Identifying drug substances of screening tool for older persons’ appropriate prescriptions for Japanese

Medication prescribing for the elderly is a complex task that requires special care and increased patient monitoring, while appropriate medications are vital for keeping elderly patients healthy, especially those with multiple diseases who use polypharmacy. Japan is known as the most aged country with 26.5% of the population older than 65 [1]. Therefore, a regulatory meeting was established in 2017 to discuss appropriate prescribing and medication use in the elderly and ensure adaptability to the changing medical status of patients [2]. Furthermore, this strategy is expected to reduce the side effects and polypharmacy and ensure reasonable medical costs [2]. Japan has been releasing new drugs to the world, and its regulatory authorities and pharmaceutical companies are expected to provide enough information and formulate precautions for the use of drugs in the elderly. However, since clinical trials mostly exclude the elderly, clinical information for this demographic is scarce for most new drugs, studies are eagerly anticipated, which is true in every country and region.

To aid physicians to prescribe appropriately, the Japan Geriatric Society (JGS) first published guidelines for safe pharmacotherapy in the elderly, and a list of potentially inappropriate medication uses in 2005 [3], which is recognized as the Japanese version of the Beers criteria [4]. It was updated in 2015, providing the Screening Tool for Older Persons’ Appropriate Prescriptions for the Japanese (STOPP-J) for drugs to be prescribed with special caution and drugs to be considered for treatment [5]. Ahead of this, in Europe, the Screening Tool of Older Persons’ potentially inappropriate Prescription (STOPP) [6, 7], proposed by the Ireland study group, is reported as a useful guide for identifying potentially inappropriate medications, particularly for hospital inpatients [8].

Recent evolutions in medical informatics and computerization have enabled researchers to use various databases and analytical tools in their studies. Studies using the databases of regulatory authorities, insurance claims, and medical records, as well as patients’ reports have become popular in public health disciplines and drug development phases recently as well as post-marketing phase. However, there are still challenges associated with the methods of collection, coding, and analysis of data for assessing the accuracy of medication use. The use of identical names or a systematic code for drugs enhances the efficiency of research with large-scale databases [9]. However, coding of medication data depends on the regulatory system, which varies between countries. For example, the National Drug Code in the US (https://​www.​fda.​gov/​Drugs/​InformationOnDru​gs/​ucm142438.​htm.​) differs from the BNF codes (https://​data.​gov.​uk/​dataset/​176ae264-2484-4afe-a297-d51798eb8228/​resource/​bac33489-b3dc-47ec-b688-da9cf40e25bd) in the UK. For research on medicine use in the elderly, the AGS Beers criteria [4], STOPP/START [7], and JGS guidelines [5] have been used. However, these guidelines mainly provide drug categories and medication considerations, which lack consistency (Table 1). In addition, they do not specifically define molecular entities, so that researchers have to select drug substances to be studied. Therefore, variation often occurs when using databases to investigate drug use. To facilitate computerized work with databases, Groot et al. [8] proposed a uniform coding for drugs approved in the Netherlands, compliant with the STOPP/START. On the other hand, Japan has several drug-coding systems, depending on the regulatory objective, such as those for labeling information, reimbursement of medical fees, and a third for logistics, but they are solely for domestic use. A variety of proprietary databases is currently available in Japan, and medical terms are mostly compared between them using the International Classification of Diseases (ICD) [10] or the Medical Dictionary for Regulatory Activities (MedDRA) [11], which are internationally recognized in pharmacoepidemiological studies. Unfortunately, due to nationally defined drug coding based on approval, the indications differ, and the classification of medication data may not be consistent across databases. Furthermore, additional efforts for drug identification and matching are necessary when coding systems are different. This process could introduce mismatching and misinterpretation flaws into studies using multiple databases. Therefore, it would be worthwhile to standardize drug codes for international use, e.g., global pharmacovigilance, as the aforementioned Dutch group did by identifying STOPP/START drugs at the substance level and using international coding systems [8]. However, while a local version of the Beers criteria and STOPP/START has been proposed in Japan [12, 13], no guidelines have been presented on how to encode medications. In this paper, we present a proposal to encode drugs in JGS medication guidelines using the Anatomical Therapeutic Chemical Classification System (ATC) [14], supporting the extraction and validity of the medication use data.

The drug list is presented in Tables 3, 4, and 5. Of the 236 encoded drug substances, 197 matched the 5th level of the ATC, along with 10 of 26 combinations. No ATC was available at the 5th level for 39 substances and, therefore, they were identified as 4th level substances. If multiple ATCs at the 5th level were available for one substance, the best pharmacological match or the indication-matched ATC was selected and presented with the rest of the possible ATCs. These lists are available as a PDF and spreadsheet at http://​docrd.​jp/​ftp_​up/​STOPP-J%20​List.​pdf and http://​docrd.​jp/​ftp_​up/​STOPP-J%20​List.​xlsx, and also on the JGS web page for the STOPP-J in Japanese, http://​www.​jpn-geriat-soc.​or.​jp/​tool/​pdf/​list_​02.​pdf and http://​www.​jpn-geriat-soc.​or.​jp/​tool/​xls/​list_​03.​xlsx. Since the JGS’s list was prepared as a support tool for daily medical practices, medicines rarely used or withdrawn were excluded from our list. Medicines used for short-term treatments were also excluded. The STOPP-J shows all Insulin products as drugs to be prescribed with special caution, however, if describing more accurately it recommends prescribers consider to stop sliding scale administration. This indicates that insulins can be prescribed and, therefore, they are excluded from coding.

Combination products were separately listed (Table 5) and were divided into three groups, consisting of one where the combination of exact substances was found in the ATC, such as amlodipine besylate and irbesartan (C09DB05), the ATC representing combination such as levodopa and decarboxylase inhibitor (N04BA02), and another where each substance had an individual ATC. Among the constituent substances in the latter case, the ATCs were presented only for the JGS listed substances. For example, only aspirin was selected from BUFFERIN Combination Tablet® with aspirin, aluminum glycinate, and magnesium carbonate. If the combination product consisted of the same substances in different proportions, different codes were assigned by the price list. For example, combinations of atorvastatin calcium hydrate, and amlodipine besylate were coded 2190101, 2190102, 2190103, or 2109104, depending on their compounding ratio. In addition, drugs can be categorized differently in the Japanese pricing list and have several codes; for example, BUFFERIN Combination Tablet® is 1143010 as “antipyretics, analgesics, and anti-inflammatory agents” and 3399100 as “other agents relating to blood and body fluids” All codes are listed in the tables.

The STOPP-J drug list is proposed in this study as a starting point for discussion for researchers. Our consolidated lists can be used for pharmacoepidemiological database studies. Some WHO ATC codes were omitted owing to regionalized drug availability or combination drugs, which must be considered when using or interpreting the present data.