 28 29 [email protected]) 30 Corresponding author: Martijn Schuemie ( 31 32 33 34 Funding Source: No funding was secured for this study. 35 36 37 Word count: 2887 38 39 40 41 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 Page 3 of 76 BMJ Open

1 2 3 Abstract 4 5 6 Objective: To measure the pediatric user and prescription prevalence in inpatient and ambulatory 7 8 settings in South Korea, Hong Kong, Taiwan, Japan and Australia by age and gender. A further objective 9 was to list the most commonly used drugs per drug class, per country. 10 11 12 Design and setting: Hospital inpatient and insurance paediatric health care data from the following 13 14 databases were used to conduct this descriptive drug utilization study: (i) the South Korean Ajou 15 16 University School of MedicineFor (AUSOM)peer database; review (ii) the Hong Kong only Clinical Data Analysis and 17 Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s National Health 18 19 Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits Scheme (PBS). 20 21 Country specific data were transformed into the Observational Medical Outcomes Partnership (OMOP) 22 Common Data Model (CDM). 23 24 25 Patients: Children (≤18 years) with at least 1 day of observation in any of the respective databases from 26 27 January 2009 until December 2013 were included. 28 29 30 Main outcome measures: For each drug class we assessed the per-protocol overall user and 31 prescription prevalence rates (per 1000 persons) per country and setting. 32 33 34 Results: Our study population comprised 1,574,524 children (52.9% male). The highest proportion of 35 36 dispensings was recorded in the youngest age category (<2 years) for inpatients (45.1%) with a relatively 37 38 high user prevalence of analgesics and antibiotics. Adrenergics, antihistamines, mucolytics and 39 corticosteroids were used in 10-15% of patients. For ambulatory patients, the highest proportion of 40 41 dispensings was recorded in the middle age category (2-11 years, 67.1%) with antibiotics the most 42 43 dispensed drug overall. 44 45 46 Conclusions: Country-specific pediatric drug utilization patterns were described, ranked and compared 47 between four East-Asian countries and Australia. The widespread east-Asian use of mucolytics warrants 48 49 further investigation. 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 4 of 76

1 2 3 Strengths and limitations of this study 4 5 6 7  We conducted the largest Western pacific pediatric drug utiIisation study to date using a 8 9 common data model (CDM) which allowed us to rank the user and prescription prevalence of 10 11 fifteen different drug classes in South Korea, Hong Kong, Taiwan, Japan and Australia. 12 13  Our comprehensive overview of country-specific pharmacological agents used in both an 14 15 16 ambulatory andFor inpatient peer setting, by genderreview and age, included only data of 1,574,524 children and 17 18 identified important differences in drug pediatric utilization patterns. 19 20  Despite the differences in databases in terms of setting and study populations, we believe our 21 22 overview of prescription patterns and rankings is an important step to further investigate and 23 24 25 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. 26 27  Over the counter (OTC) prescribing in individual countries was not captured and we may have 28 29 underestimated the true drug utilization of agents, such as paracetamol and some 30 31 antihistamines. 32 33 34  We collected data until the end of 2013 and acknowledge that, due to the rapid change in 35 36 pediatric licensing of therapeutic agents, some of our findings might be worthwhile replicating 37 38 with more current data. 39 40 41 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 Page 5 of 76 BMJ Open

1 2 3 Introduction 4 5 6 7 An important step to facilitate the rational use of drugs in pediatric populations is to investigate drug 8 9 utilization patterns [1]. Observational data in the form of electronic health records and insurance claims 10 11 data, real life data, have been used successfully to investigate the use of drugs in children[1-3]. 12 13 European studies on pediatric drug utilization patterns, have shown that the most commonly used drugs 14 15 16 in European children Forinclude anti-infective, peer respiratory review and dermatological only drugs and are largely 17 18 prescribed off-label[3]. Whilst drug-specific pediatric drug utilization data from East Asian countries are 19 20 available[4-6], a comprehensive overview of the most commonly used drugs is currently lacking. 21 22 23 24 The Asian Pharmacoepidemiology Network (AsPEN), the first multinational research network in Asia, in 25 26 collaboration with the Observational Medical Outcome Partnership (OMOP) set up an initiative to 27 28 convert domestic databases in Asian countries to a Common Data Model (CDM) to offer a multinational 29 30 research infrastructure to facilitate studies[7 8]. We used this network of observational healthcare 31 32 databases in South Korea, Hong Kong, Taiwan, Japan and Australia to measure and compare the 33 34 35 prevalence of drug prescribing in East Asian and Australian children. Our primary aim was to measure 36 37 the pediatric user and prescription prevalence in inpatient and ambulatory settings in the five 38 39 aforementioned countries by age and gender. A further objective was to list the most commonly used 40 41 drugs per drug class, per country, in both an inpatient and ambulatory setting. 42 43 44 Methods 45 46 47 Data sources 48 49 50 We conducted a drug utilisation study using pediatric patient populations from the following databases: 51 52 53 (i) Ajou University School of Medicine (AUSOM) from South Korea; (ii) the Hong Kong Clinical Data 54 55 Analysis and Reporting System (CDARS); (iii) the Japan Medical Data Center (JMDC); (iv) Taiwan’s 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 76

1 2 3 National Health Insurance Research Database (NHIRD); and (v) the Australian Pharmaceutical Benefits 4 5 6 Scheme (PBS). All data were anonymized to protect patient confidentiality. 7 8 9 All five countries have universal health care systems and none of the databases include information on 10 11 patients using private health care[7]. The South Korean and Hong Kong databases, AUSOM and CDARS, 12 13 collect and archive the electronic health records (EHR) of hospital inpatients. Briefly, AUSOM is an EHR 14 15 database of a Korean teaching hospital providing both secondary and tertiary care, with 1,096 patient 16 For peer review only 17 18 beds and 23 operating rooms with data for over 2,073,120 individuals, collected since 1994. By contrast, 19 20 CDARS contains secondary care data from all public hospitals in Hong Kong and their associated 21 22 ambulatory and primary care clinics since 1995 [9-11]. The database was developed and is maintained 23 24 by the Hong Kong Hospital Authority, a statutory body providing health care services available to all 25 26 Hong Kong residents (over 7 million) and covering about 80% of all hospital admissions. 27 28 29 30 The Japanese, Taiwanese and Australian data were extracted from insurance research databases. The 31 32 Japanese JMDC comprises data from 60 Society-Managed Health Insurances covering workers aged 18 33 34 to 65 and their dependents (children and elderly)[12]. The monthly claims data are derived from claims 35 36 issued by clinics, hospitals and community pharmacies from July 2009 onwards. Australian data consist 37 38 39 of national pharmacy claims data from the Australian Government Department of Human Services 40 41 which provides information of medicines subsidized and dispensed under the Pharmaceutical Benefits 42 43 Scheme. PBS data are collected from pharmacies and private hospitals, and discharge or outpatient 44 45 dispensing from public hospitals, but do not include inpatient public hospital prescriptions. From 46 47 Taiwan, we extracted reimbursement data from the Bureau National Health Insurance (NHI) system, 48 49 50 which has registered all medical claims since 1995. More than 99% of the citizens of Taiwan are enrolled 51 52 in the NHI, which offers mandatory and comprehensive medical care coverage to all Taiwanese 53 54 residents. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 76 BMJ Open

1 2 3 Information on specific indications of drug use was not available in the datasets from Hong Kong, Taiwan 4 5 6 and Japan. Further details of each database have been described elsewhere[13]. 7 8 9 10 11 12 Data collection 13 14 For this retrospective descriptive study we identified children, 18 years or younger, with at least 1 day of 15 16 For peer review only 17 observation in any of the respective databases. The follow-up period for all children started in January 18 19 2009 or the start date of observation, whichever was last. Follow-up ended in December 2013, the last 20 21 date observation or the date a child turned 18, whichever was first. Specifically, observation time was 22 23 defined as: 1) The start of the first visit (inpatient, outpatient or ER) to the end of the last visit for the 24 25 26 Korean AUSOM database; 2) The date of birth until death in the Hong Kong CDARS database and 3) The 27 28 insurance enrollment date in the Japan JMDC, Taiwan NHIRD, and Australian PBS. Data were available 29 30 from the end of 2009 onwards for the Japanese JMDC and until December 2011 for the Taiwanese 31 32 database (NHIRD). We used randomly selected samples from CDARS, NHIRD and PBS as only ~ 10% of 33 34 35 the total data were made available for research. 36 37 38 Data extraction 39 40 41 Data extraction, a population file with information on demographics and dispensing records, was 42 43 performed through a shared analysis program combining R and SQL. This program was distributed to the 44 45 data partners, executed locally against the data in OMOP CDM format, and results were returned to the 46 47 central coordinating site (University of Hong Kong). Both the extraction software and the analysis code 48 49 50 are available as open source: https://github.com/OHDSI/StudyProtocols/tree/master/DrugsInPeds. 51 52 53 Each database's full set of drug codes were mapped to RxNorm concepts using a semi-automated 54 55 process; using known ATC codes for each code, a set of one or more RxNorm ingredients was identified 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 76

1 2 3 based on the OMOP Standardized Vocabularies link between ATC and RxNorm. In case of ambiguity, 4 5 6 manual adjudication was used to select the appropriate RxNorm ingredient. Structured information on 7 8 strength and formulation was used to further link drug codes do RxNorm clinical drugs (e.g. 9 10 'Paracetamol 100mg Oral Tablet'), although this more granular information was not used in this study. 11 12 13 Research ethics approval 14 15 16 This study received approvalFor from peer the Institutional review Review Board ofonly the University of Hong 17 18 Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB), reference number: UW 13-504. 19 20 21 Patient and Public Involvement 22 23 24 25 We did not involve patients or the public in our work. 26 27 28 Statistical analysis 29 30 31 Total follow-up time was calculated for each child, stratified by age group and by calendar year. Age was 32 33 assessed on a day-by-day basis, and grouped according to the guidelines of the International Conference 34 35 of Harmonization (ICH) as < 2 years, 2-11 years, and 12-18 years[14]. Drugs were classified according to 36 37 a custom defined drug classification (Supplemental Material 1). This classification was based on 38 39 40 pharmacological class, and where appropriate aggregated further by indication. For each drug class we 41 42 assessed the overall user and prescription prevalence rates (per 1000 persons) per country and setting 43 44 (inpatient or ambulatory) by counting the number of children using or number of dispensings of a 45 46 specific drug (numerator). We used the total person count per database and per setting (inpatient or 47 48 49 ambulatory) as the denominator to calculate prevalence rates. If a person was observed for at least one 50 51 day in a particular category (e.g. age group) that person was counted in the denominator for that 52 53 category. Over the study period, and within a calendar year, children could contribute to more than one 54 55 age category. For all 15 different custom drug classes the prevalence per 1000 persons was calculated as 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 76 BMJ Open

1 2 3 the percentage of the total country specific user prevalence (class specific user prevalence/ total user 4 5 6 prevalence). Lastly, we identified the five drugs with the highest user prevalence (per 1000 persons) per 7 8 drug class in each country. 9 10 11 12 Results 13 14 Study population 15 16 For peer review only 17 Our dynamic study cohort comprised 1,574,524 children (52.9 % male). The total number of follow-up 18 19 20 years was 4,783,549 years, with a mean individual follow-up of 3.0 years. The database that contributed 21 22 most person years to the study was the Japanese JDMC (58 %) (Table 1). Altogether, we recorded close 23 24 to 9 million pediatric inpatient dispensings (8,848,699) and more than 44 million ambulatory 25 26 dispensings (44,652,871). The relative number of dispensings prescribed per age category differed 27 28 between the inpatient and ambulatory patient settings, with the highest proportion of dispensings 29 30 31 recorded in the youngest age category (<2 years) for inpatients (45.1%) and in the middle age category 32 33 (2-11 years) for ambulatory patients (67.1%). 34 35 36 User- and prescription prevalence 37 38 39 The recorded user- and prescription prevalence of all therapeutic agents was lower in the inpatient 40 41 population than the ambulatory population (Table 2a & Table 2b). Analgesics (including non-steroidal 42 43 44 anti-inflammatory drugs [NSAIDs]) had the highest user prevalence in Korea, Hong Kong and Taiwan in 45 46 the inpatient setting, however, antibiotics had the highest prescription prevalence in most countries 47 48 (Hong Kong, Japan and Taiwan). In the ambulatory setting, antibiotics had the highest user prevalence in 49 50 all countries, however, the highest prescription prevalence differed across countries. In Japan, the 51 52 53 highest prescription prevalence was recorded for corticosteroids, while in Taiwan the highest 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 76

1 2 3 prescription prevalence was for antihistamines and lastly, in Australia the highest prevalence was 4 5 6 recorded for antibiotics. 7 8 9 Inpatient user- and prescription prevalence 10 11 12 Overall, the inpatient user prevalence of analgesics and antibiotics was high relative to the user 13 14 prevalence of other agents in all countries (Table 2a). Adrenergics, antihistamines, mucolytics and 15 16 corticosteroids were usedFor in 10-15% peer of patients review while the remaining only categories of medicines were used 17 18 in <5% of patients. The user prevalence of mucolytics in Korea and Japan was high compared the user 19 20 21 prevalence of other agents. Inpatient prescription prevalence for different classes of agents showed 22 23 patterns similar to those seen for the user prevalence. 24 25 26 For pediatric inpatients, overall medication use was highest in males (see Supplemental Material 2). The 27 28 use of contraceptives, antidiabetic, psychotherapeutic, antineoplastic and immunomodulating agents 29 30 was more common in females. 31 32 33 Results stratified by age show that the inpatient use of drugs was highest in the youngest age group (<2 34 35 36 years) in all but four classes (contraceptives, antidiabetic, psychotherapeutic, antineoplastic and 37 38 immunomodulating agents) (Figure 1). 39 40 41 Ambulatory user- and prescription prevalence 42 43 44 The pediatric use of different classes of drugs in an ambulatory setting was measured in Japan, Taiwan 45 46 and Australia (Table 2b). The highest ambulatory user prevalence across all drug classes was country 47 48 49 specific with antibiotics ranked high in Japan (22%) and Australia (46%), followed by corticosteroids 50 51 (20% and 23% respectively). In Taiwan the highest user prevalence of any drug class was measured for 52 53 analgesics (17%), closely followed by antihistamines (16%). The pattern of inpatient prescription 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 76 BMJ Open

1 2 3 prevalence for different classes of agents was similar to the pattern seen for the user prevalence. A very 4 5 6 low prescription prevalence of antiinfectives (not including antibiotics) was measured in all countries. 7 8 9 The ambulatory dispensing of drugs stratified by gender showed fewer differences between males and 10 11 females in all databases (Figure 2). In contrast to the gender difference seen in an inpatient setting, the 12 13 ambulatory use of antibiotic agents, antihistamines and corticosteroids was higher in females. 14 15 16 The user prevalence byFor age showed peer a very different review pattern when onlycompared to inpatient use: The use of 17 18 most drugs, by class, was highest in the middle age category (2-11 years) in Japan and Australia (see 19 20 21 Supplemental Material 3). For Taiwan, the highest use for many drug classes was measured in the 22 23 youngest age category. The use of contraceptives, antidiabetic, psychotherapeutic, antineoplastic and 24 25 immunomodulating agents was highest in the oldest age group across all three databases. 26 27 28 Most commonly used drugs by class in an inpatient setting 29 30 31 Paracetamol was the most prevalent analgesic used in all countries, however, the prevalence of 32 33 paracetamol users differed across countries with Hong Kong and Japan using mostly paracetamol while 34 35 36 Korea and Taiwan had a greater spread of analgesic product use (Table 3a). Phenobarbital was the most 37 38 prescribed antiepileptic agent in three countries and the second most prescribed antiepileptic agent in 39 40 Taiwan. Chlorpheniramine was one of the most used antihistamines in all countries with the exception 41 42 of Japan. 43 44 45 Differences in the most used pediatric drugs in an inpatient setting were seen for drugs with a high user 46 47 48 prevalence overall, such as antibiotic and adrenergic agents. An outlying pattern of the user prevalence 49 50 for specific agents was seen in South Korea: The most used antibiotic (ceftriaxone) and adrenergic agent 51 52 (formoterol) in Korea were not among the five drugs with the highest inpatient user prevalence in any of 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 76

1 2 3 the other East Asian countries. Furthermore, the most used mucolytic (bromhexine) and corticosteroid 4 5 6 (dexamethasone) in Korea were less frequently used in other countries. 7 8 9 Most commonly used drugs by class in an ambulatory setting 10 11 12 As in the inpatient setting, the most used analgesic in an ambulatory setting in Japan, Taiwan and 13 14 Australia was paracetamol (Table 3b). Overall, more similarities in the most commonly used drugs per 15 16 custom defined drug Forclass were peerseen between review Japan and Taiwan. onlyFor antibiotic agents, the use of 17 18 amoxicillin, cephalexin and erythoromicin was very similar in Taiwan and Australia. For other drug 19 20 21 classes there was less overlap. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 Page 13 of 76 BMJ Open

1 2 3 Discussion 4 5 6 To our knowledge, this is the first comprehensive overview of pediatric drug use in Korea, Hong Kong, 7 8 Japan, Taiwan and Australia. This study has shown a high inpatient user prevalence of analgesics and 9 10 antibiotics relative to the user prevalence of other drug classes. The highest ambulatory user prevalence 11 12 across all drug classes was country specific with antibiotics and corticosteroids ranked high in Japan and 13 14 Australia. In Taiwan, the user prevalence of analgesics was highest followed by antihistamines. 15 16 For peer review only 17 Mucolytics were amongst the most frequently used drugs in Korea, Japan and Taiwan, but not in Hong 18 19 Kong and Australia. For pediatric inpatients, medication use was highest in males and the lowest age 20 21 category (<2 years), whilst for outpatients gender differences were less pronounced and medication use 22 23 was highest in 2-11 year olds in Japan and Australia. 24 25 26 Comparison with literature 27 28 29 30 Whilst we used a custom therapeutic classification and not ATC classification, the most commonly used 31 32 drugs in every class were compared to those as reported by Sturkenboom in 2005[3]. Overall, the choice 33 34 of specific pediatric therapeutic agents differed widely between the aforementioned three European 35 36 countries and the East Asian countries in our study. Exceptions were similarities in the use of amoxicillin, 37 38 39 salbutamol and paracetamol. The inpatient study results (Tables 2a & 3a) were compared to results of a 40 41 study by Rashed et al. (2015), who reported on the drug utilization patterns of children admitted to a 42 43 pediatric ward in the UK, Germany, Australia, Hong Kong and Malaysia[2]. As in our study, antibacterials 44 45 and analgesics were the two most used therapeutic groups in all five countries. 46 47 National Korean outpatient data on pediatric polypharmacy show that in pediatric users of two or more 48 49 50 drugs (younger than 12 years), respiratory agents are most often prescribed, followed by drugs to treat 51 52 allergies, central nervous system agents and antibiotics[5]. Whilst our study was not directly comparable 53 54 as we had information on Korean inpatient dispensings only, our Taiwanese outpatient data showed a 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 76

1 2 3 high ambulatory use of analgesics and antihistamines, whilst Australian and Japanese data showed a 4 5 6 high ambulatory use of antibiotics and corticosteroids. 7 8 9 Implications for Practice and Policy: Pediatric licensing of drugs in the Western Pacific region 10 11 12 National agencies responsible for regulating therapeutic goods often base their regulations on 13 14 international guidelines, especially for new drug licensing[15 16]. For instance, in Korea it is not 15 16 obligatory to carry outFor clinical trialspeer for pediatrics review and to develop pediatriconly drugs at present, whilst 17 18 various support policies are being developed in recognition of the need for the development and 19 20 21 provision of information on pediatric drugs (personal communication, S. Cho, 2017). Out of the five 22 23 countries included in this study, Japan is the only country with a specific pediatric working group within 24 25 the Pharmaceuticals and Medical Devices Agency[17]. 26 27 28 Results of the current study suggest that the extent to which international pediatric prescribing 29 30 guidelines affect local prescribing practices differs from country to country. For instance, our study, in 31 32 33 line with other studies, shows the widespread of mucolytics in children in Korea, Japan and Taiwan[6]. 34 35 This is a finding of note as in 2010 several European drug agencies withdrew the licenses for 36 37 carbocysteine and acetylcysteine for children younger than two years of age because their use was 38 39 associated with worsening of respiratory tract infections[18]. More recently, the European Medicines 40 41 42 Agency (EMA) published a revised assessment report on products containing ambroxol and bromhexine 43 44 in which the use of these products in children below <2 years of age is discouraged[19]. Our study 45 46 showed that the use of mucolytics was very high in the youngest age group in all countries but Hong 47 48 Kong and Australia. 49 50 51 Another drug that is contraindicated for use in children in some European countries is 52 53 tulobuterol. This drug, a β2-agonist, is licensed in seven countries worldwide for childhood asthma[20 54 55 21]. In 2010, the European Medicines Agency refused a paediatric investigation plan for tulobuterol and 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 76 BMJ Open

1 2 3 granted a waiver (restricting potential use to patients >18 years) as tulobuterol was considered likely to 4 5 6 be ineffective or unsafe in the pediatric population[22]. Yet, in this study tulobuterol was the most used 7 8 adrenergic agent in an outpatient setting in Japan with 74% of all tulobuterol prescribed as patches 9 10 (hokunalin tape) and the remaining 26% prescribed as a liquid (oral). 11 12 A further finding of note was the relatively common ambulatory use of dihydrocodeine in Japan 13 14 and codeine in Taiwan and Australia. Both codeine and dihydrocodeine are morphine derivatives and 15 16 For peer review only 17 are contraindicated for use in children younger than 12 in Europe since 2013[23]. This is mainly due to 18 19 the unpredictable metabolism of codeine to morphine[24]. At the time of data collection (2009-2012) 20 21 Australia already had prescribing guidelines in place in which it was recommended to restrict the use of 22 23 codeine in children under 12. 24 25 26 Lastly, we found that sulfamethoxazole is still one of the most used antibiotic agents in Taiwan. 27 28 In many European countries, including the UK, the importance of the sulfonamides has decreased as a 29 30 result of increasing bacterial resistance and their replacement by antibacterials which are generally 31 32 more active and less toxic[25]. 33 34 35 36 37 Strengths and limitations 38 39 We conducted the largest Western pacific pediatric drug utiIisation study to date. Data extraction was 40 41 performed through a shared analysis program and a standardized analysis process was applied to all 42 43 44 databases. Using a common data model (CDM), and CDM vocabulary concept identifiers, we were able 45 46 to use standardised drug codes across countries which allowed us to rank the user and prescription 47 48 prevalence of fifteen different drug classes in five different countries. We found some important 49 50 similarities and differences in country specific drug utilization patterns between Korea, Hong Kong, 51 52 53 Japan, Taiwan and Australia. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 76

1 2 3 It is important to highlight that our study did not aim to directly compare the drug prevalence 4 5 6 rates between the countries in this study, rather we aimed to provide a comprehensive overview of the 7 8 country-specific pharmacological agents used in both an ambulatory and inpatient setting by gender and 9 10 age. Differences in user and prescription prevalence patterns between the five countries in our study 11 12 may reflect differences in the underlying prevalence of diseases, differences in physician prescribing 13 14 behavior and differences in medicine availability and data capture. Like other drug utilization studies 15 16 For peer review only 17 using electronic health records, we could not distinguish between these. Additionally, as medical 18 19 indications were not available in all data sets we were unable to report the reasons for prescriptions. 20 21 We acknowledge that this limits the clinical interpretation of our data. Formularies were different across 22 23 countries as well, particularly with regard to which medicines were subsidized in the data and for which 24 25 26 indication. It is also worth noting that we did not distinguish between formulations and we recognize 27 28 that this limits the clinical interpretation of our data. Lastly, the five databases captured different source 29 30 populations. 31 32 Despite the differences in databases in terms of size, setting and study populations, we believe 33 34 35 our overview of prescription patterns and rankings is an important step to further investigate and 36 37 facilitate the rational use of drugs in pediatric populations in East Asia and Australia. Standardizing 38 39 medication use across countries will help when implementing adverse event monitoring programs 40 41 across the region. 42 43 44 Over the counter (OTC) prescribing in individual countries was not captured and we may have 45 46 underestimated the true drug utilization of agents, such as paracetamol and some antihistamines. OTC 47 48 prescribing is most likely to have affected any ambulatory drug utilization estimates. 49 50 Future studies could be conducted using the current dataset in OMOP CDM format to capture any 51 52 53 changes in pediatric drug dispensing over time. We collected data until the end of 2013 and 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 76 BMJ Open

1 2 3 acknowledge that, due to the rapid change in pediatric licensing of therapeutic agents, some of our 4 5 6 findings might be worthwhile replicating with more current data. 7 8 9 10 Conclusion 11 12 13 Country-specific pediatric drug utilization patterns were described, ranked and compared between four 14 15 East-Asian countries and Australia. The widespread east-Asian use of mucolytics and the use of 16 For peer review only 17 18 tulobuterol in Japan warrants further investigation. 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 18 of 76

1 2 3 4 5 6 Acknowledgments: The analysis is based in part on work from the Observational Health Sciences and 7 8 Informatics collaborative (OHDSI). OHDSI (http://ohdsi.org) is a multi-stakeholder, interdisciplinary 9 10 collaborative to create open-source solutions that bring out the value of observational health data 11 12 through large-scale analytics. 13 14 15 16 For peer review only 17 18 Financial Disclosure: Dr. Schuemie is an employee of Janssen Research & Development. None of the 19 20 remaining authors have financial relationships relevant to this article to disclose. 21 22 23 24 Potential Conflicts of Interest: The authors have no conflicts of interest relevant to this article to 25 26 disclose. 27 28 29 30 31 32 Author’s contribution: MS and ICKW designed the study. MS wrote the protocol for this study and was 33 34 responsible for the statistical programming. RB wrote the first draft of the manuscript. MS, KM, NP, 35 36 RWP, SYC, YCL, UI and AN ran country specific analyses and contributed original data. All authors 37 38 39 contributed to critical revisions of the manuscript. All authors read and approved the final manuscript. 40 41 42 43 44 45 Data sharing statement: No data are available. The extraction software and the analysis code are 46 47 available as open source: https://github.com/OHDSI/StudyProtocols/tree/master/DrugsInPeds. 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 Page 19 of 76 BMJ Open

References 1 2 3 1. Wong IC, Murray ML. The potential of UK clinical databases in enhancing paediatric medication research. Br J Clin 4 Pharmacol 2005;59(6):750-5. doi: 10.1111/j.1365-2125.2005.02450.x [published Online First: 2005/06/14] 5 6 2. Rashed AN, Wong IC, Wilton L, et al. Drug Utilisation Patterns in Children Admitted to a Paediatric General Medical 7 Ward in Five Countries. Drugs - real world outcomes 2015;2(4):397-410. doi: 10.1007/s40801-015-0049-y 8 3. Sturkenboom MC, Verhamme KM, Nicolosi A, et al. Drug use in children: cohort study in three European countries. 9 Bmj 2008;337:a2245. doi: 10.1136/bmj.a2245 10 4. Chua KL, Soh SE, Ma S, et al. Pediatric asthma mortality and hospitalization trends across Asia pacific: relationship with 11 asthma drug utilization patterns. World Allergy Organ J 2009;2(5):77-82. doi: 10.1097/WOX.0b013e3181a7c288 12 [published Online First: 2009/05/01] 13 5. Jeon SM, Park S, Rhie SJ, et al. Prescribing patterns of polypharmacy in Korean pediatric patients. PLoS One 14 15 2019;14(10):e0222781. doi: 10.1371/journal.pone.0222781 [published Online First: 2019/10/02] 16 6. Cheng CL, Kao Yang YH, LiuFor CC, et al. Apeer retrospective review study on the usage only of cough and cold medications in viral 17 respiratory tract infections in Taiwanese children. Pharmacoepidemiol Drug Saf 2014;23(1):36-42. doi: 18 10.1002/pds.3460 [published Online First: 2013/05/29] 19 7. Lai EC, Ryan P, Zhang Y, et al. Applying a common data model to Asian databases for multinational 20 pharmacoepidemiologic studies: opportunities and challenges. Clin Epidemiol 2018;10:875-85. doi: 21 10.2147/CLEP.S149961 [published Online First: 2018/08/14] 22 8. As PENc, Andersen M, Bergman U, et al. The Asian Pharmacoepidemiology Network (AsPEN): promoting multi- 23 national collaboration for pharmacoepidemiologic research in Asia. Pharmacoepidemiol Drug Saf 24 25 2013;22(7):700-4. doi: 10.1002/pds.3439 [published Online First: 2013/05/09] 26 9. Chan EW, Lau WC, Leung WK, et al. Prevention of Dabigatran-Related Gastrointestinal Bleeding With Gastroprotective 27 Agents: A Population-Based Study. Gastroenterology 2015;149(3):586-95 e3. doi: 10.1053/j.gastro.2015.05.002 28 [published Online First: 2015/05/12] 29 10. Chui CS, Man KK, Cheng CL, et al. An investigation of the potential association between retinal detachment and oral 30 fluoroquinolones: a self-controlled case series study. The Journal of antimicrobial chemotherapy 31 2014;69(9):2563-7. doi: 10.1093/jac/dku145 [published Online First: 2014/05/17] 32 11. Man KK, Chan EW, Coghill D, et al. Methylphenidate and the risk of trauma. Pediatrics 2015;135(1):40-8. doi: 33 34 10.1542/peds.2014-1738 [published Online First: 2014/12/17] 35 12. Tanaka S, Seto K, Kawakami K. Pharmacoepidemiology in Japan: medical databases and research achievements. 36 Journal of Pharmaceutical Health Care and Sciences 2015;1(1):16. doi: 10.1186/s40780-015-0016-5 37 13. Lai EC, Man KK, Chaiyakunapruk N, et al. Brief Report: Databases in the Asia-Pacific Region: The Potential for a 38 Distributed Network Approach. Epidemiology 2015;26(6):815-20. doi: 10.1097/EDE.0000000000000325 39 [published Online First: 2015/07/02] 40 14. Rose K, Stötter H. ICH E 11: clinical investigation of medicinal products in the paediatric population. In: Rose K, JN 41 vdA, eds. Guide to paediatric clinical research. Basel: KArger 2007:33-37. 42 43 15. Woo Y, Kim HE, Chung S, et al. Pediatric medication error reports in Korea adverse event reporting system database, 44 1989-2012: comparing with adult reports. Journal of Korean medical science 2015;30(4):371-7. doi: 45 10.3346/jkms.2015.30.4.371 46 16. Taiwan Food and Drugs Administration. 2016 Taiwan Food and Drug Administration Annual Report. [updated 47 October 2016. Available from: http://www.fda.gov.tw/upload/ebook/AnnuaReport/2016. 48 17. Sato J. Global Pediatric Development: We Are Making Progress. PMDA Perspective.: Japanese Pharmaceuticals and 49 Medical Devices Agency (PMDA), 2014. 50 18. Mallet P, Mourdi N, Dubus JC, et al. Respiratory paradoxical adverse drug reactions associated with acetylcysteine 51 and carbocysteine systemic use in paediatric patients: a national survey. PLoS One 2011;6(7):e22792. doi: 52 53 10.1371/journal.pone.0022792 54 19. European Medicines Agency (EMA). Revised assessment report: Ambroxol and bromhexine containing medicinal 55 products. 10 September 2015. [Available from: 56 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ambroxol_and_bromhexine_ 57 31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500184106.pdf 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 76

20. Schmiedl S, Fischer R, Ibanez L, et al. Utilisation and off-label prescriptions of respiratory drugs in children. PLoS One 1 2014;9(9):e105110. doi: 10.1371/journal.pone.0105110 2 3 21. Arakawa H, Hamasaki Y, Kohno Y, et al. Japanese guidelines for childhood asthma 2017. Allergology international : 4 official journal of the Japanese Society of Allergology 2017 doi: 10.1016/j.alit.2016.11.003 5 22. European Medicines Agency (EMA). Opinion of the Paediatric Committee on the refusal of a Paediatric Investigation 6 Plan and on the granting of a product-specific waiver. 6 July 2010. [cited 2017 February 27]. Available from: 7 http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500095327.pdf. 8 23. European Medicines Agency (EMA). Assessment report: Codeine containing medicinal products for the treatment of 9 cough and/or cold in paediatric patients. 12 March 2015. [Available from: 10 http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Codeine_cough_or_cold_in_c 11 hildren/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500186522.pdf. 12 13 24. Ciszkowski C, Madadi P, Phillips MS, et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. The 14 New England journal of medicine 2009;361(8):827-8. doi: 10.1056/NEJMc0904266 15 25. British National Formulary (BNF). CLARITHROMYCIN [updated 30-03-2017. Available from: 16 https://www.evidence.nhs.uk/formulary/bnf/current/5-infections/51-antibacterial-drugs/515-For peer review only 17 macrolides/clarithromycin. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 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 Page 21 of 76 BMJ Open

Tables and Figures 1 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 22 of 76 Table 1. Patient characteristics, person years and number of prescription by age and calendar year 1 Korea (AUSOM) Hong Kong (CDARS)* Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 2 (n = 220,076) (n = 18,634) (n = 913,006) (n = 235,214) (n = 187,594) 3 Total number of person years 259,750 71,502 3,006,825 630,051 774,420 4 Gender (number of children/ 5 6 number of person years[%]) 7 Female 98,921/ 8,389/ 433,918/ 113,179/ 87,129/ 8 115,868 (44.61) 31,433 (43.96) 1,459,304 (48.53) 301,824 (47.90) 360,099 (46.50) 9 Male 121,155/ 9,656/ 479,088/ 122,035/ 100,465/ 10 143,882 (55.39) 36,875 (51.57) 1,547,521 (51.47) 328,226 (52.10) 414,322 (53.50) 11 Age (number of children/ 12 number of person years [%]) For peer review only 13 <2 years 69,121/ 5,758/ 175,070/ 31,659/ 62,021/ 14 15 32,909 (12.7) 7,937 (11.1) 304,672 (10.1) 42,445 (6.7) 86,181 (11.1) 16 2-11 years 122,177/ 11,120/ 448,008/ 133,727/ 138,714/ 17 152,352 (58.7) 34,767 (48.6) 1,613,909 (53.7) 305,543 (48.5) 462,755 (59.8) 18 12-18 years 60,230/ 9,458/ 348,343/ 131,969/ 86,051/ 19 74,489 (28.7) 28,798 (40.3) 1,088,244 (36.2) 282,063 (44.8) 225,484 (29.1) 20 Calendar year (number of children/ 21 number of person years [%]) 22 2009 109,462/ 14,797/ 519,973/ 228,059/ 165,735/ 23 72,472 (27.9) 14,148 (19.8) 311,734 (10.4) 216,660 (34.4) 149,157 (19.3) 24 25 2010 101,055/ 14,843/ 573,486/ 221,661/ 168,702/ 26 66,090 (25.4) 14,147 (19.8) 644,681 (21.4) 211,666 (33.6) 152,689 (19.7) 27 2011 93,416/ 15,001/ 590,384/ 208,643/ 171,233/ 28 57,515 (22.1) 14,274 (20.0) 665,955 (22.2) 201,725 (32.0) 155,597 (20.1) 29 2012 83,504/ 15,215/ 594,331/ 172,842/ 30 44,161 (17.1) 14,459 (20.2) 686,775 (22.8) 158,117 (20.4) 31 2013 51,575/ 15,182/ 589,192/ 173,286/ 32 19,512 (7.5) 14,475 (20.2) 697,680 (23.2) 158,861 (20.5) 33 34 Number of drugs dispensed 35 (inpatient) 36 Total 3,126,567 48,166 5,311,981 361,985 - 37 <2 years, n (%) 1,354,036 (43.3) 17,816 (37.0) 2,523,959 (47.5) 92,518 (25.6) - 38 2-11 years, n (%) 1,158,851 (37.1) 12,852 (26.7) 1,980,742 (37.3) 156,401 (43.2) - 39 40 12-18 years, n (%) 613,680 (19.6) 17,498 (36.3) 807,280 (15.2) 113,066 (31.2) - 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 23 of 76 BMJ Open

Number of drugs dispensed 1 (ambulatory) 2 3 Total - 19,511,710 23,520,356 1,620,805 4 <2 years, n (%) - 1,346,903 (6.9) 2,880,951 (12.2) 187,486 (11.5) 5 2-11 years, n (%) - 14,036,081 (71.9) 14,984,130 (63.7) 950,984 (58.7) 6 12-18 years, n (%) - 5,655,275 (24.0) 482,335 (29.8) 7 4,128,726 (21.2) 8 9 *For 589 children in CDARS gender was not recorded at admission 10 11 12 For peer review only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 24 of 76 Table 2a. User prevalence & prescription prevalence and in an inpatient setting by therapeutic level: Prevalence per 1000 persons Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 Class* User Prescription User Prescription User Prescription User Prescription 2 prevalence prevalence prevalence prevalence prevalence prevalence prevalence prevalence 3 (%)** (%)*** (%)** (%)*** (%)** (%)*** (%)** (%)*** 4 Analgesics (inc. NSAIDs) 109 (23) 1269 (23) 131 (36) 314 (19) 31 (19) 380 (24) 43 (25) 195 (23) 5 6 Antibiotics 107 (22) 1141 (20) 91 (25) 634 (37) 43 (26) 496 (31) 37 (21) 233 (27) 7 8 Adrenergics 65 (14) 520 (9) 31 (9) 101 (6) 23 (14) 161 (10) 23 (13) 110 (13) 9 10 Antihistamines 53 (11) 520 (9) 55 (15) 136 (8) 11 (7) 48 (3) 23 (13) 77 (9) 11 12 Mucolytics 53 (11) For614 (11) peer4 (1) review7 (0) 22 (13) only168 (11) 19 (11) 69 (8) 13 14 Corticosteroids 45 (9) 425 (8) 21 (6) 89 (5) 15 (9) 89 (6) 18 (10) 72 (8) 15 16 Antiinfectives (excluding 9 (2) 130 (2) 14 (4) 48 (3) 2 (1) 28 (2) 2 (1) 15 (2) 17 antibiotics and vaccines) 18 Antiepileptics 8 (2) 431 (8) 3 (1) 36 (2) 2 (1) 27 (2) 2 (1) 23 (3) 19 20 Diuretics 8 (2) 170 (3) 3 (1) 39 (2) 2 (1) 42 (3) 2 (1) 14 (2) 21 22 Anticlotting and 7 (1) 188 (3) 1 (0) 25 (1) 12 (7) 99 (6) 2 (1) 8 (1) 23 antifibrinolytic agents 24 Antidiabetic drugs 4 (1) 19 (0) 0 (0) 7 (0) 1 (1) 4 (0) 1 (1) 5 (1) 25 26 Psychotherapeutic agents 2 (0) 65 (1) 3 (1) 138 (8) 2 (1) 17 (1) 1 (1) 14 (2) 27 28 Antineoplastic and 2 (0) 100 (2) 1 (0) 61 (4) 1 (1) 26 (2) 0 (0) 14 (2) 29 immunomodulating 30 agents 31 Central nervous system 1 (0) 20 (0) 2 (1) 62 (4) 0 (0) 2 (0) 0 (0) 3 (0) 32 stimulants 33 Contraceptives 0 (0) 2 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 34 35 Total 473 (100%) 5614 (100%) 360 (100%) 1697 (100%) 167 (100%) 1587 (100%) 173 (100%) 852 (100%) 36 37 38 *custom classification, see Supplemental Material 1 39 **For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific user prevalence (class 40 specific user prevalence/ total user prevalence) 41 *** For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific prescription 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 76 BMJ Open

prevalence (class specific prescription prevalence/ total prescription prevalence) 1 2 Table 2b. User prevalence & prescription prevalence and in an ambulatory setting by therapeutic level (prevalence per 1000 persons) 3 Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 4 5 Class* User prevalence Prescription User prevalence Prescription User prevalence Prescription 6 (%)** prevalence (%)** prevalence (%)** prevalence 7 (%)*** (%)*** (%)*** 8 Antibiotics 440 (22) 882 (25) 796 (14) 2010 (8) 679 (46) 918 (52) 9 10 Corticosteroids 401 (20) 954 (27) 701 (13) 1352 (6) 348 (23) 281 (16) 11 12 Analgesics (inc. NSAIDs) For333 (16) peer428 (12) review933 (17) only5889 (24) 96 (6) 61 (3) 13 14 Adrenergics 242 (12) 405 (11) 814 (15) 4666 (19) 184 (12) 193 (11) 15 16 Antihistamines 261 (13) 415 (12) 883 (16) 6246 (26) 3 (0) 1 (0) 17 18 Mucolytics 240 (12) 353 (10) 756 (14) 3053 (13) 0 (0) 0 (0) 19 Antiinfectives (excluding antibiotics 20 91 (4) 60 (2) 490 (9) 842 (3) 72 (5) 25 (1) 21 and vaccines) 22 Contraceptives 1 (0) 1 (0) 23 (0) 17 (0) 34 (2) 27 (2) 23 24 Psychotherapeutic agents 2 (0) 7 (0) 23 (0) 41 (0) 33 (2) 86 (5) 25 26 Central nervous system stimulants 3 (0) 5 (0) 20 (0) 65 (0) 25 (2) 117 (7) 27 Antineoplastic and 28 4 (0) 7 (0) 9 (0) 15 (0) 1 (0) 3 (0) immunomodulating agents 29 30 Antiepileptics 2 (0) 5 (0) 15 (0) 44 (0) 6 (0) 41 (2) 31 32 Anticlotting and antifibrinolytic agents 3 (0) 2 (0) 13 (0) 10 (0) 1 (0) 2 (0) 33 34 Diuretics 0 (0) 1 (0) 4 (0) 5 (0) 2 (0) 2 (0) 35 36 Antidiabetic drugs 0 (0) 1 (0) 2 (0) 8 (0) 3 (0) 5 (0) 37 38 Total 2023 (100%) 3526 (100%) 5482 (100%) 24263 (100%) 1487 (100%) 1762 (100%) 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 26 of 76

*custom classification, see Supplemental Material 1 1 2 **For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific user prevalence (class specific user 3 prevalence/ total user prevalence) 4 *** For all 15 different drug classes the prevalence per 1000 persons was calculated as % of the total country specific prescription prevalence (class specific 5 prescription prevalence/ total prescription prevalence) 6 7 8 9 10 11 12 For peer review only 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 27 of 76 BMJ Open

Table 3a. Most commonly used drugs per custom defined drug class, per country, in an inpatient setting 1 2 Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 3 Drug name Number Drug name Number Drug name Number Drug name Number per 4 per 1000 per 1000 per 1000 1000 users 5 users users users 6 Antibiotics Ceftriaxone 27.02 Amoxicillin 34.08 Cefazolin 10.09 Cefazolin 15.17 7 Roxithromycin 19.03 Gentamicin Sulfate 18.09 Ampicillin 9.2 Amoxicillin 10.9 8 9 Cefotaxime 17.11 Penicillin G 14.33 Sulbactam 5.56 Gentamicin Sulfate 8.79 10 Ofloxacin 16.84 Cefuroxime 12.72 Clarithromycin 5.25 Ampicillin 7 11 Clarithromycin 10.9 Ampicillin 12.4 Cefcapene 4.61 Cephalexin 6.64 12 Analgesics (inc. Paracetamol For50.94 peerParacetamol review127.67 Paracetamol only 19.32 Paracetamol 30.17 13 14 NSAIDs) Ibuprofen 50.45 Tramadol 4.99 Remifentanil 7.34 Diclofenac 17.94 15 Tramadol 28.9 Ibuprofen 4.78 Flurbiprofen 5.2 Ibuprofen 15.07 16 Fentanyl 26.85 Diclofenac 1.66 Loxoprofen 4.39 Meperidine 5.21 17 Ketorolac 19.11 Aspirin 1.29 Pentazocine 3.91 Ketorolac 4.81 18 19 Adrenergics Formoterol 27.63 Salbutamol 22.81 Tulobuterol 10.32 Terbutaline 8.09 20 Epinephrine 26.85 Pseudoephedrine 6.01 Procaterol 8.12 Pseudoephedrine 7.79 21 Phenylephrine 14.97 Propranolol 1.02 Salbutamol 7.51 Procaterol 7.5 22 Salbutamol 14.64 Terbutaline 0.97 Epinephrine 4.62 Fenoterol 4.97 23 24 Pseudoephedrine 6.12 Phenylephrine 0.59 Ephedrine 1.8 Salbutamol 4.74 25 Antihistamines Chlorpheniramine 51.7 Chlorpheniramine 38.37 Cyproheptadine 5.23 Cyproheptadine 14.26 26 Ketotifen 4.02 Diphenhydramine 19.59 Epinastine 1.24 Chlorpheniramine 4.4 27 Levocetirizine 1.85 Triprolidine 6.01 Ketotifen 1.12 Diphenhydramine 3.01 28 29 Ebastine 1.23 Promethazine 2.36 Diphenhydramine 1 Brompheniramine 1.94 30 Fexofenadine 1 Cetirizine 0.8 Mequitazine 0.77 Cetirizine 1.91 31 Mucolytics Bromhexine 39.3 Bromhexine 2.09 Carbocysteine 18.93 Acetylcysteine 11.04 32 Acetylcysteine 24.28 Acetylcysteine 1.02 Ambroxol 8.23 Ambroxol 7.18 33 34 Mannitol 4.7 Carbocysteine 0.48 Bromhexine 4.6 Bromhexine 3.32 35 Erdosteine 3.54 Mesna 0.27 Acetylcysteine 0.21 Mannitol 1.16 36 Carbocysteine 0.69 - - Eprazinone 0.17 Carbocysteine 0.22 37 Corticosteroids Dexamethasone 23.48 Prednisolone 9.34 prednisolone 4.09 Prednisolone 4.92 38 39 Budesonide 15.45 Hydrocortisone 7.89 Methylprednisolone 3.95 Hydrocortisone 4.61 40 Prednisolone 12.11 Beclomethasone 3.6 Dexamethasone 3.36 Dexamethasone 4.4 41 Hydrocortisone 10.15 Dexamethasone 2.9 Hydrocortisone 3.17 Triamcinolone 4.13 42 Prednicarbate 7.74 Budesonide 1.29 Betamethasone 1.95 Methylprednisolone 3.61 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 28 of 76

Drug class Korea (AUSOM) Hong Kong (CDARS) Japan (JMDC) Taiwan (NHIRD) 1 2 3 Antiinfectives Oseltamivir 3.27 Hep.B hyp. globulin 4.35 Oseltamivir 0.5 Lysozyme 0.62 4 Acyclovir 2.53 Oseltamivir 2.84 lysozyme 0.31 Nystatin 0.54 5 Fluconazole 1.3 Acyclovir 2.15 palivizumab 0.26 Fluconazole 0.37 6 Palivizumab 0.55 Clotrimazole 2.09 Acyclovir 0.24 Clotrimazole 0.29 7 Itraconazole 0.49 Nystatin 1.82 Fluconazole 0.2 Acyclovir 0.24 8 9 Anticlotting and Heparin 5.98 Heparin 0.91 Heparin 11.5 Heparin 1.33 10 antifibrinolytic Antithrombin III 1.59 Dipyridamole 0.32 Dipyridamole 0.28 Streptokinase 0.19 11 agents Streptokinase 0.6 Urokinase 0.27 Warfarin 0.25 Urokinase 0.11 12 Urokinase For0.54 peerWarfarin review0.16 Antithrombin only III 0.24 Dipyridamole 0.1 13 14 Enoxaparin 0.1 Enoxaparin 0.11 Urokinase 0.07 Warfarin 0.06 15 Antiepileptics Phenobarbital 3.64 Phenobarbital 1.18 Phenobarbital 0.95 Phenytoin 0.66 16 Levetiracetam 2.58 Phenytoin 0.7 Carbamazepine 0.63 Phenobarbital 0.59 17 Lamotrigine 2.41 Carbamazepine 0.64 Zonisamide 0.15 Clonazepam 0.51 18 19 Topiramate 1.38 Levetiracetam 0.59 Levetiracetam 0.14 Oxcarbazepine 0.23 20 Fosphenytoin 0.8 Topiramate 0.32 Clonazepam 0.14 Topiramate 0.19 21 Diuretics Furosemide 6.54 Furosemide 2.41 Furosemide 1.78 Furosemide 1.58 22 Spironolactone 1.32 Spironolactone 1.45 Spironolactone 0.87 Spironolactone 0.17 23 24 Theobromine 1.2 Hydrochlorothiazide 0.43 Trichlormethiazide 0.06 Bumetanide 0.03 25 Hydrochlorothiazide 0.08 - Hydrochlorothiazide 0.02 Trichlormethiazide 0.02 26 - - Torsemide 0.02 Amiloride 0.01 27 Psychotherapeutic Haloperidol 0.58 Risperidone 1.34 Droperidol 0.79 Haloperidol 0.34 28 agents 29 Risperidone 0.52 Haloperidol 1.02 Chlorpromazine 0.37 Risperidone 0.2 30 Quetiapine 0.42 Fluoxetine 0.75 Risperidone 0.26 Quetiapine 0.13 31 Escitalopram 0.3 Olanzapine 0.48 olanzapine 0.11 Aripiprazole 0.09 32 Fluoxetine 0.28 Sertraline 0.43 Haloperidol 0.1 Sulpiride 0.08 33 34 Antineoplastic & Filgrastim 0.68 Vincristine 0.43 Methotrexate 0.16 Methotrexate 0.2 35 immunomodulating Methotrexate 0.5 Doxorubicin 0.38 Vincristine 0.14 Cytarabine 0.16 36 agents Cyclophosphamide 0.45 Methotrexate 0.32 Cyclophosphamide 0.14 Filgrastim 0.16 37 Vincristine 0.35 Cyclophosphamide 0.32 Tacrolimus 0.13 Vincristine 0.14 38 39 Cyclosporine 0.34 Cytarabine 0.32 Cyclosporine 0.13 Cyclophosphamide 0.14 40 Central nervous Caffeine 0.66 Caffeine 1.4 Caffeine 0.1 Piracetam 0.27 41 system stimulants Methylphenidate 0.23 Methylphenidate 0.8 Atomoxetine 0.03 Methylphenidate 0.08 42 Acetylcarnitine 0.05 Tomoxetine 0.11 Methylphenidate 0.02 atomoxetine <0.01 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 76 BMJ Open

Drug class Korea (AUSOM) Hong Japan (JMDC) Taiwan Drug Korea (AUSOM) Hong Kong 1 Kong (NHIRD) class (CDARS) 2 3 (CDARS) 4 Antidiabetic drugs Regular Insulin 3.24 Metformin 0.27 Regular Insulin 0.5 Regular Insulin 0.54 5 Insulin Detemir 0.32 Insulin Detemir 0.11 Insulin Glargine 0.06 Insulin Glargine 0.09 6 Insulin Glargine 0.12 Gliclazide 0.11 Insulin Lispro 0.04 Metformin 0.05 7 Metformin 0.06 - Metformin 0.01 Insulin Detemir 0.04 8 9 Insuline Glulisine 0.05 - Insuline Glulisine 0.01 Glimepiride 0.01 10 Contraceptives Megestrol 0.16 Levonorgestrel 0.16 Norethindrone <0.01 Medroxyprogeste 0.02 11 Medroxyprogeste 0.04 Medroxyprogeste 0.05 Medroxyprogeste <0.01 Megestrol 0.01 12 - For peerNorethindrone review0.05 - only - 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 30 of 76

Table 3b. Most commonly used drugs per custom defined drug class, per country, in an ambulatory setting 1 2 Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 3 Drug name Number Drug name Number Drug name Number 4 per 1000 per per 1000 5 users 1000 users 6 users 7 Antibiotics Clarithromycin 112.34 Amoxicillin 443.86 Amoxicillin 506.88 8 9 Gentamicin 109.87 Cephalexin 276.72 Cephalexin 279.23 10 Cefcapene 84.12 Sulfamethoxazole 217.87 Chloramphenicol 148.45 11 Gentamicin Sulfate 73.38 Erythromycin 170.63 Erythromycin 147.04 12 Ofloxacin 72.45 Clindamycin 168.23 Cefaclor 116.35 13 14 Corticosteroids Betamethasone 232.34 Betamethasone 353.29 Prednisolone 165.53 15 Dexamethasone 154.65 Dexamethasone 285.17 Hydrocortisone 83.38 16 HydrocortisoneFor peer64.61 reviewTriamcinolone only198.38 fluticasone 71.28 17 Prednisolone 60.3 Prednisolone 194.59 Betamethasone 65.42 18 19 Fluorometholone 57.76 Fluorometholone 180.39 Dexamethasone 63.29 20 Analgesics (inc. Paracetamol 253.67 Paracetamol 879.68 Paracetamol 72.78 21 NSAIDs) Loxoprofen 63.76 Diclofenac 679.67 Codeine 27.87 22 Salicylamide 42.91 Ibuprofen 615.18 Ibuprofen 9.71 23 24 Dihydrocodeine 34.9 Codeine 194.02 Oxycodone 6.08 25 Ketoprofen 31.47 Naproxen 101.18 Diclofenac 4.85 26 Antihistamines Cyproheptadine 75.51 Dexchlorpheniramine 461.81 Cyproheptadine 3.11 27 Ketotifen 57.63 Cyproheptadine 442.32 Promethazine 0.07 28 29 Olopatadine 48.02 Cetirizine 381.81 - - 30 Clemastine 46.31 Mequitazine 338.95 - - 31 Mequitazine 35.14 Chlorpheniramine 309.08 - - 32 Adrenergics Tulobuterol 103.78 Pseudoephedrine 728.27 Salbutamol 164.14 33 34 Epinephrine 86.05 Fenoterol 301.3 Salmeterol 32.61 35 Procaterol 70.65 Procaterol 279.84 Clonidine 9.54 36 Salbutamol 57.82 Tretoquinol 209.47 Epinephrine 4.15 37 Phenylephrine 9.87 Terbutaline 177.29 Terbutaline 3.04 38 39 Mucolytics Carbocysteine 175.47 Ambroxol 546.33 Dornase Alfa 0.19 40 Ambroxol 78.67 Bromhexine 335.46 Mannitol 0.01 41 Bromhexine 49.24 Eprazinone 274.49 Acetylcysteine 0.01 42 Eprazinone 8.95 Acetylcysteine 265.77 Mesna 0.01 43 44 Acetylcysteine 8.46 Carbocysteine 197.11 - - 45 Antiinfectives Oseltamivir 41.17 Lysozyme 377.54 Nystatin 63.5 46 Lysozyme 25.34 Oseltamivir 73.71 Acyclovir 1.78 47 Acyclovir 14.65 Econazole 44.27 Terbinafine 1.43 48 49 Vidarabine 6.63 Clotrimazole 29.53 Amphotericin B 1.41 50 Valacyclovir 5.05 Ketoconazole 29 Ketoconazole 1.4 51 Psychotherapeutic Risperidone 0.72 Sulpiride 7.64 Fluoxetine 9 52 agents Sulpiride 0.37 Imipramine 3.24 Risperidone 6.59 53 54 Imipramine 0.32 Doxepin 2.27 Sertraline 5.8 55 Aripiprazole 0.32 Fluoxetine 2.12 Escitalopram 4.3 56 Fluvoxamine 0.27 Risperidone 2.06 Amitriptyline 3.4 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 76 BMJ Open

Drug class Japan (JMDC) Taiwan (NHIRD) Australia (PBS) 1 2 Contraceptives Norethindrone 0.48 Norethindrone 15.18 Levonorgestrel 26.22 3 Medroxyprogesterone 0.29 Medroxyprogesterone 9.53 Etonogestrel 7.82 4 - - Lynestrenol 0.09 Medroxyprogesterone 4.81 5 - - Megestrol <0.01 Norethindrone 3.73 6 7 - - - - Megestrol 0.01 8 Central nervous Caffeine 2.11 Methylphenidate 13.54 Methylphenidate 21.24 9 system stimulants Methylphenidate 0.68 Piracetam 3.22 Dextroamphetamine 6.09 10 Atomoxetine 0.32 Caffeine 3.2 Atomoxetine 3.28 11 12 Modafinil 0.01 Atomoxetine 1.36 Modafinil 0.02 13 Citicoline 0.01 Modafinil 0.02 - - 14 Antineoplastic and Tacrolimus 3.44 Tretinoin 6.81 Methotrexate 0.52 15 immunomodulating Cyclosporine 0.26 Tacrolimus 0.93 Azathioprine 0.29 16 agents For peer review only 17 Leuprolide 0.21 Methotrexate 0.38 Mercaptopurine 0.2 18 Methotrexate 0.09 Azathioprine 0.29 Cyclosporine 0.16 19 Vincristine 0.08 Leuprolide 0.15 Tacrolimus 0.15 20 Antiepileptics Phenobarbital 1.19 Phenobarbital 9.4 Carbamazepine 2.51 21 22 Carbamazepine 0.63 Clonazepam 2.56 Lamotrigine 1.47 23 Zonisamide 0.15 Oxcarbazepine 0.99 Levetiracetam 1.18 24 Clonazepam 0.15 Carbamazepine 0.99 Topiramate 1.09 25 Levetiracetam 0.13 Topiramate 0.98 Phenytoin 0.41 26 27 Anticlotting and Heparin 2.66 Streptokinase 9.55 Warfarin 0.42 28 antifibrinolytic Dipyridamole 0.12 Dipyridamole 1.82 Enoxaparin 0.27 29 agents Warfarin 0.11 Heparin 0.94 Clopidogrel 0.14 30 Beraprost 0.04 Epoprostenol 0.16 Dipyridamole 0.02 31 32 Ticlopidine 0.02 Warfarin 0.12 Dalteparin 0.01 33 Diuretics Furosemide 0.42 Furosemide 1.78 Furosemide 0.82 34 Spironolactone 0.27 Spironolactone 1.52 Spironolactone 0.51 35 Trichlormethiazide 0.02 Hydrochlorothiazide 0.49 Hydrochlorothiazide 0.51 36 37 Hydrochlorothiazide 0 Trichlormethiazide 0.4 Indapamide 0.12 38 Torsemide 0 Bumetanide 0.06 Amiloride 0.03 39 Antidiabetic drugs Regular Insulin, 0.09 Metformin 0.76 Metformin 1.46 40 Human 41 Insulin Glargine 0.07 Gliclazide 0.49 Insulin Glargine 0.98 42 43 Insulin Lispro 0.04 Regular Insulin, 0.36 Regular Insulin, 0.79 44 Human Human 45 Metformin 0.01 Tolbutamide 0.26 Insulin Detemir 0.64 46 Voglibose 0.01 Acarbose 0.25 Insulin Lispro 0.22 47 48 *custom classification, see Supplemental Material 1 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 32 of 76

Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 1 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 2 3 4 5 6 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 34 35 36 37 38 39 40 41 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 Page 33 of 76 BMJ Open

1 2 3 4 5 6 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 Figure 1: User prevalence by therapeutic level (prevalence per 1000 persons) and age in an inpatient setting 33 34 35 36 37 38 39 40 41 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 34 of 76

1 2 3 4 5 6 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 34 35 36 37 38 39 Figure 2: User prevalence by therapeutic level (prevalence per 1000 persons) and gender in an ambulatory setting 40 41 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 Page 35 of 76 BMJ Open

1 2 3 Concept ID Name Class 4 5 1319998 Acebutolol Adrenergics 6 1154343 Albuterol Adrenergics 7 930021 alfuzosin Adrenergics 8 919986 apraclonidine Adrenergics 9 10 1111220 arformoterol Adrenergics 11 1314002 Atenolol Adrenergics 12 19034275 bambuterol Adrenergics 13 1322081 Betaxolol Adrenergics 14 15 1338005 Bisoprolol Adrenergics 16 915542 brimonidine Adrenergics 17 21603320 carbuterol Adrenergics 18 950370 CarteololFor peer review onlyAdrenergics 19 20 1346823 carvedilol Adrenergics 21 19097824 Clenbuterol Adrenergics 22 1398937 Clonidine Adrenergics 23 19086622 dapiprazole Adrenergics 24 25 19061088 Dexmedetomidine Adrenergics 26 990009 Dipivefrin Adrenergics 27 1337720 Dobutamine Adrenergics 28 1363053 Doxazosin Adrenergics 29 30 1143374 Ephedrine Adrenergics 31 1343916 Epinephrine Adrenergics 32 19063575 esmolol Adrenergics 33 19053979 Fenoterol Adrenergics 34 35 1196677 formoterol Adrenergics 36 1366237 Guanabenz Adrenergics 37 1344965 Guanfacine Adrenergics 38 19068969 Hexoprenaline Adrenergics 39 40 1181809 Isoetharine Adrenergics 41 21603309 isoprenaline, combinations Adrenergics 42 1183554 Isoproterenol Adrenergics 43 1386957 Labetalol Adrenergics 44 45 1192218 Levalbuterol Adrenergics 46 932815 Levobunolol Adrenergics 47 1123995 metaproterenol Adrenergics 48 19009365 methoxyphenamine Adrenergics 49 50 1305447 Methyldopa Adrenergics 51 905531 Metipranolol Adrenergics 52 1307046 Metoprolol Adrenergics 53 1308368 Midodrine Adrenergics 54 55 42873636 mirabegron Adrenergics 56 1313200 Nadolol Adrenergics 57 21603310 orciprenaline, combinations Adrenergics 58 19026274 p-Hydroxyamphetamine Adrenergics 59 60 1327978 Penbutolol Adrenergics

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1 2 3 1335301 Phenoxybenzamine Adrenergics 4 5 1335539 Phentolamine Adrenergics 6 1135766 Phenylephrine Adrenergics 7 1345858 Pindolol Adrenergics 8 1125449 pirbuterol Adrenergics 9 10 1350489 Prazosin Adrenergics 11 19028950 Procaterol Adrenergics 12 1353766 Propranolol Adrenergics 13 1154332 Pseudoephedrine Adrenergics 14 15 19035396 reproterol Adrenergics 16 1137529 salmeterol Adrenergics 17 19012925 silodosin Adrenergics 18 924566 tamsulosinFor peer review onlyAdrenergics 19 20 1341238 Terazosin Adrenergics 21 1236744 Terbutaline Adrenergics 22 21603325 terbutaline, combinations Adrenergics 23 902427 Timolol Adrenergics 24 25 778474 tizanidine Adrenergics 26 21603319 tretoquinol Adrenergics 27 19043191 tulobuterol Adrenergics 28 43532539 vilanterol Adrenergics 29 30 19029393 aceclofenac Analgesics (inc. NSAIDs) 31 19029398 acemetacin Analgesics (inc. NSAIDs) 32 1125315 Acetaminophen Analgesics (inc. NSAIDs) 33 21603946 alclofenac Analgesics (inc. NSAIDs) 34 35 19059528 Alfentanil Analgesics (inc. NSAIDs) 36 19018431 alminoprofen Analgesics (inc. NSAIDs) 37 1103552 almotriptan Analgesics (inc. NSAIDs) 38 19018432 aloxiprin Analgesics (inc. NSAIDs) 39 aminophenazone, combinations excl. 40 21604337 psycholeptics Analgesics (inc. NSAIDs) 41 aminophenazone, combinations with 42 21604341 psycholeptics Analgesics (inc. NSAIDs) 43 44 19125628 Aminopyrine Analgesics (inc. NSAIDs) 45 1036059 Antipyrine Analgesics (inc. NSAIDs) 46 19136654 Apazone Analgesics (inc. NSAIDs) 47 1112807 Aspirin Analgesics (inc. NSAIDs) 48 49 40254364 avocado and soyabean oil, unsaponifiables Analgesics (inc. NSAIDs) 50 19016435 benorilate Analgesics (inc. NSAIDs) 51 21603972 benoxaprofen Analgesics (inc. NSAIDs) 52 19019620 Benzydamine Analgesics (inc. NSAIDs) 53 54 21604279 bezitramide Analgesics (inc. NSAIDs) 55 1139179 bromfenac Analgesics (inc. NSAIDs) 56 21604346 bucetin Analgesics (inc. NSAIDs) 57 21604350 bucetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 58 59 21604353 bucetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 60 19032724 Bufexamac Analgesics (inc. NSAIDs)

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1 2 3 19039703 bumadizone Analgesics (inc. NSAIDs) 4 5 1133201 Buprenorphine Analgesics (inc. NSAIDs) 6 1133732 Butorphanol Analgesics (inc. NSAIDs) 7 21604363 cannabinoids Analgesics (inc. NSAIDs) 8 21604318 carbasalate calcium Analgesics (inc. NSAIDs) 9 carbasalate calcium combinations excl. 10 21604324 psycholeptics Analgesics (inc. NSAIDs) 11 12 1118084 celecoxib Analgesics (inc. NSAIDs) 13 1395573 Chondroitin Sulfates Analgesics (inc. NSAIDs) 14 19018512 clofezone Analgesics (inc. NSAIDs) 15 1201620 Codeine Analgesics (inc. NSAIDs) 16 17 21604268 codeine, combinations with psycholeptics Analgesics (inc. NSAIDs) 18 21603980 dexibuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 19056874 Dexketoprofen Analgesics (inc. NSAIDs) 20 19021940 Dextromoramide Analgesics (inc. NSAIDs) 21 dextropropoxyphene, combinations with 22 21604282 psycholeptics Analgesics (inc. NSAIDs) 23 24 19088393 dezocine Analgesics (inc. NSAIDs) 25 19088915 diacetylrhein Analgesics (inc. NSAIDs) 26 21604262 DIAMORPHINE Analgesics (inc. NSAIDs) 27 1124300 Diclofenac Analgesics (inc. NSAIDs) 28 29 21603952 difenpiramide Analgesics (inc. NSAIDs) 30 1126128 Diflunisal Analgesics (inc. NSAIDs) 31 1189596 dihydrocodeine Analgesics (inc. NSAIDs) 32 1126557 Dihydroergotamine Analgesics (inc. NSAIDs) 33 34 21604370 dihydroergotamine, combinations Analgesics (inc. NSAIDs) 35 21604313 dipyrocetyl Analgesics (inc. NSAIDs) 36 21604323 dipyrocetyl, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 37 21604328 dipyrocetyl, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 39 19056645 droxicam Analgesics (inc. NSAIDs) 40 1189697 eletriptan Analgesics (inc. NSAIDs) 41 1145379 Ergotamine Analgesics (inc. NSAIDs) 42 21604372 ergotamine, combinations with psycholeptics Analgesics (inc. NSAIDs) 43 44 19059506 ethenzamide Analgesics (inc. NSAIDs) 45 21604322 ethenzamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 46 21604327 ethenzamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 47 1195492 Etodolac Analgesics (inc. NSAIDs) 48 49 19011355 etoricoxib Analgesics (inc. NSAIDs) 50 19095703 fenbufen Analgesics (inc. NSAIDs) 51 1153928 Fenoprofen Analgesics (inc. NSAIDs) 52 1154029 Fentanyl Analgesics (inc. NSAIDs) 53 54 21603950 fentiazac Analgesics (inc. NSAIDs) 55 19135796 Feprazone Analgesics (inc. NSAIDs) 56 21604014 feprazone, combinations Analgesics (inc. NSAIDs) 57 19054931 floctafenine Analgesics (inc. NSAIDs) 58 59 19110711 Flufenamic Acid Analgesics (inc. NSAIDs) 60 21604374 flumedroxone Analgesics (inc. NSAIDs)

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1 2 3 21603981 flunoxaprofen Analgesics (inc. NSAIDs) 4 5 19064698 flupirtine Analgesics (inc. NSAIDs) 6 1156378 Flurbiprofen Analgesics (inc. NSAIDs) 7 19113015 fonazine Analgesics (inc. NSAIDs) 8 1189458 frovatriptan Analgesics (inc. NSAIDs) 9 10 21604356 glafenine Analgesics (inc. NSAIDs) 11 1360332 Glucosamine Analgesics (inc. NSAIDs) 12 21604004 glucosaminoglycan polysulfate Analgesics (inc. NSAIDs) 13 21604317 guacetisal Analgesics (inc. NSAIDs) 14 15 1174888 Hydrocodone Analgesics (inc. NSAIDs) 16 1126658 Hydromorphone Analgesics (inc. NSAIDs) 17 21604295 hydromorphone and antispasmodics Analgesics (inc. NSAIDs) 18 1177480 IbuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 21603979 ibuproxam Analgesics (inc. NSAIDs) 21 19069104 imidazole-2-hydroxybenzoate Analgesics (inc. NSAIDs) 22 21603958 indometacin, combinations Analgesics (inc. NSAIDs) 23 1178663 Indomethacin Analgesics (inc. NSAIDs) 24 25 21603976 indoprofen Analgesics (inc. NSAIDs) 26 19113032 iprazochrome Analgesics (inc. NSAIDs) 27 19069191 kebuzone Analgesics (inc. NSAIDs) 28 21604270 ketobemidone Analgesics (inc. NSAIDs) 29 30 21604293 ketobemidone and antispasmodics Analgesics (inc. NSAIDs) 31 1185922 Ketoprofen Analgesics (inc. NSAIDs) 32 21603985 ketoprofen, combinations Analgesics (inc. NSAIDs) 33 1136980 Ketorolac Analgesics (inc. NSAIDs) 34 35 1189766 Levorphanol Analgesics (inc. NSAIDs) 36 19071933 lonazolac Analgesics (inc. NSAIDs) 37 19049709 lornoxicam Analgesics (inc. NSAIDs) 38 19071936 loxoprofen Analgesics (inc. NSAIDs) 39 40 21603997 lumiracoxib Analgesics (inc. NSAIDs) 41 19125097 Meclofenamic Acid Analgesics (inc. NSAIDs) 42 19125195 Mefenamic Acid Analgesics (inc. NSAIDs) 43 1150345 meloxicam Analgesics (inc. NSAIDs) 44 45 40254075 meloxicam, combinations Analgesics (inc. NSAIDs) 46 1102527 Meperidine Analgesics (inc. NSAIDs) 47 19003010 Meptazinol Analgesics (inc. NSAIDs) 48 metamizole sodium, combinations excl. 49 21604336 psycholeptics Analgesics (inc. NSAIDs) 50 metamizole sodium, combinations with 51 21604340 psycholeptics Analgesics (inc. NSAIDs) 52 1103640 Methadone Analgesics (inc. NSAIDs) 53 54 21604280 methadone, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 55 19005257 Methoxyflurane Analgesics (inc. NSAIDs) 56 1106740 Methysergide Analgesics (inc. NSAIDs) 57 19072129 mofebutazone Analgesics (inc. NSAIDs) 58 59 19072152 morniflumate Analgesics (inc. NSAIDs) 60 1110410 Morphine Analgesics (inc. NSAIDs)

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1 2 3 21604292 morphine and antispasmodics Analgesics (inc. NSAIDs) 4 5 19056115 MORPHOLINE SALICYLATE Analgesics (inc. NSAIDs) 6 1113648 nabumetone Analgesics (inc. NSAIDs) 7 1114122 Nalbuphine Analgesics (inc. NSAIDs) 8 40254094 naproxcinod Analgesics (inc. NSAIDs) 9 10 1115008 Naproxen Analgesics (inc. NSAIDs) 11 40254098 naproxen and misoprostol Analgesics (inc. NSAIDs) 12 1118117 naratriptan Analgesics (inc. NSAIDs) 13 19015602 Nefopam Analgesics (inc. NSAIDs) 14 15 909795 nepafenac Analgesics (inc. NSAIDs) 16 21604259 nicomorphine Analgesics (inc. NSAIDs) 17 21604334 nifenazone Analgesics (inc. NSAIDs) 18 19019023 NiflumicFor Acid peer review onlyAnalgesics (inc. NSAIDs) 19 20 19069425 nimesulide Analgesics (inc. NSAIDs) 21 923829 Opium Analgesics (inc. NSAIDs) 22 19082874 orgotein Analgesics (inc. NSAIDs) 23 19003691 oxaceprol Analgesics (inc. NSAIDs) 24 25 21603953 oxametacin Analgesics (inc. NSAIDs) 26 1118045 oxaprozin Analgesics (inc. NSAIDs) 27 19082880 oxetorone Analgesics (inc. NSAIDs) 28 1124957 Oxycodone Analgesics (inc. NSAIDs) 29 30 1125765 Oxymorphone Analgesics (inc. NSAIDs) 31 19025925 Oxyphenbutazone Analgesics (inc. NSAIDs) 32 19129648 Papaveretum Analgesics (inc. NSAIDs) 33 19003570 parecoxib Analgesics (inc. NSAIDs) 34 35 1130585 Pentazocine Analgesics (inc. NSAIDs) 36 21604294 pethidine and antispasmodics Analgesics (inc. NSAIDs) 37 21604274 pethidine, combinations with psycholeptics Analgesics (inc. NSAIDs) 38 19033710 Phenacetin Analgesics (inc. NSAIDs) 39 40 21604349 phenacetin, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 41 21604352 phenacetin, combinations with psycholeptics Analgesics (inc. NSAIDs) 42 19132884 Phenazocine Analgesics (inc. NSAIDs) 43 21604335 phenazone, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 44 45 21604339 phenazone, combinations with psycholeptics Analgesics (inc. NSAIDs) 46 1135710 Phenylbutazone Analgesics (inc. NSAIDs) 47 19134009 Pirinitramide Analgesics (inc. NSAIDs) 48 1146810 Piroxicam Analgesics (inc. NSAIDs) 49 50 21603974 pirprofen Analgesics (inc. NSAIDs) 51 19047076 Pizotyline Analgesics (inc. NSAIDs) 52 19029327 proglumetacin Analgesics (inc. NSAIDs) 53 21604347 propacetamol Analgesics (inc. NSAIDs) 54 55 1153664 Propoxyphene Analgesics (inc. NSAIDs) 56 19029322 propyphenazone Analgesics (inc. NSAIDs) 57 propyphenazone, combinations excl. 58 21604338 psycholeptics Analgesics (inc. NSAIDs) 59 propyphenazone, combinations with 60 21604342 psycholeptics Analgesics (inc. NSAIDs)

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1 2 3 21604005 proquazone Analgesics (inc. NSAIDs) 4 5 19016749 remifentanil Analgesics (inc. NSAIDs) 6 21604355 rimazolium Analgesics (inc. NSAIDs) 7 1154077 rizatriptan Analgesics (inc. NSAIDs) 8 1189754 rofecoxib Analgesics (inc. NSAIDs) 9 10 1164108 salicylamide Analgesics (inc. NSAIDs) 11 21604321 salicylamide, combinations excl. psycholeptics Analgesics (inc. NSAIDs) 12 21604326 salicylamide, combinations with psycholeptics Analgesics (inc. NSAIDs) 13 1137460 Salsalate Analgesics (inc. NSAIDs) 14 15 19078219 Sufentanil Analgesics (inc. NSAIDs) 16 1236607 Sulindac Analgesics (inc. NSAIDs) 17 1140643 Sumatriptan Analgesics (inc. NSAIDs) 18 1036636 SuprofenFor peer review onlyAnalgesics (inc. NSAIDs) 19 20 19026459 tapentadol Analgesics (inc. NSAIDs) 21 21604011 tenidap Analgesics (inc. NSAIDs) 22 19041220 tenoxicam Analgesics (inc. NSAIDs) 23 19002431 Tilidine Analgesics (inc. NSAIDs) 24 25 19042155 tolfenamic acid Analgesics (inc. NSAIDs) 26 1102917 Tolmetin Analgesics (inc. NSAIDs) 27 1103314 Tramadol Analgesics (inc. NSAIDs) 28 1103374 valdecoxib Analgesics (inc. NSAIDs) 29 30 21604358 viminol Analgesics (inc. NSAIDs) 31 19005061 ziconotide Analgesics (inc. NSAIDs) 32 1116031 zolmitriptan Analgesics (inc. NSAIDs) 33 19102108 zomepirac Analgesics (inc. NSAIDs) 34 35 19123877 Amdinocillin Antibiotics 36 19088223 Amdinocillin Pivoxil Antibiotics 37 1790868 Amikacin Antibiotics 38 1713332 Amoxicillin Antibiotics 39 40 1717327 Ampicillin Antibiotics 41 21602839 ampicillin, combinations Antibiotics 42 40255264 aspoxicillin Antibiotics 43 19018516 azidocillin Antibiotics 44 45 1734104 Azithromycin Antibiotics 46 45893479 azithromycin, fluconazole and secnidazole Antibiotics 47 19015123 Azlocillin Antibiotics 48 1715117 Aztreonam Antibiotics 49 50 1734205 bacampicillin Antibiotics 51 915175 Bacitracin Antibiotics 52 40255908 bekanamycin Antibiotics 53 21602924 biapenem Antibiotics 54 55 19018742 brodimoprim Antibiotics 56 1740546 Carbenicillin Antibiotics 57 40255589 carumonam Antibiotics 58 21602879 cefacetrile Antibiotics 59 60 1768849 Cefaclor Antibiotics

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1 2 3 1769535 Cefadroxil Antibiotics 4 5 19070174 Cefamandole Antibiotics 6 19070680 Cefatrizine Antibiotics 7 21602875 cefazedone Antibiotics 8 1771162 Cefazolin Antibiotics 9 10 40255561 cefbuperazone Antibiotics 11 21602911 cefcapene Antibiotics 12 1796458 cefdinir Antibiotics 13 1747005 cefditoren Antibiotics 14 15 1748975 cefepime Antibiotics 16 45893466 cefepime and amikacin Antibiotics 17 19028241 cefetamet Antibiotics 18 1796435 CefiximeFor peer review onlyAntibiotics 19 20 21602899 cefmenoxime Antibiotics 21 19072255 Cefmetazole Antibiotics 22 40255560 cefminox Antibiotics 23 19028286 cefodizime Antibiotics 24 25 19072857 Cefonicid Antibiotics 26 1773402 Cefoperazone Antibiotics 27 21602913 cefoperazone, combinations Antibiotics 28 19028288 ceforanide Antibiotics 29 30 1774470 Cefotaxime Antibiotics 31 45893191 cefotaxime, combinations Antibiotics 32 1774932 Cefotetan Antibiotics 33 19051271 Cefotiam Antibiotics 34 35 1775741 Cefoxitin Antibiotics 36 21602917 cefozopran Antibiotics 37 21602905 cefpiramide Antibiotics 38 19001904 cefpirome Antibiotics 39 40 1749008 cefpodoxime Antibiotics 41 1738366 cefprozil Antibiotics 42 21602880 cefroxadine Antibiotics 43 19051345 Cefsulodin Antibiotics 44 45 40230597 ceftaroline Antibiotics 46 1776684 Ceftazidime Antibiotics 47 21602881 ceftezole Antibiotics 48 1749083 ceftibuten Antibiotics 49 50 1777254 Ceftizoxime Antibiotics 51 21602928 ceftobiprole medocaril Antibiotics 52 45892599 ceftolozane Antibiotics 53 1777806 Ceftriaxone Antibiotics 54 55 21602912 ceftriaxone, combinations Antibiotics 56 1778162 Cefuroxime Antibiotics 57 21603039 cefuroxime and metronidazole Antibiotics 58 1786621 Cephalexin Antibiotics 59 60 19052683 Cephaloridine Antibiotics

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1 2 3 19086759 Cephalothin Antibiotics 4 5 19086790 Cephapirin Antibiotics 6 1786842 Cephradine Antibiotics 7 990069 Chloramphenicol Antibiotics 8 19095043 Chlortetracycline Antibiotics 9 10 997496 Cinoxacin Antibiotics 11 1797513 Ciprofloxacin Antibiotics 12 45893269 ciprofloxacin and metronidazole Antibiotics 13 45893270 ciprofloxacin and ornidazole Antibiotics 14 15 45893513 ciprofloxacin and tinidazole Antibiotics 16 1750500 Clarithromycin Antibiotics 17 997881 Clindamycin Antibiotics 18 19047240 clofoctolFor peer review onlyAntibiotics 19 20 21602847 clometocillin Antibiotics 21 19047265 clomocycline Antibiotics 22 1800835 Cloxacillin Antibiotics 23 1701677 colistimethate Antibiotics 24 25 901845 Colistin Antibiotics 26 21602811 combinations of tetracyclines Antibiotics 27 45774861 dalbavancin Antibiotics 28 1789517 dalfopristin Antibiotics 29 30 1786617 Daptomycin Antibiotics 31 1714527 Demeclocycline Antibiotics 32 19023508 Dibekacin Antibiotics 33 1724666 Dicloxacillin Antibiotics 34 35 1790024 dirithromycin Antibiotics 36 1713905 doripenem Antibiotics 37 1738521 Doxycycline Antibiotics 38 1743222 Enoxacin Antibiotics 39 40 21602826 epicillin Antibiotics 41 1717963 ertapenem Antibiotics 42 1746940 Erythromycin Antibiotics 43 43534793 faropenem Antibiotics 44 45 40239985 fidaxomicin Antibiotics 46 19050750 Fleroxacin Antibiotics 47 40255562 flomoxef Antibiotics 48 19054936 Floxacillin Antibiotics 49 50 19064329 flumequine Antibiotics 51 21602982 flurithromycin Antibiotics 52 956653 Fosfomycin Antibiotics 53 45893495 furazidin Antibiotics 54 55 21603026 garenoxacin Antibiotics 56 1789276 gatifloxacin Antibiotics 57 1716721 gemifloxacin Antibiotics 58 45892419 Gentamicin Antibiotics 59 60 919345 Gentamicin Sulfate (USP) Antibiotics

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1 2 3 1747032 grepafloxacin Antibiotics 4 5 19101402 habekacin Antibiotics 6 19069006 hetacillin Antibiotics 7 21602933 iclaprim Antibiotics 8 1778262 Imipenem Antibiotics 9 10 21603004 isepamicin Antibiotics 11 19123240 Josamycin Antibiotics 12 1784749 Kanamycin Antibiotics 13 1742253 Levofloxacin Antibiotics 14 15 43534794 levofloxacin and ornidazole Antibiotics 16 1790692 Lincomycin Antibiotics 17 1736887 linezolid Antibiotics 18 1707800 lomefloxacinFor peer review onlyAntibiotics 19 20 1708100 loracarbef Antibiotics 21 19092353 Lymecycline Antibiotics 22 992716 Mafenide Antibiotics 23 19008870 mandelic acid Antibiotics 24 25 1709170 meropenem Antibiotics 26 19003644 Methacycline Antibiotics 27 19072054 methampicillin Antibiotics 28 904356 Methenamine Antibiotics 29 30 1707164 Metronidazole Antibiotics 31 19007701 Mezlocillin Antibiotics 32 19072122 midecamycin Antibiotics 33 1708880 Minocycline Antibiotics 34 35 19009138 Miocamycin Antibiotics 36 19126622 Moxalactam Antibiotics 37 1716903 moxifloxacin Antibiotics 38 951511 Mupirocin Antibiotics 39 40 1713930 Nafcillin Antibiotics 41 915981 Neomycin Antibiotics 42 19017585 Netilmicin Antibiotics 43 21603059 nifurtoinol Antibiotics 44 45 920293 Nitrofurantoin Antibiotics 46 45893503 nitrofurantoin, combinations Antibiotics 47 19015464 nitroxoline Antibiotics 48 1721543 Norfloxacin Antibiotics 49 50 45893468 norfloxacin and tinidazole Antibiotics 51 923081 Ofloxacin Antibiotics 52 45893194 ofloxacin and ornidazole Antibiotics 53 19023254 Oleandomycin Antibiotics 54 55 45776147 oritavancin Antibiotics 56 19024197 Ornidazole Antibiotics 57 1724703 Oxacillin Antibiotics 58 19129642 Oxolinic Acid Antibiotics 59 60 925952 Oxytetracycline Antibiotics

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1 2 3 21602926 panipenem and betamipron Antibiotics 4 5 21603025 pazufloxacin Antibiotics 6 19027679 Pefloxacin Antibiotics 7 21602846 penamecillin Antibiotics 8 19126544 Penicillin Antibiotics 9 10 1728416 Penicillin G Antibiotics 11 1729720 Penicillin V Antibiotics 12 penicillins, combinations with other 13 21603037 antibacterials Antibiotics 14 21602808 penimepicycline Antibiotics 15 19088795 phenethicillin Antibiotics 16 17 1746114 Piperacillin Antibiotics 18 21603030 piromidicFor acid peer review onlyAntibiotics 19 19047071 Pivampicillin Antibiotics 20 948582 Polymyxin B Antibiotics 21 22 19125201 Pristinamycin Antibiotics 23 19096054 propicillin Antibiotics 24 21603024 prulifloxacin Antibiotics 25 1789515 quinupristin Antibiotics 26 27 991003 retapamulin Antibiotics 28 21603003 ribostamycin Antibiotics 29 1763204 Rifampin Antibiotics 30 19136008 Rifamycins Antibiotics 31 32 1735947 rifaximin Antibiotics 33 21602980 rokitamycin Antibiotics 34 19136024 Rolitetracycline Antibiotics 35 19036545 rosoxacin Antibiotics 36 37 19063874 Roxithromycin Antibiotics 38 21603017 rufloxacin Antibiotics 39 966956 silver sulfadiazine Antibiotics 40 19136044 Sisomicin Antibiotics 41 42 40256175 sitafloxacin Antibiotics 43 1733765 sparfloxacin Antibiotics 44 1701651 Spectinomycin Antibiotics 45 19070251 Spiramycin Antibiotics 46 47 21603040 spiramycin and metronidazole Antibiotics 48 21602993 streptoduocin Antibiotics 49 1836191 Streptomycin Antibiotics 50 1836241 Sulbactam Antibiotics 51 52 19000817 Sulbenicillin Antibiotics 53 1036252 Sulfacetamide Antibiotics 54 1836391 Sulfadiazine Antibiotics 55 21602966 sulfadiazine and tetroxoprim Antibiotics 56 57 21602962 sulfadiazine and trimethoprim Antibiotics 58 19000818 Sulfadimethoxine Antibiotics 59 21602965 sulfadimidine and trimethoprim Antibiotics 60

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1 2 3 19136423 Sulfalene Antibiotics 4 5 21602958 sulfamazone Antibiotics 6 19136426 Sulfamerazine Antibiotics 7 21602967 sulfamerazine and trimethoprim Antibiotics 8 19136429 Sulfamethazine Antibiotics 9 10 1036425 Sulfamethizole Antibiotics 11 1836430 Sulfamethoxazole Antibiotics 12 19000820 Sulfamethoxypyridazine Antibiotics 13 21602952 sulfametomidine Antibiotics 14 15 21602953 sulfametoxydiazine Antibiotics 16 21602963 sulfametrole and trimethoprim Antibiotics 17 19136481 Sulfamoxole Antibiotics 18 21602964 sulfamoxoleFor and peer trimethoprim review onlyAntibiotics 19 20 1036475 Sulfanilamide Antibiotics 21 21602955 sulfaperin Antibiotics 22 21602957 sulfaphenazole Antibiotics 23 19136493 Sulfapyridine Antibiotics 24 25 1036487 sulfathiazole Antibiotics 26 21602942 sulfathiourea Antibiotics 27 19000821 Sulfisomidine Antibiotics 28 1836503 Sulfisoxazole Antibiotics 29 30 19040627 sultamicillin Antibiotics 31 19002077 Talampicillin Antibiotics 32 1741122 tazobactam Antibiotics 33 45775686 tedizolid Antibiotics 34 35 19078399 Teicoplanin Antibiotics 36 40166675 telavancin Antibiotics 37 1702911 telithromycin Antibiotics 38 19041153 temafloxacin Antibiotics 39 40 19100438 temocillin Antibiotics 41 1836948 Tetracycline Antibiotics 42 45893484 tetracycline and oleandomycin Antibiotics 43 19137362 Thiamphenicol Antibiotics 44 45 21602817 thiamphenicol, combinations Antibiotics 46 1702364 Ticarcillin Antibiotics 47 1742432 tigecycline Antibiotics 48 1702559 Tinidazole Antibiotics 49 50 902722 Tobramycin Antibiotics 51 1705674 Trimethoprim Antibiotics 52 19006043 Troleandomycin Antibiotics 53 1712549 trovafloxacin Antibiotics 54 55 1707687 Vancomycin Antibiotics 56 19102105 xibornol Antibiotics 57 19047423 abciximab Anticlotting and antifibrinolytic 58 19024063 Acenocoumarol Anticlotting and antifibrinolytic 59 60

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1 2 3 acetylsalicylic acid, combinations with proton 4 40252642 pump inhibitors Anticlotting and antifibrinolytic 5 1347450 alteplase Anticlotting and antifibrinolytic 6 7 19024544 Ancrod Anticlotting and antifibrinolytic 8 19044890 Anistreplase Anticlotting and antifibrinolytic 9 1436169 Antithrombin III Anticlotting and antifibrinolytic 10 43013024 apixaban Anticlotting and antifibrinolytic 11 12 1322207 argatroban Anticlotting and antifibrinolytic 13 19069137 bemiparin Anticlotting and antifibrinolytic 14 21601002 beraprost Anticlotting and antifibrinolytic 15 19084670 bivalirudin Anticlotting and antifibrinolytic 16 17 21601012 brinase Anticlotting and antifibrinolytic 18 46275677 cangrelorFor peer review onlyAnticlotting and antifibrinolytic 19 1350310 cilostazol Anticlotting and antifibrinolytic 20 1322184 clopidogrel Anticlotting and antifibrinolytic 21 22 21600987 cloricromen Anticlotting and antifibrinolytic 23 21600969 clorindione Anticlotting and antifibrinolytic 24 40228152 dabigatran etexilate Anticlotting and antifibrinolytic 25 1301065 Dalteparin Anticlotting and antifibrinolytic 26 27 19026343 danaparoid Anticlotting and antifibrinolytic 28 42898933 defibrotide Anticlotting and antifibrinolytic 29 21601029 dermatan sulfate Anticlotting and antifibrinolytic 30 19011712 desirudin Anticlotting and antifibrinolytic 31 32 1325124 Dicumarol Anticlotting and antifibrinolytic 33 21600970 diphenadione Anticlotting and antifibrinolytic 34 1331270 Dipyridamole Anticlotting and antifibrinolytic 35 21600986 ditazole Anticlotting and antifibrinolytic 36 37 1731597 drotrecogin alfa Anticlotting and antifibrinolytic 38 1301025 Enoxaparin Anticlotting and antifibrinolytic 39 1354118 Epoprostenol Anticlotting and antifibrinolytic 40 1322199 eptifibatide Anticlotting and antifibrinolytic 41 42 21600968 ethyl biscoumacetate Anticlotting and antifibrinolytic 43 19113013 fluindione Anticlotting and antifibrinolytic 44 1315865 fondaparinux Anticlotting and antifibrinolytic 45 1367571 Heparin Anticlotting and antifibrinolytic 46 47 21600984 heparin, combinations Anticlotting and antifibrinolytic 48 19069107 indobufen Anticlotting and antifibrinolytic 49 19092139 lepirudin Anticlotting and antifibrinolytic 50 21601023 melagatran Anticlotting and antifibrinolytic 51 52 19001014 Nadroparin Anticlotting and antifibrinolytic 53 19008276 parnaparin Anticlotting and antifibrinolytic 54 19033934 Phenindione Anticlotting and antifibrinolytic 55 19035344 Phenprocoumon Anticlotting and antifibrinolytic 56 57 21600988 picotamide Anticlotting and antifibrinolytic 58 954696 Plasmin Anticlotting and antifibrinolytic 59 40163718 prasugrel Anticlotting and antifibrinolytic 60

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1 2 3 42801108 Protein C Anticlotting and antifibrinolytic 4 5 19024191 Reteplase Anticlotting and antifibrinolytic 6 19129274 reviparin Anticlotting and antifibrinolytic 7 40241331 rivaroxaban Anticlotting and antifibrinolytic 8 21601014 saruplase Anticlotting and antifibrinolytic 9 10 19136187 Streptokinase Anticlotting and antifibrinolytic 11 21600982 sulodexide Anticlotting and antifibrinolytic 12 19098548 Tenecteplase Anticlotting and antifibrinolytic 13 40241186 Ticagrelor Anticlotting and antifibrinolytic 14 15 1302398 Ticlopidine Anticlotting and antifibrinolytic 16 1308473 tinzaparin Anticlotting and antifibrinolytic 17 19018364 tioclomarol Anticlotting and antifibrinolytic 18 19017067 tirofibanFor peer review onlyAnticlotting and antifibrinolytic 19 20 19042778 triflusal Anticlotting and antifibrinolytic 21 1307515 Urokinase Anticlotting and antifibrinolytic 22 44818499 vorapaxar Anticlotting and antifibrinolytic 23 1310149 Warfarin Anticlotting and antifibrinolytic 24 25 21601024 ximelagatran Anticlotting and antifibrinolytic 26 1529331 Acarbose Antidiabetic drugs 27 1530014 Acetohexamide Antidiabetic drugs 28 44816332 albiglutide Antidiabetic drugs 29 30 43013884 alogliptin Antidiabetic drugs 31 19035533 benfluorex Antidiabetic drugs 32 21600748 buformin Antidiabetic drugs 33 43526465 canagliflozin Antidiabetic drugs 34 35 19033498 Carbutamide Antidiabetic drugs 36 1594973 Chlorpropamide Antidiabetic drugs 37 21600734 combinations Antidiabetic drugs 38 44785829 dapagliflozin Antidiabetic drugs 39 40 45774751 empagliflozin Antidiabetic drugs 41 1583722 exenatide Antidiabetic drugs 42 43534752 gemigliptin Antidiabetic drugs 43 19001409 glibornuride Antidiabetic drugs 44 45 19059796 Gliclazide Antidiabetic drugs 46 1597756 glimepiride Antidiabetic drugs 47 1560171 Glipizide Antidiabetic drugs 48 19097821 gliquidone Antidiabetic drugs 49 50 21600760 glisoxepide Antidiabetic drugs 51 1559684 Glyburide Antidiabetic drugs 52 19001441 glymidine Antidiabetic drugs 53 1000979 guar gum Antidiabetic drugs 54 55 21600730 insulin (beef) Antidiabetic drugs 56 43534747 insulin degludec Antidiabetic drugs 57 44819155 insulin degludec and insulin aspart Antidiabetic drugs 58 1516976 insulin detemir Antidiabetic drugs 59 60 1502905 Insulin Glargine Antidiabetic drugs

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1 2 3 1550023 Insulin Lispro Antidiabetic drugs 4 5 1544838 Insulin, Glulisine, Human Antidiabetic drugs 6 42899447 Insulin, Pork Antidiabetic drugs 7 40239216 Linagliptin Antidiabetic drugs 8 45893517 linagliptin and empagliflozin Antidiabetic drugs 9 10 40170911 liraglutide Antidiabetic drugs 11 44506754 Lixisenatide Antidiabetic drugs 12 21600759 metahexamide Antidiabetic drugs 13 1503297 Metformin Antidiabetic drugs 14 15 45893467 metformin and acarbose Antidiabetic drugs 16 45893267 metformin and canagliflozin Antidiabetic drugs 17 43534751 metformin and dapagliflozin Antidiabetic drugs 18 45893491 metforminFor and peer gemigliptin review onlyAntidiabetic drugs 19 20 21600773 metformin and vildagliptin Antidiabetic drugs 21 1510202 miglitol Antidiabetic drugs 22 21600796 mitiglinide Antidiabetic drugs 23 1502826 nateglinide Antidiabetic drugs 24 25 19033909 Phenformin Antidiabetic drugs 26 21600766 phenformin and sulfonamides Antidiabetic drugs 27 1525215 pioglitazone Antidiabetic drugs 28 43534748 pioglitazone and sitagliptin Antidiabetic drugs 29 30 1517998 Pramlintide Antidiabetic drugs 31 1596977 Regular Insulin, Human Antidiabetic drugs 32 1516766 repaglinide Antidiabetic drugs 33 1547504 rosiglitazone Antidiabetic drugs 34 35 40166035 saxagliptin Antidiabetic drugs 36 1580747 sitagliptin Antidiabetic drugs 37 1502809 Tolazamide Antidiabetic drugs 38 1502855 Tolbutamide Antidiabetic drugs 39 40 19042191 tolrestat Antidiabetic drugs 41 1515249 troglitazone Antidiabetic drugs 42 19122137 vildagliptin Antidiabetic drugs 43 21600778 voglibose Antidiabetic drugs 44 45 19112534 barbexaclone Antiepileptics 46 19018520 Beclamide Antiepileptics 47 740275 Carbamazepine Antiepileptics 48 798874 Clonazepam Antiepileptics 49 50 19054995 dipropylacetamide Antiepileptics 51 44507780 eslicarbazepine Antiepileptics 52 750119 Ethosuximide Antiepileptics 53 750146 Ethotoin Antiepileptics 54 55 40239995 ezogabine Antiepileptics 56 795661 felbamate Antiepileptics 57 713192 fosphenytoin Antiepileptics 58 797399 gabapentin Antiepileptics 59 60 19087394 lacosamide Antiepileptics

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1 2 3 705103 lamotrigine Antiepileptics 4 5 711584 Levetiracetam Antiepileptics 6 702661 Mephenytoin Antiepileptics 7 702685 Mephobarbital Antiepileptics 8 19004254 metharbital Antiepileptics 9 10 759401 methsuximide Antiepileptics 11 718122 oxcarbazepine Antiepileptics 12 19021932 paramethadione Antiepileptics 13 42904177 perampanel Antiepileptics 14 15 19023286 phenacemide Antiepileptics 16 734275 Phenobarbital Antiepileptics 17 19023842 phensuximide Antiepileptics 18 740910 PhenytoinFor peer review onlyAntiepileptics 19 20 734354 pregabalin Antiepileptics 21 751347 Primidone Antiepileptics 22 19095776 progabide Antiepileptics 23 19006586 rufinamide Antiepileptics 24 25 19000921 sulthiame Antiepileptics 26 715458 tiagabine Antiepileptics 27 742267 topiramate Antiepileptics 28 19005629 Trimethadione Antiepileptics 29 30 19010963 Valproic Acid Antiepileptics 31 19020002 Vigabatrin Antiepileptics 32 744798 zonisamide Antiepileptics 33 1140123 acrivastine Antihistamines 34 35 951237 Antazoline Antihistamines 36 1150770 Astemizole Antihistamines 37 1133993 azatadine Antihistamines 38 934075 azelastine Antihistamines 39 40 19034280 bamipine Antihistamines 41 40166571 bepotastine Antihistamines 42 40256760 bilastine Antihistamines 43 1139216 bromodiphenhydramine Antihistamines 44 45 1130863 Brompheniramine Antihistamines 46 21603466 brompheniramine, combinations Antihistamines 47 19081195 buclizine Antihistamines 48 21603499 buclizine, combinations Antihistamines 49 50 1141018 carbinoxamine Antihistamines 51 1149196 Cetirizine Antihistamines 52 990413 chlorcyclizine Antihistamines 53 19049437 chloropyramine Antihistamines 54 55 21603478 chloropyramine, combinations Antihistamines 56 1192710 Chlorpheniramine Antihistamines 57 19049707 chlorphenoxamine Antihistamines 58 21603456 chlorphenoxamine, combinations Antihistamines 59 60 1197677 Clemastine Antihistamines

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1 2 3 21603455 clemastine, combinations Antihistamines 4 5 909358 Cyclizine Antihistamines 6 21603500 cyclizine, combinations Antihistamines 7 1110727 Cyproheptadine Antihistamines 8 21603516 deptropine Antihistamines 9 10 1103006 desloratadine Antihistamines 11 1188052 dexbrompheniramine Antihistamines 12 21603469 dexbrompheniramine, combinations Antihistamines 13 1188114 dexchlorpheniramine Antihistamines 14 15 21603467 dexchlorpheniramine, combinations Antihistamines 16 19028947 Dimethindene Antihistamines 17 1129625 Diphenhydramine Antihistamines 18 21603454 diphenhydramine,For peer combinations review onlyAntihistamines 19 20 19090000 diphenylpyraline Antihistamines 21 21603457 diphenylpyraline, combinations Antihistamines 22 738818 Doxylamine Antihistamines 23 40254475 doxylamine, combinations Antihistamines 24 25 19092433 ebastine Antihistamines 26 903893 emedastine Antihistamines 27 943634 epinastine Antihistamines 28 1153428 fexofenadine Antihistamines 29 30 21603472 histapyrrodine Antihistamines 31 21603477 histapyrrodine, combinations Antihistamines 32 21603484 hydroxyethylpromethazine Antihistamines 33 21603490 hydroxyethylpromethazine, combinations Antihistamines 34 35 19003593 isothipendyl Antihistamines 36 986117 Ketotifen Antihistamines 37 1136422 levocetirizine Antihistamines 38 1107830 Loratadine Antihistamines 39 40 19008999 mebhydroline Antihistamines 41 994341 Meclizine Antihistamines 42 21603501 meclozine, combinations Antihistamines 43 19009145 mequitazine Antihistamines 44 45 19004158 Methapyrilene Antihistamines 46 19009250 methdilazine Antihistamines 47 19086100 mizolastine Antihistamines 48 915855 olopatadine Antihistamines 49 50 19071314 oxatomide Antihistamines 51 21603487 oxomemazine Antihistamines 52 1123534 phenindamine Antihistamines 53 933952 Pheniramine Antihistamines 54 55 19093165 pimethixene Antihistamines 56 1153013 Promethazine Antihistamines 57 21603489 promethazine, combinations Antihistamines 58 1159811 Pyrilamine Antihistamines 59 60 21603510 pyrrobutamine Antihistamines

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1 2 3 21603529 pyrrobutamine, combinations Antihistamines 4 5 43534851 quifenadine Antihistamines 6 21603527 rupatadine Antihistamines 7 43534852 sequifenadine Antihistamines 8 21603465 talastine Antihistamines 9 10 1150836 Terfenadine Antihistamines 11 21603506 thenalidine Antihistamines 12 21603528 thenalidine, combinations Antihistamines 13 21603485 thiazinam Antihistamines 14 15 1037358 Thiethylperazine Antihistamines 16 43012162 thonzylamine Antihistamines 17 19005570 Trimeprazine Antihistamines 18 942799 trimethobenzamideFor peer review onlyAntihistamines 19 20 1105853 Tripelennamine Antihistamines 21 1105889 Triprolidine Antihistamines 22 19101651 tritoqualine Antihistamines 23 Antiinfectives (excluding antibiotics 24 1736971 abacavir and vaccines) 25 Antiinfectives (excluding antibiotics 26 1703687 Acyclovir and vaccines) 27 Antiinfectives (excluding antibiotics 28 21603125 aldesulfone sodium and vaccines) 29 Antiinfectives (excluding antibiotics 30 1726228 aminosalicylic acid and vaccines) 31 Antiinfectives (excluding antibiotics 32 1717240 Amphotericin B and vaccines) 33 Antiinfectives (excluding antibiotics 34 1789428 Amprenavir and vaccines) 35 Antiinfectives (excluding antibiotics 36 19026450 anidulafungin and vaccines) 37 Antiinfectives (excluding antibiotics 38 19063179 Antifungal Agents and vaccines) 39 Antiinfectives (excluding antibiotics 40 46233931 asunaprevir and vaccines) 41 Antiinfectives (excluding antibiotics 42 1727223 Atazanavir and vaccines) 43 44 Antiinfectives (excluding antibiotics 45 43012518 bedaquiline and vaccines) 46 Antiinfectives (excluding antibiotics 47 40238770 boceprevir and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601251 botulinum antitoxin and vaccines) 50 Antiinfectives (excluding antibiotics 51 19122130 brivudine and vaccines) 52 Antiinfectives (excluding antibiotics 53 958396 butenafine and vaccines) 54 Antiinfectives (excluding antibiotics 55 939784 butoconazole and vaccines) 56 Antiinfectives (excluding antibiotics 57 21603094 calcium aminosalicylate and vaccines) 58 Antiinfectives (excluding antibiotics 59 1718054 Caspofungin and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1745072 Cidofovir and vaccines) 5 Antiinfectives (excluding antibiotics 6 21603171 clevudine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1798476 Clofazimine and vaccines) 9 Antiinfectives (excluding antibiotics 10 1000632 Clotrimazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 586491 cytomegalovirus immune globulin and vaccines) 13 Antiinfectives (excluding antibiotics 14 46221696 daclatasvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1711759 Dapsone and vaccines) 17 Antiinfectives (excluding antibiotics 18 1756831 darunavirFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 45893458 darunavir and cobicistat and vaccines) 21 Antiinfectives (excluding antibiotics 22 44819157 delamanid and vaccines) 23 Antiinfectives (excluding antibiotics 24 25 1747157 Delavirdine and vaccines) 26 Antiinfectives (excluding antibiotics 27 1724869 Didanosine and vaccines) 28 Antiinfectives (excluding antibiotics 29 19031041 Diphtheria Antitoxin and vaccines) 30 Antiinfectives (excluding antibiotics 31 43560385 dolutegravir and vaccines) 32 Antiinfectives (excluding antibiotics 33 940864 Econazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1738135 efavirenz and vaccines) 36 Antiinfectives (excluding antibiotics 37 45775080 efinaconazole and vaccines) 38 Antiinfectives (excluding antibiotics 39 42874212 elvitegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 1703069 emtricitabine and vaccines) 42 Antiinfectives (excluding antibiotics 43 21601270 encephalitis, tick borne immunoglobulin and vaccines) 44 Antiinfectives (excluding antibiotics 45 1717002 enfuvirtide and vaccines) 46 Antiinfectives (excluding antibiotics 47 1711246 entecavir and vaccines) 48 Antiinfectives (excluding antibiotics 49 1749301 Ethambutol and vaccines) 50 Antiinfectives (excluding antibiotics 51 21603117 ethambutol and isoniazid and vaccines) 52 Antiinfectives (excluding antibiotics 53 1750074 Ethionamide and vaccines) 54 Antiinfectives (excluding antibiotics 55 1758536 etravirine and vaccines) 56 Antiinfectives (excluding antibiotics 57 45893487 faldaprevir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703603 famciclovir and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1754994 Fluconazole and vaccines) 5 Antiinfectives (excluding antibiotics 6 1755112 Flucytosine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1736829 fosamprenavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724700 Foscarnet and vaccines) 11 Antiinfectives (excluding antibiotics 12 21603147 fosfonet and vaccines) 13 Antiinfectives (excluding antibiotics 14 1757803 Ganciclovir and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601252 gas-gangrene sera and vaccines) 17 Antiinfectives (excluding antibiotics 18 21601269 hepatitisFor A immunoglobulin peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 501343 hepatitis B immune globulin and vaccines) 21 Antiinfectives (excluding antibiotics 22 19078156 Idoxuridine and vaccines) 23 Antiinfectives (excluding antibiotics 24 25 1711523 Indinavir and vaccines) 26 Antiinfectives (excluding antibiotics 27 19083285 Inosine Pranobex and vaccines) 28 Antiinfectives (excluding antibiotics 29 1782521 isoniazid and vaccines) 30 Antiinfectives (excluding antibiotics 31 1703653 Itraconazole and vaccines) 32 Antiinfectives (excluding antibiotics 33 985708 Ketoconazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 1704183 Lamivudine and vaccines) 36 Antiinfectives (excluding antibiotics 37 45893193 lamivudine and tenofovir disoproxil and vaccines) 38 Antiinfectives (excluding antibiotics 39 45893478 lamivudine, abacavir and dolutegravir and vaccines) 40 Antiinfectives (excluding antibiotics 41 43534799 lamivudine, tenofovir disoproxil and efavirenz and vaccines) 42 Antiinfectives (excluding antibiotics 43 44507693 luliconazole and vaccines) 44 Antiinfectives (excluding antibiotics 45 43532424 lysozyme and vaccines) 46 Antiinfectives (excluding antibiotics 47 1787101 maraviroc and vaccines) 48 Antiinfectives (excluding antibiotics 49 21601244 maribavir and vaccines) 50 Antiinfectives (excluding antibiotics 51 21601272 measles immunoglobulin and vaccines) 52 Antiinfectives (excluding antibiotics 53 21603129 metisazone and vaccines) 54 Antiinfectives (excluding antibiotics 55 19018013 micafungin and vaccines) 56 Antiinfectives (excluding antibiotics 57 907879 Miconazole and vaccines) 58 Antiinfectives (excluding antibiotics 59 21603113 morinamide and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 19010924 moroxydine and vaccines) 5 Antiinfectives (excluding antibiotics 6 40252180 motavizumab and vaccines) 7 Antiinfectives (excluding antibiotics 8 21601273 mumps immunoglobulin and vaccines) 9 Antiinfectives (excluding antibiotics 10 914053 naftifine and vaccines) 11 Antiinfectives (excluding antibiotics 12 21601277 nebacumab and vaccines) 13 Antiinfectives (excluding antibiotics 14 1715472 Nelfinavir and vaccines) 15 Antiinfectives (excluding antibiotics 16 1769389 Nevirapine and vaccines) 17 Antiinfectives (excluding antibiotics 18 922570 NystatinFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 1799139 Oseltamivir and vaccines) 21 Antiinfectives (excluding antibiotics 22 918222 oxiconazole and vaccines) 23 Antiinfectives (excluding antibiotics 24 25 537647 palivizumab and vaccines) 26 Antiinfectives (excluding antibiotics 27 981654 penciclovir and vaccines) 28 Antiinfectives (excluding antibiotics 29 21601271 pertussis immunoglobulin and vaccines) 30 Antiinfectives (excluding antibiotics 31 21603192 pleconaril and vaccines) 32 Antiinfectives (excluding antibiotics 33 1704139 posaconazole and vaccines) 34 Antiinfectives (excluding antibiotics 35 19135812 Prothionamide and vaccines) 36 Antiinfectives (excluding antibiotics 37 1759455 Pyrazinamide and vaccines) 38 Antiinfectives (excluding antibiotics 39 19135830 rabies immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 1712889 raltegravir and vaccines) 42 Antiinfectives (excluding antibiotics 43 43013193 raxibacumab and vaccines) 44 Antiinfectives (excluding antibiotics 45 535714 Rho(D) Immune Globulin and vaccines) 46 Antiinfectives (excluding antibiotics 47 1762711 Ribavirin and vaccines) 48 Antiinfectives (excluding antibiotics 49 1777417 Rifabutin and vaccines) 50 rifampicin, pyrazinamide, ethambutol and Antiinfectives (excluding antibiotics 51 21603120 isoniazid and vaccines) 52 Antiinfectives (excluding antibiotics 53 19035924 rifamycin SV and vaccines) 54 Antiinfectives (excluding antibiotics 55 19035953 rifapentine and vaccines) 56 Antiinfectives (excluding antibiotics 57 40238930 Rilpivirine and vaccines) 58 Antiinfectives (excluding antibiotics 59 1763339 Rimantadine and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 1748921 Ritonavir and vaccines) 5 Antiinfectives (excluding antibiotics 6 21601264 rubella immunoglobulin and vaccines) 7 Antiinfectives (excluding antibiotics 8 1746244 Saquinavir and vaccines) 9 Antiinfectives (excluding antibiotics 10 939134 sertaconazole and vaccines) 11 Antiinfectives (excluding antibiotics 12 44785086 simeprevir and vaccines) 13 Antiinfectives (excluding antibiotics 14 44785094 sofosbuvir and vaccines) 15 Antiinfectives (excluding antibiotics 16 21601266 staphylococcus immunoglobulin and vaccines) 17 Antiinfectives (excluding antibiotics 18 1781406 StavudineFor peer review onlyand vaccines) 19 Antiinfectives (excluding antibiotics 20 21603187 stavudine, lamivudine and nevirapine and vaccines) 21 Antiinfectives (excluding antibiotics 22 940535 sulconazole and vaccines) 23 Antiinfectives (excluding antibiotics 24 25 45776537 tavaborole and vaccines) 26 Antiinfectives (excluding antibiotics 27 40239330 telaprevir and vaccines) 28 Antiinfectives (excluding antibiotics 29 1758392 telbivudine and vaccines) 30 Antiinfectives (excluding antibiotics 31 1710281 tenofovir disoproxil and vaccines) 32 Antiinfectives (excluding antibiotics 33 1741309 terbinafine and vaccines) 34 Antiinfectives (excluding antibiotics 35 941472 terconazole and vaccines) 36 Antiinfectives (excluding antibiotics 37 19078424 terizidone and vaccines) 38 Antiinfectives (excluding antibiotics 39 561401 Tetanus immune globulin, human and vaccines) 40 Antiinfectives (excluding antibiotics 41 45893523 thioacetazone and vaccines) 42 Antiinfectives (excluding antibiotics 43 21603118 thioacetazone and isoniazid and vaccines) 44 Antiinfectives (excluding antibiotics 45 21603107 tiocarlide and vaccines) 46 Antiinfectives (excluding antibiotics 47 942028 tioconazole and vaccines) 48 Antiinfectives (excluding antibiotics 49 1736999 tipranavir and vaccines) 50 Antiinfectives (excluding antibiotics 51 19101679 tromantadine and vaccines) 52 Antiinfectives (excluding antibiotics 53 45893141 umifenovir and vaccines) 54 Antiinfectives (excluding antibiotics 55 21601265 vaccinia immunoglobulin and vaccines) 56 Antiinfectives (excluding antibiotics 57 1717704 valacyclovir and vaccines) 58 Antiinfectives (excluding antibiotics 59 1703063 valganciclovir and vaccines) 60

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1 2 3 Antiinfectives (excluding antibiotics 4 543291 varicella-zoster immune globulin and vaccines) 5 Antiinfectives (excluding antibiotics 6 908126 Vidarabine and vaccines) 7 Antiinfectives (excluding antibiotics 8 1714277 voriconazole and vaccines) 9 Antiinfectives (excluding antibiotics 10 1724827 Zalcitabine and vaccines) 11 Antiinfectives (excluding antibiotics 12 1708748 Zanamivir and vaccines) 13 Antiinfectives (excluding antibiotics 14 1710612 Zidovudine and vaccines) 15 Antiinfectives (excluding antibiotics 16 21603185 zidovudine, lamivudine and nevirapine and vaccines) 17 Antineoplastic and 18 19010868 abarelixFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1186087 abatacept immunomodulating agents 21 Antineoplastic and 22 42900395 abetimus immunomodulating agents 23 Antineoplastic and 24 25 40239056 abiraterone immunomodulating agents 26 Antineoplastic and 27 19057483 Aclarubicin immunomodulating agents 28 Antineoplastic and 29 1119119 adalimumab immunomodulating agents 30 Antineoplastic and 31 43525787 ado-trastuzumab emtansine immunomodulating agents 32 Antineoplastic and 33 43533090 Afatinib immunomodulating agents 34 Antineoplastic and 35 21603910 afelimomab immunomodulating agents 36 Antineoplastic and 37 40244266 aflibercept immunomodulating agents 38 Antineoplastic and 39 40253734 albinterferon alfa-2b immunomodulating agents 40 Antineoplastic and 41 1309770 Aldesleukin immunomodulating agents 42 Antineoplastic and 43 909959 alefacept immunomodulating agents 44 Antineoplastic and 45 1312706 alemtuzumab immunomodulating agents 46 Antineoplastic and 47 941052 alitretinoin immunomodulating agents 48 Antineoplastic and 49 1368823 Altretamine immunomodulating agents 50 Antineoplastic and 51 1503057 Aminoglutethimide immunomodulating agents 52 Antineoplastic and 53 904351 Aminolevulinic Acid immunomodulating agents 54 Antineoplastic and 55 40253109 amrubicin immunomodulating agents 56 Antineoplastic and 57 19017810 Amsacrine immunomodulating agents 58 Antineoplastic and 59 1381253 anagrelide immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1114375 anakinra immunomodulating agents 5 Antineoplastic and 6 1348265 anastrozole immunomodulating agents 7 Antineoplastic and 8 19018070 ancestim immunomodulating agents 9 Antineoplastic and 10 44816294 apremilast immunomodulating agents 11 Antineoplastic and 12 1333379 arsenic trioxide immunomodulating agents 13 Antineoplastic and 14 19012585 ASPARAGINASE immunomodulating agents 15 Antineoplastic and 16 42709322 axitinib immunomodulating agents 17 Antineoplastic and 18 1314865 AzacitidineFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19014878 Azathioprine immunomodulating agents 21 Antineoplastic and 22 45893268 balugrastim immunomodulating agents 23 Antineoplastic and 24 25 19038440 basiliximab immunomodulating agents 26 Antineoplastic and 27 40239665 belatacept immunomodulating agents 28 Antineoplastic and 29 40236987 belimumab immunomodulating agents 30 Antineoplastic and 31 19015523 bendamustine immunomodulating agents 32 Antineoplastic and 33 1397141 bevacizumab immunomodulating agents 34 Antineoplastic and 35 1389888 bexarotene immunomodulating agents 36 Antineoplastic and 37 1344381 bicalutamide immunomodulating agents 38 Antineoplastic and 39 1329241 Bleomycin immunomodulating agents 40 Antineoplastic and 41 1336825 bortezomib immunomodulating agents 42 Antineoplastic and 43 42900401 bosutinib immunomodulating agents 44 Antineoplastic and 45 40241969 brentuximab vedotin immunomodulating agents 46 Antineoplastic and 47 40253793 briakinumab immunomodulating agents 48 Antineoplastic and 49 19033280 Buserelin immunomodulating agents 50 Antineoplastic and 51 1333357 Busulfan immunomodulating agents 52 Antineoplastic and 53 40222431 cabazitaxel immunomodulating agents 54 Antineoplastic and 55 43012292 cabozantinib immunomodulating agents 56 Antineoplastic and 57 40161669 canakinumab immunomodulating agents 58 Antineoplastic and 59 1337620 capecitabine immunomodulating agents 60

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1 2 3 Antineoplastic and 4 1344905 Carboplatin immunomodulating agents 5 Antineoplastic and 6 21601405 carboquone immunomodulating agents 7 Antineoplastic and 8 42873638 carfilzomib immunomodulating agents 9 Antineoplastic and 10 21601438 carmofur immunomodulating agents 11 Antineoplastic and 12 1350066 Carmustine immunomodulating agents 13 Antineoplastic and 14 21603763 catumaxomab immunomodulating agents 15 Antineoplastic and 16 45893501 cepeginterferon alfa-2b immunomodulating agents 17 Antineoplastic and 18 44818466 ceritinibFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 912263 certolizumab pegol immunomodulating agents 21 Antineoplastic and 22 1315411 cetuximab immunomodulating agents 23 Antineoplastic and 24 25 1390051 Chlorambucil immunomodulating agents 26 Antineoplastic and 27 1397599 Cisplatin immunomodulating agents 28 Antineoplastic and 29 19054825 Cladribine immunomodulating agents 30 Antineoplastic and 31 19054821 clofarabine immunomodulating agents 32 Antineoplastic and 33 43534820 cridanimod immunomodulating agents 34 Antineoplastic and 35 40242675 crizotinib immunomodulating agents 36 Antineoplastic and 37 1310317 Cyclophosphamide immunomodulating agents 38 Antineoplastic and 39 19010482 Cyclosporine immunomodulating agents 40 Antineoplastic and 41 1311078 Cytarabine immunomodulating agents 42 Antineoplastic and 43 43532299 dabrafenib immunomodulating agents 44 Antineoplastic and 45 1311409 Dacarbazine immunomodulating agents 46 Antineoplastic and 47 19036892 Daclizumab immunomodulating agents 48 Antineoplastic and 49 1311443 Dactinomycin immunomodulating agents 50 Antineoplastic and 51 1358436 dasatinib immunomodulating agents 52 Antineoplastic and 53 45893271 dasiprotimut-T immunomodulating agents 54 Antineoplastic and 55 1311799 Daunorubicin immunomodulating agents 56 Antineoplastic and 57 19024728 decitabine immunomodulating agents 58 Antineoplastic and 59 19058410 degarelix immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603721 demecolcine immunomodulating agents 5 Antineoplastic and 6 19051642 denileukin diftitox immunomodulating agents 7 Antineoplastic and 8 1525866 Diethylstilbestrol immunomodulating agents 9 Antineoplastic and 10 46221699 dinutuximab immunomodulating agents 11 Antineoplastic and 12 1315942 docetaxel immunomodulating agents 13 Antineoplastic and 14 1338512 Doxorubicin immunomodulating agents 15 Antineoplastic and 16 19080458 eculizumab immunomodulating agents 17 Antineoplastic and 18 19132294 EdrecolomabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 936429 efalizumab immunomodulating agents 21 Antineoplastic and 22 21603770 efaproxiral immunomodulating agents 23 Antineoplastic and 24 25 42900250 enzalutamide immunomodulating agents 26 Antineoplastic and 27 1344354 Epirubicin immunomodulating agents 28 Antineoplastic and 29 40230712 eribulin immunomodulating agents 30 Antineoplastic and 31 1325363 erlotinib immunomodulating agents 32 Antineoplastic and 33 1349025 Estramustine immunomodulating agents 34 Antineoplastic and 35 1151789 Etanercept immunomodulating agents 36 Antineoplastic and 37 19104221 Ethoglucid immunomodulating agents 38 Antineoplastic and 39 1350504 Etoposide immunomodulating agents 40 Antineoplastic and 41 19011440 everolimus immunomodulating agents 42 Antineoplastic and 43 1398399 exemestane immunomodulating agents 44 Antineoplastic and 45 1304850 Filgrastim immunomodulating agents 46 Antineoplastic and 47 40226579 fingolimod immunomodulating agents 48 Antineoplastic and 49 1395557 fludarabine immunomodulating agents 50 Antineoplastic and 51 955632 Fluorouracil immunomodulating agents 52 Antineoplastic and 53 21601443 fluorouracil, combinations immunomodulating agents 54 Antineoplastic and 55 1356461 Flutamide immunomodulating agents 56 Antineoplastic and 57 19020079 formestane immunomodulating agents 58 Antineoplastic and 59 19065450 fosfestrol immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21601411 fotemustine immunomodulating agents 5 Antineoplastic and 6 1304044 fulvestrant immunomodulating agents 7 Antineoplastic and 8 1319193 gefitinib immunomodulating agents 9 Antineoplastic and 10 1314924 gemcitabine immunomodulating agents 11 Antineoplastic and 12 19098566 gemtuzumab immunomodulating agents 13 Antineoplastic and 14 21603822 gestonorone immunomodulating agents 15 Antineoplastic and 16 19041065 golimumab immunomodulating agents 17 Antineoplastic and 18 1366310 GoserelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603901 gusperimus immunomodulating agents 21 Antineoplastic and 22 1366773 histrelin immunomodulating agents 23 Antineoplastic and 24 25 1377141 hydroxyurea immunomodulating agents 26 Antineoplastic and 27 44507848 Ibrutinib immunomodulating agents 28 Antineoplastic and 29 19078097 Idarubicin immunomodulating agents 30 Antineoplastic and 31 45776944 idelalisib immunomodulating agents 32 Antineoplastic and 33 19078187 Ifosfamide immunomodulating agents 34 Antineoplastic and 35 1304107 imatinib immunomodulating agents 36 Antineoplastic and 37 21603883 immunocyanin immunomodulating agents 38 Antineoplastic and 39 937368 infliximab immunomodulating agents 40 Antineoplastic and 41 1379969 Interferon Alfa-2a immunomodulating agents 42 Antineoplastic and 43 1380068 Interferon Alfa-2b immunomodulating agents 44 Antineoplastic and 45 19044394 Interferon Alfa-n1 immunomodulating agents 46 Antineoplastic and 47 1781314 interferon alfacon-1 immunomodulating agents 48 Antineoplastic and 49 722424 Interferon beta-1a immunomodulating agents 50 Antineoplastic and 51 713196 interferon beta-1b immunomodulating agents 52 Antineoplastic and 53 19122123 Interferon Type II immunomodulating agents 54 Antineoplastic and 55 19109079 Interferon-beta immunomodulating agents 56 Antineoplastic and 57 40238188 ipilimumab immunomodulating agents 58 Antineoplastic and 59 1367268 irinotecan immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19025348 ixabepilone immunomodulating agents 5 Antineoplastic and 6 1359548 lapatinib immunomodulating agents 7 Antineoplastic and 8 1101898 leflunomide immunomodulating agents 9 Antineoplastic and 10 19026972 lenalidomide immunomodulating agents 11 Antineoplastic and 12 19009705 lenograstim immunomodulating agents 13 Antineoplastic and 14 21603875 lentinan immunomodulating agents 15 Antineoplastic and 16 1315946 letrozole immunomodulating agents 17 Antineoplastic and 18 1351541 LeuprolideFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 44506753 lipegfilgrastim immunomodulating agents 21 Antineoplastic and 22 1391846 Lomustine immunomodulating agents 23 Antineoplastic and 24 25 21603788 lonidamine immunomodulating agents 26 Antineoplastic and 27 21601401 mannosulfan immunomodulating agents 28 Antineoplastic and 29 43534811 masitinib immunomodulating agents 30 Antineoplastic and 31 988447 Masoprocol immunomodulating agents 32 Antineoplastic and 33 1394337 Mechlorethamine immunomodulating agents 34 Antineoplastic and 35 1301267 Melphalan immunomodulating agents 36 Antineoplastic and 37 21603920 mepolizumab immunomodulating agents 38 Antineoplastic and 39 1436650 mercaptopurine immunomodulating agents 40 Antineoplastic and 41 1305058 Methotrexate immunomodulating agents 42 Antineoplastic and 43 19025194 methyl 5-aminolevulinate immunomodulating agents 44 Antineoplastic and 45 21603888 mifamurtide immunomodulating agents 46 Antineoplastic and 47 44816310 miltefosine immunomodulating agents 48 Antineoplastic and 49 19125635 Mitobronitol immunomodulating agents 50 Antineoplastic and 51 21603794 mitoguazone immunomodulating agents 52 Antineoplastic and 53 1389036 Mitomycin immunomodulating agents 54 Antineoplastic and 55 1309161 Mitotane immunomodulating agents 56 Antineoplastic and 57 1309188 Mitoxantrone immunomodulating agents 58 Antineoplastic and 59 19009676 molgramostim immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19051865 Muromonab-CD3 immunomodulating agents 5 Antineoplastic and 6 19012565 Mycophenolic Acid immunomodulating agents 7 Antineoplastic and 8 735843 natalizumab immunomodulating agents 9 Antineoplastic and 10 19002912 nelarabine immunomodulating agents 11 Antineoplastic and 12 1394023 nilotinib immunomodulating agents 13 Antineoplastic and 14 1315286 nilutamide immunomodulating agents 15 Antineoplastic and 16 21601412 nimustine immunomodulating agents 17 Antineoplastic and 18 44507676 obinutuzumabFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 21603807 oblimersen immunomodulating agents 21 Antineoplastic and 22 40167582 ofatumumab immunomodulating agents 23 Antineoplastic and 24 25 45892579 olaparib immunomodulating agents 26 Antineoplastic and 27 19069046 omacetaxine mepesuccinate immunomodulating agents 28 Antineoplastic and 29 1318030 Oprelvekin immunomodulating agents 30 Antineoplastic and 31 1318011 oxaliplatin immunomodulating agents 32 Antineoplastic and 33 1378382 Paclitaxel immunomodulating agents 34 Antineoplastic and 35 21603725 paclitaxel poliglumex immunomodulating agents 36 Antineoplastic and 37 19100985 panitumumab immunomodulating agents 38 Antineoplastic and 39 46221435 panobinostat immunomodulating agents 40 Antineoplastic and 41 40167554 pazopanib immunomodulating agents 42 Antineoplastic and 43 581480 pegademase bovine immunomodulating agents 44 Antineoplastic and 45 1326481 pegaspargase immunomodulating agents 46 Antineoplastic and 47 1325608 pegfilgrastim immunomodulating agents 48 Antineoplastic and 49 1714165 peginterferon alfa-2a immunomodulating agents 50 Antineoplastic and 51 21603870 peginterferon alfa-2a, combinations immunomodulating agents 52 Antineoplastic and 53 1797155 peginterferon alfa-2b immunomodulating agents 54 Antineoplastic and 55 21603869 peginterferon alfa-2b, combinations immunomodulating agents 56 Antineoplastic and 57 45775146 peginterferon beta-1a immunomodulating agents 58 Antineoplastic and 59 1304919 pemetrexed immunomodulating agents 60

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1 2 3 Antineoplastic and 4 19031224 Pentostatin immunomodulating agents 5 Antineoplastic and 6 42801287 pertuzumab immunomodulating agents 7 Antineoplastic and 8 19102785 pidotimod immunomodulating agents 9 Antineoplastic and 10 19046625 Pipobroman immunomodulating agents 11 Antineoplastic and 12 19093366 Pirarubicin immunomodulating agents 13 Antineoplastic and 14 45775206 pirfenidone immunomodulating agents 15 Antineoplastic and 16 40253110 pixantrone immunomodulating agents 17 Antineoplastic and 18 19017581 PlerixaforFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19009165 Plicamycin immunomodulating agents 21 Antineoplastic and 22 21603880 poly I:C immunomodulating agents 23 Antineoplastic and 24 25 21603881 poly ICLC immunomodulating agents 26 Antineoplastic and 27 40253122 polyplatillen immunomodulating agents 28 Antineoplastic and 29 43014237 pomalidomide immunomodulating agents 30 Antineoplastic and 31 43013182 ponatinib immunomodulating agents 32 Antineoplastic and 33 40166461 Pralatrexate immunomodulating agents 34 Antineoplastic and 35 19135793 Prednimustine immunomodulating agents 36 Antineoplastic and 37 1351779 Procarbazine immunomodulating agents 38 Antineoplastic and 39 19038536 raltitrexed immunomodulating agents 40 Antineoplastic and 41 21601413 ranimustine immunomodulating agents 42 Antineoplastic and 43 42903460 regorafenib immunomodulating agents 44 Antineoplastic and 45 43534809 ridaforolimus immunomodulating agents 46 Antineoplastic and 47 19023450 rilonacept immunomodulating agents 48 Antineoplastic and 49 1314273 rituximab immunomodulating agents 50 Antineoplastic and 51 40168385 romidepsin immunomodulating agents 52 Antineoplastic and 53 21603876 roquinimex immunomodulating agents 54 Antineoplastic and 55 40244464 ruxolitinib immunomodulating agents 56 Antineoplastic and 57 1308432 sargramostim immunomodulating agents 58 Antineoplastic and 59 21603751 satraplatin immunomodulating agents 60

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1 2 3 Antineoplastic and 4 45892883 secukinumab immunomodulating agents 5 Antineoplastic and 6 21601409 semustine immunomodulating agents 7 Antineoplastic and 8 44818461 siltuximab immunomodulating agents 9 Antineoplastic and 10 40224095 sipuleucel-T immunomodulating agents 11 Antineoplastic and 12 19034726 Sirolimus immunomodulating agents 13 Antineoplastic and 14 21603808 sitimagene ceradenovec immunomodulating agents 15 Antineoplastic and 16 1363387 sorafenib immunomodulating agents 17 Antineoplastic and 18 19136210 StreptozocinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 1336539 sunitinib immunomodulating agents 21 Antineoplastic and 22 950637 Tacrolimus immunomodulating agents 23 Antineoplastic and 24 25 1436678 Tamoxifen immunomodulating agents 26 Antineoplastic and 27 19071159 TASONERMIN immunomodulating agents 28 Antineoplastic and 29 19056756 Tegafur immunomodulating agents 30 Antineoplastic and 31 21601444 tegafur, combinations immunomodulating agents 32 Antineoplastic and 33 19011067 temoporfin immunomodulating agents 34 Antineoplastic and 35 1341149 temozolomide immunomodulating agents 36 Antineoplastic and 37 19092845 temsirolimus immunomodulating agents 38 Antineoplastic and 39 19136750 Teniposide immunomodulating agents 40 Antineoplastic and 41 42900584 teriflunomide immunomodulating agents 42 Antineoplastic and 43 19137042 Thalidomide immunomodulating agents 44 Antineoplastic and 45 1437379 Thioguanine immunomodulating agents 46 Antineoplastic and 47 19137385 Thiotepa immunomodulating agents 48 Antineoplastic and 49 19102231 Thymopentin immunomodulating agents 50 Antineoplastic and 51 21603796 tiazofurine immunomodulating agents 52 Antineoplastic and 53 40171288 tocilizumab immunomodulating agents 54 Antineoplastic and 55 42904205 tofacitinib immunomodulating agents 56 Antineoplastic and 57 1378509 Topotecan immunomodulating agents 58 Antineoplastic and 59 1342346 Toremifene immunomodulating agents 60

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1 2 3 Antineoplastic and 4 21603727 trabectedin immunomodulating agents 5 Antineoplastic and 6 43532497 trametinib immunomodulating agents 7 Antineoplastic and 8 1387104 trastuzumab immunomodulating agents 9 Antineoplastic and 10 19042545 treosulfan immunomodulating agents 11 Antineoplastic and 12 903643 Tretinoin immunomodulating agents 13 Antineoplastic and 14 21601404 triaziquone immunomodulating agents 15 Antineoplastic and 16 45893469 trifluridine, combinations immunomodulating agents 17 Antineoplastic and 18 1343039 TriptorelinFor peer review onlyimmunomodulating agents 19 Antineoplastic and 20 19101677 trofosfamide immunomodulating agents 21 Antineoplastic and 22 40161532 ustekinumab immunomodulating agents 23 Antineoplastic and 24 25 19012543 valrubicin immunomodulating agents 26 Antineoplastic and 27 40238052 Vandetanib immunomodulating agents 28 Antineoplastic and 29 45774639 vedolizumab immunomodulating agents 30 Antineoplastic and 31 40241937 Vemurafenib immunomodulating agents 32 Antineoplastic and 33 19008264 Vinblastine immunomodulating agents 34 Antineoplastic and 35 1308290 Vincristine immunomodulating agents 36 Antineoplastic and 37 19008336 Vindesine immunomodulating agents 38 Antineoplastic and 39 21601451 vinflunine immunomodulating agents 40 Antineoplastic and 41 1343346 vinorelbine immunomodulating agents 42 Antineoplastic and 43 43534805 vintafolide immunomodulating agents 44 Antineoplastic and 45 42709321 vismodegib immunomodulating agents 46 Antineoplastic and 47 40253798 voclosporin immunomodulating agents 48 Antineoplastic and 49 1337651 Vorinostat immunomodulating agents 50 Antineoplastic and 51 21603843 vorozole immunomodulating agents 52 Antineoplastic and 53 21603736 zorubicin immunomodulating agents 54 19037596 Acetylcarnitine Central nervous system stimulants 55 56 19112518 adrafinil Central nervous system stimulants 57 714785 Amphetamine Central nervous system stimulants 58 19032667 aniracetam Central nervous system stimulants 59 742185 atomoxetine Central nervous system stimulants 60

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1 2 3 1134439 Caffeine Central nervous system stimulants 4 5 40223464 Citicoline Central nervous system stimulants 6 1311826 Deanol Central nervous system stimulants 7 731533 dexmethylphenidate Central nervous system stimulants 8 719311 Dextroamphetamine Central nervous system stimulants 9 10 21604759 fencamfamin Central nervous system stimulants 11 19061288 fenethylline Central nervous system stimulants 12 19061392 fenozolone Central nervous system stimulants 13 21604773 fipexide Central nervous system stimulants 14 15 19067036 idebenone Central nervous system stimulants 16 21604777 linopirdine Central nervous system stimulants 17 709567 Lisdexamfetamine Central nervous system stimulants 18 43534829 mebicarFor peer review onlyCentral nervous system stimulants 19 20 19052682 Meclofenoxate Central nervous system stimulants 21 704053 Methamphetamine Central nervous system stimulants 22 705944 Methylphenidate Central nervous system stimulants 23 710650 modafinil Central nervous system stimulants 24 25 21604778 nizofenone Central nervous system stimulants 26 19082891 oxiracetam Central nervous system stimulants 27 727835 Pemoline Central nervous system stimulants 28 44819159 phenibut Central nervous system stimulants 29 30 43534828 PHENIBUT Central nervous system stimulants 31 21604783 pipradrol Central nervous system stimulants 32 19046654 Piracetam Central nervous system stimulants 33 21604784 pramiracetam Central nervous system stimulants 34 35 19029018 prolintane Central nervous system stimulants 36 19096031 propentofylline Central nervous system stimulants 37 19097999 pyrisuccideanol Central nervous system stimulants 38 19060358 Pyrithioxin Central nervous system stimulants 39 40 19095462 vinpocetine Central nervous system stimulants 41 21602495 chlormadinone and ethinylestradiol Contraceptives 42 40253989 chlormadinone and ethinylestradiol Contraceptives 43 1588000 Desogestrel Contraceptives 44 45 43534785 dienogest and ethinylestradiol Contraceptives 46 1519936 Etonogestrel Contraceptives 47 21602483 gestodene and ethinylestradiol Contraceptives 48 21602494 gestodene and ethinylestradiol Contraceptives 49 50 1589505 Levonorgestrel Contraceptives 51 19092358 Lynestrenol Contraceptives 52 21602490 lynestrenol and ethinylestradiol Contraceptives 53 21602476 lynestrenol and ethinylestradiol Contraceptives 54 55 1500211 Medroxyprogesterone Contraceptives 56 1300978 Megestrol Contraceptives 57 21602477 megestrol and ethinylestradiol Contraceptives 58 21602489 megestrol and ethinylestradiol Contraceptives 59 60 21602487 nomegestrol and estradiol Contraceptives

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1 2 3 1521369 Norethindrone Contraceptives 4 5 19128258 Norgestrienone Contraceptives 6 21602500 quingestanol Contraceptives 7 21602475 quingestanol and ethinylestradiol Contraceptives 8 40225722 ulipristal Contraceptives 9 10 905151 Alclometasone Corticosteroid 11 930747 amcinonide Corticosteroid 12 1115572 Beclomethasone Corticosteroid 13 920458 Betamethasone Corticosteroid 14 15 939259 Budesonide Corticosteroid 16 998415 Clobetasol Corticosteroid 17 950882 clocortolone Corticosteroid 18 1507705 CortisoneFor peer review onlyCorticosteroid 19 20 917205 Desonide Corticosteroid 21 917336 Desoximetasone Corticosteroid 22 1518254 Dexamethasone Corticosteroid 23 960988 Diflorasone Corticosteroid 24 25 1196514 flunisolide Corticosteroid 26 19110714 Fluocinolone Acetonide Corticosteroid 27 955252 Fluocinonide Corticosteroid 28 19055344 Fluocortolone Corticosteroid 29 30 955583 Fluorometholone Corticosteroid 31 956266 Flurandrenolide Corticosteroid 32 1149380 fluticasone Corticosteroid 33 966468 Halcinonide Corticosteroid 34 35 949759 halobetasol Corticosteroid 36 975125 Hydrocortisone Corticosteroid 37 992127 Loteprednol Corticosteroid 38 909021 medrysone Corticosteroid 39 40 1506270 Methylprednisolone Corticosteroid 41 905233 Mometasone Corticosteroid 42 928110 prednicarbate Corticosteroid 43 1550557 prednisolone Corticosteroid 44 45 1551099 Prednisone Corticosteroid 46 977421 rimexolone Corticosteroid 47 903963 Triamcinolone Corticosteroid 48 21601546 altizide and potassium-sparing agents Diuretics 49 50 991382 Amiloride Diuretics 51 1316354 Bendroflumethiazide Diuretics 52 21601475 bendroflumethiazide and potassium Diuretics 53 bendroflumethiazide and potassium-sparing 54 21601551 agents Diuretics 55 932745 Bumetanide Diuretics 56 57 21601524 bumetanide and potassium Diuretics 58 21601555 bumetanide and potassium-sparing agents Diuretics 59 21601552 butizide and potassium-sparing agents Diuretics 60

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1 2 3 19019698 Canrenone Diuretics 4 5 992590 Chlorothiazide Diuretics 6 21601478 chlorothiazide and potassium Diuretics 7 21601485 chlorothiazide, combinations Diuretics 8 21601506 chlortalidone and potassium Diuretics 9 10 21601548 chlortalidone and potassium-sparing agents Diuretics 11 1395058 Chlorthalidone Diuretics 12 19051444 cicletanine Diuretics 13 21601495 clofenamide Diuretics 14 15 21601508 clofenamide and potassium Diuretics 16 19099181 Clopamide Diuretics 17 21601505 clopamide and potassium Diuretics 18 21601500 clorexoloneFor peer review onlyDiuretics 19 20 21601502 clorexolone, combinations with psycholeptics Diuretics 21 19010927 conivaptan Diuretics 22 19010015 Cyclopenthiazide Diuretics 23 21601481 cyclopenthiazide and potassium Diuretics 24 25 21601549 cyclopenthiazide and potassium-sparing agents Diuretics 26 19082886 cyclothiazide Diuretics 27 21601483 cyclothiazide and potassium Diuretics 28 21601545 epitizide and potassium-sparing agents Diuretics 29 30 1309799 eplerenone Diuretics 31 19103548 Ethacrynic Acid Diuretics 32 21601531 etozolin Diuretics 33 21601501 fenquizone Diuretics 34 35 956874 Furosemide Diuretics 36 21601523 furosemide and potassium Diuretics 37 21601554 furosemide and potassium-sparing agents Diuretics 38 974166 Hydrochlorothiazide Diuretics 39 40 21601477 hydrochlorothiazide and potassium Diuretics 41 21601488 hydrochlorothiazide, combinations Diuretics 42 1376289 Hydroflumethiazide Diuretics 43 21601476 hydroflumethiazide and potassium Diuretics 44 45 21601486 hydroflumethiazide, combinations Diuretics 46 978555 Indapamide Diuretics 47 21601473 mebutizide Diuretics 48 21601547 mebutizide and potassium-sparing agents Diuretics 49 50 19000556 Mefruside Diuretics 51 21601507 mefruside and potassium Diuretics 52 19003070 Mersalyl Diuretics 53 905273 Methyclothiazide Diuretics 54 55 21601482 methyclothiazide and potassium Diuretics 56 21601497 meticrane Diuretics 57 907013 Metolazone Diuretics 58 21601550 metolazone and potassium-sparing agents Diuretics 59 60 21601529 muzolimine Diuretics

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1 2 3 19025498 piretanide Diuretics 4 5 948787 Polythiazide Diuretics 6 21601479 polythiazide and potassium Diuretics 7 19081320 quinethazone Diuretics 8 21601504 quinethazone and potassium Diuretics 9 10 970250 Spironolactone Diuretics 11 19137056 Theobromine Diuretics 12 21601527 tienilic acid Diuretics 13 19036797 tolvaptan Diuretics 14 15 942350 torsemide Diuretics 16 904542 Triamterene Diuretics 17 904639 Trichlormethiazide Diuretics 18 21601480 trichlormethiazideFor peer and potassium review onlyDiuretics 19 20 21601544 trichlormethiazide and potassium-sparing agents Diuretics 21 19010493 Xipamide Diuretics 22 1139042 Acetylcysteine Mucolytics 23 19088167 Ambroxol Mucolytics 24 25 19030493 Bromhexine Mucolytics 26 19041843 Carbocysteine Mucolytics 27 21603389 combinations Mucolytics 28 21603387 domiodol Mucolytics 29 30 1125443 Dornase Alfa Mucolytics 31 19095266 eprazinone Mucolytics 32 19058933 erdosteine Mucolytics 33 19071861 letosteine Mucolytics 34 35 994058 Mannitol Mucolytics 36 1354698 Mesna Mucolytics 37 21603393 neltenexine Mucolytics 38 19039512 sobrerol Mucolytics 39 40 21603390 stepronin Mucolytics 41 903031 tiopronin Mucolytics 42 1363516 5-Hydroxytryptophan Psychotherapeutic agents 43 19018226 Acepromazine Psychotherapeutic agents 44 45 19029555 acetophenazine Psychotherapeutic agents 46 21604750 agomelatine Psychotherapeutic agents 47 21604715 alaproclate Psychotherapeutic agents 48 19032424 amineptin Psychotherapeutic agents 49 50 19057607 Amisulpride Psychotherapeutic agents 51 710062 Amitriptyline Psychotherapeutic agents 52 713109 Amoxapine Psychotherapeutic agents 53 757688 aripiprazole Psychotherapeutic agents 54 55 40164052 Asenapine Psychotherapeutic agents 56 19016440 Benperidol Psychotherapeutic agents 57 19058055 bifemelane Psychotherapeutic agents 58 19039227 bromperidol Psychotherapeutic agents 59 60 750982 Bupropion Psychotherapeutic agents

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1 2 3 21604508 butaperazine Psychotherapeutic agents 4 5 19039883 butriptyline Psychotherapeutic agents 6 45893485 cariprazine Psychotherapeutic agents 7 19122262 chlorproethazine Psychotherapeutic agents 8 794852 Chlorpromazine Psychotherapeutic agents 9 10 19095002 Chlorprothixene Psychotherapeutic agents 11 797617 Citalopram Psychotherapeutic agents 12 798834 Clomipramine Psychotherapeutic agents 13 21604532 clopenthixol Psychotherapeutic agents 14 15 19100363 clothiapine Psychotherapeutic agents 16 800878 Clozapine Psychotherapeutic agents 17 19051234 cyamemazine Psychotherapeutic agents 18 716968 DesipramineFor peer review onlyPsychotherapeutic agents 19 20 717607 Desvenlafaxine Psychotherapeutic agents 21 19023846 dibenzepin Psychotherapeutic agents 22 21604705 dimetacrine Psychotherapeutic agents 23 21604500 dixyrazine Psychotherapeutic agents 24 25 19037989 Dothiepin Psychotherapeutic agents 26 738156 Doxepin Psychotherapeutic agents 27 739323 Droperidol Psychotherapeutic agents 28 715259 duloxetine Psychotherapeutic agents 29 30 715939 Escitalopram Psychotherapeutic agents 31 21604717 etoperidone Psychotherapeutic agents 32 21604524 fluanisone Psychotherapeutic agents 33 755695 Fluoxetine Psychotherapeutic agents 34 35 19055982 Flupenthixol Psychotherapeutic agents 36 756018 Fluphenazine Psychotherapeutic agents 37 19056465 Fluspirilene Psychotherapeutic agents 38 751412 Fluvoxamine Psychotherapeutic agents 39 40 21604748 gepirone Psychotherapeutic agents 41 766529 Haloperidol Psychotherapeutic agents 42 19017241 iloperidone Psychotherapeutic agents 43 778268 Imipramine Psychotherapeutic agents 44 45 21604690 imipramine oxide Psychotherapeutic agents 46 19122204 Iprindole Psychotherapeutic agents 47 21604725 iproclozide Psychotherapeutic agents 48 21604724 iproniazide Psychotherapeutic agents 49 50 781705 Isocarboxazid Psychotherapeutic agents 51 43560354 levomilnacipran Psychotherapeutic agents 52 21604554 levosulpiride Psychotherapeutic agents 53 19124477 Lithium Psychotherapeutic agents 54 55 19091830 Lofepramine Psychotherapeutic agents 56 792263 Loxapine Psychotherapeutic agents 57 40230761 lurasidone Psychotherapeutic agents 58 794147 Maprotiline Psychotherapeutic agents 59 60 19072021 medifoxamine Psychotherapeutic agents

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1 2 3 19110751 MELITRACEN Psychotherapeutic agents 4 5 703083 Mesoridazine Psychotherapeutic agents 6 19005147 Methotrimeprazine Psychotherapeutic agents 7 19072088 metylperon Psychotherapeutic agents 8 19007737 Mianserin Psychotherapeutic agents 9 10 19080226 milnacipran Psychotherapeutic agents 11 19072123 minaprine Psychotherapeutic agents 12 725131 Mirtazapine Psychotherapeutic agents 13 19010652 Moclobemide Psychotherapeutic agents 14 15 709699 Molindone Psychotherapeutic agents 16 21604519 moperone Psychotherapeutic agents 17 21604560 mosapramine Psychotherapeutic agents 18 714684 nefazodoneFor peer review onlyPsychotherapeutic agents 19 20 19127550 Nialamide Psychotherapeutic agents 21 19128066 Nomifensine Psychotherapeutic agents 22 721724 Nortriptyline Psychotherapeutic agents 23 785788 olanzapine Psychotherapeutic agents 24 25 19129635 Opipramol Psychotherapeutic agents 26 21604739 oxaflozane Psychotherapeutic agents 27 19025922 oxypertine Psychotherapeutic agents 28 703244 paliperidone Psychotherapeutic agents 29 30 722031 Paroxetine Psychotherapeutic agents 31 19028044 Penfluridol Psychotherapeutic agents 32 19131663 Perazine Psychotherapeutic agents 33 19053565 periciazine Psychotherapeutic agents 34 35 733008 Perphenazine Psychotherapeutic agents 36 733896 Phenelzine Psychotherapeutic agents 37 745790 Pimozide Psychotherapeutic agents 38 19093225 pipamperone Psychotherapeutic agents 39 40 19133992 pipothiazine Psychotherapeutic agents 41 21604744 pivagabine Psychotherapeutic agents 42 19052903 Promazine Psychotherapeutic agents 43 19115044 prothipendyl Psychotherapeutic agents 44 45 754270 Protriptyline Psychotherapeutic agents 46 766814 quetiapine Psychotherapeutic agents 47 19098514 quinupramine Psychotherapeutic agents 48 715710 rasagiline Psychotherapeutic agents 49 50 19084693 reboxetine Psychotherapeutic agents 51 19035226 Remoxipride Psychotherapeutic agents 52 735979 Risperidone Psychotherapeutic agents 53 766209 Selegiline Psychotherapeutic agents 54 55 19050633 sertindole Psychotherapeutic agents 56 739138 Sertraline Psychotherapeutic agents 57 19136626 Sulpiride Psychotherapeutic agents 58 19100431 sultopride Psychotherapeutic agents 59 60 19041817 thiopropazate Psychotherapeutic agents

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1 2 3 19000305 thioproperazine Psychotherapeutic agents 4 5 700299 Thioridazine Psychotherapeutic agents 6 700465 Thiothixene Psychotherapeutic agents 7 19041910 tianeptine Psychotherapeutic agents 8 19008012 Tiapride Psychotherapeutic agents 9 10 19100775 toloxatone Psychotherapeutic agents 11 703470 Tranylcypromine Psychotherapeutic agents 12 703547 Trazodone Psychotherapeutic agents 13 704984 Trifluoperazine Psychotherapeutic agents 14 15 19005101 Trifluperidol Psychotherapeutic agents 16 19005104 Triflupromazine Psychotherapeutic agents 17 705755 Trimipramine Psychotherapeutic agents 18 19006186 TryptophanFor peer review onlyPsychotherapeutic agents 19 20 743670 venlafaxine Psychotherapeutic agents 21 19043327 veralipride Psychotherapeutic agents 22 40234834 vilazodone Psychotherapeutic agents 23 19008261 Viloxazine Psychotherapeutic agents 24 25 44507700 vortioxetine Psychotherapeutic agents 26 21604710 zimeldine Psychotherapeutic agents 27 712615 ziprasidone Psychotherapeutic agents 28 19102109 zotepine Psychotherapeutic agents 29 30 19010886 Zuclopenthixol Psychotherapeutic agents 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 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 34 35 36 37 38 39 40 155x156mm (300 x 300 DPI) 41 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 74 of 76

1 2 3 4 5 6 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 34 154x124mm (300 x 300 DPI) 35 36 37 38 39 40 41 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 Page 75 of 76 BMJ Open

1 2 STROBE Statement—Checklist of items that should be included 3 4 Item Location in manuscript where items 5 No Recommendation are reported 6 Title and abstract 1 (a) Indicate the study’s design with a Abstract: Design and setting: 7 commonly used term in the title or the “descriptive drug utilization study” 8 abstract 9 10 (b) Provide in the abstract an informative Abstract 11 and balanced summary of what was done 12 and what was found 13 14 Introduction 15 Background/rationale 2 Explain the scientific background and Introduction 16 rationale for the investigation being 17 reported 18 For peer review only 19 Objectives 3 State specific objectives, including any Introduction: From “Our primary aim 20 prespecified hypotheses was ..” until “ambulatory setting” 21 Methods 22 23 Study design 4 Present key elements of study design early Abstract: Design and setting 24 in the paper Methods: Data sources: “We conducted 25 a drug utilisation study using pediatric 26 27 patient populations…” 28 Setting 5 Describe the setting, locations, and relevant Abstract: Design and setting 29 dates, including periods of recruitment, 30 Methods: Data sources, Data collection 31 exposure, follow-up, and data collection 32 Participants 6 (a) Give the eligibility criteria, and the Abstract: Design and setting, Patients 33 sources and methods of selection of Methods: Data collection 34 participants 35 36 Variables 7 Clearly define all outcomes, exposures, Methods: Data sources, Data collection, 37 predictors, potential confounders, and effect Statistical analysis 38 modifiers. Give diagnostic criteria, if 39 applicable 40 41 Data sources/ 8* For each variable of interest, give sources Methods: Data extraction & Statistical 42 measurement of data and details of methods of assessment analysis 43 (measurement). Describe comparability of 44 assessment methods if there is more than 45 46 one group 47 Bias 9 Describe any efforts to address potential Discussion: Strengths and limitations 48 sources of bias 49 Study size 10 Explain how the study size was arrived at Methods: Data sources, Data collection 50 51 Results: Study population 52 53 Quantitative 11 Explain how quantitative variables were Methods: Statistical analysis 54 variables handled in the analyses. If applicable, 55 describe which groupings were chosen and 56 why 57 58 Statistical methods 12 (a) Describe all statistical methods, Methods: Statistical analysis 59 including those used to control for 60 confounding

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1 2 (b) Describe any methods used to examine Methods: Statistical analysis 3 subgroups and interactions 4 5 (c) Explain how missing data were n/a 6 addressed 7 (d) If applicable, describe analytical Methods: Data collection 8 9 methods taking account of sampling 10 strategy 11 (e) Describe any sensitivity analyses n/a 12 13 Results 14 Participants 13* (a) Report numbers of individuals at each Results: Study population 15 stage of study—eg numbers potentially 16 eligible, examined for eligibility, confirmed 17 18 Foreligible, peer included in thereview study, completing only 19 follow-up, and analysed 20 (b) Give reasons for non-participation at n/a 21 each stage 22 23 (c) Consider use of a flow diagram n/a 24 Descriptive data 14* (a) Give characteristics of study participants Results: Study population, User- and 25 (eg demographic, clinical, social) and prescription prevalence 26 27 information on exposures and potential 28 confounders 29 (b) Indicate number of participants with n/a 30 missing data for each variable of interest 31 32 Outcome data 15* Report numbers of outcome events or Results: (Inpatients) (Ambulatory) user- 33 summary measures and prescription prevalence, Most 34 commonly used drugs by class in an 35 inpatient/ambulatory setting 36 37 Main results 16 (a) Give unadjusted estimates and, if Results 38 applicable, confounder-adjusted estimates Tables & Figures 39 40 and their precision (eg, 95% confidence 41 interval). Make clear which confounders 42 were adjusted for and why they were 43 included 44 45 (b) Report category boundaries when n/a 46 continuous variables were categorized 47 (c) If relevant, consider translating n/a 48 estimates of relative risk into absolute risk 49 50 for a meaningful time period 51 Other analyses 17 Report other analyses done—eg analyses of n/a 52 subgroups and interactions, and sensitivity 53 54 analyses 55 Discussion 56 Key results 18 Summarise key results with reference to Discussion: From “To our 57 58 study objectives knowledge…” until “Australia” 59 Limitations 19 Discuss limitations of the study, taking into Discussion: Strengths and limitations 60 account sources of potential bias or imprecision. Discuss both direction and

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1 2 magnitude of any potential bias 3 Interpretation 20 Give a cautious overall interpretation of Discussion: Comparison with literature, 4 5 results considering objectives, limitations, Implications for Practice and Policy 6 multiplicity of analyses, results from similar 7 studies, and other relevant evidence 8 Generalisability 21 Discuss the generalisability (external Discussion: Implications for Practice 9 10 validity) of the study results and Policy 11 12 Other information 13 14 Funding 22 Give the source of funding and the role of Title Page: Funding Source 15 the funders for the present study and, if 16 applicable, for the original study on which 17 the present article is based 18 For peer review only 19 20 *Give information separately for exposed and unexposed groups. 21 22 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 23 24 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 25 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 26 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 27 available at www.strobe-statement.org. 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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