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  • Research article
  • Open Access
  • Open Peer Review

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

BMC Geriatrics201818:154

https://doi.org/10.1186/s12877-018-0835-y

©  The Author(s). 2018

  • Received: 19 September 2017
  • Accepted: 10 June 2018
  • Published:
Open Peer Review reports

Abstract

Background

In 2015, the Japan Geriatric Society (JGS) updated “the Guidelines for Medical Treatment and its Safety in the elderly,” accompanied with the Screening Tool for Older Persons’ Appropriate Prescriptions for Japanese (STOPP-J): “drugs to be prescribed with special caution” and “drugs to consider starting.” The JGS proposed the STOPP-J to contribute to improving prescribing quality; however, each decision should be carefully based on medical knowledge. The STOPP-J shows examples of commonly prescribed drug substances, but not all relevant drugs. This research aimed to identify substances using such coding, as a standardized classification system would support medication monitoring and pharmacoepidemiologic research using such health-related information.

Methods

A voluntary team of three physicians and two pharmacists identified possible approved medicines based on the STOPP-J, and matched certain drug substances to the Anatomical Therapeutic Chemical Classification (ATC) and the Japanese price list as of 2017 February. Injectables and externally used drugs were excluded, except for self-injecting insulin, since the STOPP-J guidelines are intended to cover medicines used chronically for more than one month. Some vaccines are not available in the Japanese price list since they not reimbursed through the national health insurance.

Results

The ATC 5th level was not available for 39 of the 235 identified substances, resulting in their classification at the ATC 4th level. Furthermore, among 26 combinations, 10 products were matched directly to the ATC 5th level of the exact substances, and others were linked to the ATC representing the combination or divided into multiple substances for classification if the combination was not listed in the ATC.

Conclusion

This initial work demonstrates the challenge of matching ATC codes and the Japan standard commodity classification codes corresponding to STOPP-J substances. Since coding facilitates database analysis, the proposed drug list could be applied to research using large databases to examine prescribing patterns in patients older than 75 years or who are frail. Since ATC is not available for some substances, Japanese medicines need the process to be registered in the ATC for an effective screening tool to be developed for STOPP-J.

Keywords

  • ATC
  • Geriatric patients
  • STOPP-J
  • Database
  • Appropriate prescribing

Background

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/InformationOnDrugs/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.
Table 1

Characteristics of pharmacotherapy criteria for older adults

 

AGS Beer’s criteria 2015 1)

STOPP/START v2 2015 2)

JGS STOPP-J 2015 3)

Latest version Developed

AGS

Study group at University College Cork

JGS

Original version (year, developer)

1991, Dr. Beers

2008, Study group at University College Cork

2005, JGS

Target population

United States; 65 and older; Ambulatory, acute, and institutionalized settings

Europe-wide prescribing practices;65 and older; in most clinical settings

Japan; 75 and older; 74 and younger with frailty; 65 and older in need of nursing care; chronic treatment

Therapeutic category / drug

26 potentially inappropriate medication (PIM)

12 PIM due to drug-disease/ drug-syndrome interactions

5 PIM to be used with caution

10 PIM non-anti-infective drug-drug interactions that should be avoided in older adults

80 criteria in STOPP

34 criteria in START

29 groups for drugs to be prescribed with special caution

8 groups for drugs to consider starting

Remarks

Supplement information: “Quality of evidence” and “Strength of Recommendation”

For adverse drug events prevention and cost reduction

Supplement information: “Quality of evidence” and “Strength of Recommendation”

Abbreviations:

AGS: American Geriatric Society

JGS: Japan Geriatric Society

PIM: Potentially Inappropriate Medication use in older adults

STOPP: Screening Tool of Older People’s potentially inappropriate Prescriptions

START: Screening Tool to Alert doctors to Right Treatment

STOPP-J: Screening Tool for Older Persons’ Appropriate Prescriptions for Japanese

1)American Geriatrics Society. 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63:2227–2246

2)O’Mahony D, O’Sullivan D, Byrne S, O’Connor M, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44:213–218

3)Kojima T, Mizukami K, Tomita N, Arai H, Ohrui T, Eto M, et al. Screening Tool for Older Persons’ Appropriate Prescriptions for Japanese: Report of the Japan Geriatrics Society Working Group on“Guidelines for medical treatment and its safety in the elderly.” Geriatrics Gerontology Int. 2016;16:983–1001

Methods

Process for listing drug substances

This study was set up voluntarily by three physicians (Akishita, Kojima, and Ishii) and two pharmacists (Akazawa and Nomura) who have experience with studies on drug use in the elderly, using both clinical observations and databases. The STOPP-J 2015 developed by the JGS through systematic review, repeated group discussion, and review by the related academic societies, followed by public consultation [15], was the basis for this study. This JGS tool for medications for older persons does not include details on drug dosage, frequency, or duration of administration, but rather includes drug categories or names. The first step involved drafting a list of approved proprietary names based on JGS guidelines with the support of the Japan Pharmaceutical Information Center (JAPIC), an organization that provides drug information and codes to the Ministry of Health, Labour and Welfare, and pharmaceutical companies. JAPIC provided the English and Japanese names of medicinal substances, supervised by Akazawa and Nomura. The National Health Insurance Drug Price List as of February 2017 [16] was referenced for substance names in Japanese. They included all relevant active substances approved in Japan, which were grouped into specific categories, e.g., the statin category included atorvastatin, simvastatin, pitavastatin, pravastatin, fluvastatin, and rosuvastatin.

In the second step, the physicians, Kojima and Ishii, reviewed the drafted drug names in parallel from the perspectives of clinical treatment of the elderly, supervised by Akishita to reach a consensus. Since the JGS guidelines suggest controlling long-term medication for older persons to avoid untoward systemic adverse events occurring in any case where a drug is used or unused, external drugs and injections were excluded, except for self-injection. Simultaneously, the pharmacists matched the Japanese drug names with the national price list and the English drug names with ATC codes according to pharmacological criteria. Yonekawa helped encoding work. All possible oral indications were considered. Table 2 shows the criteria used to choose substances, categories, and codes.
Table 2

Procedures and concepts for listing drugs and codes

Listing drugs

- Listed JGS substances were limited to those approved as medicinal product for oral use in Japan, except insulin.

- Listed JGS substances were prescribed for long-term use in general.

- If a combination drug is comprised with more than one of listed therapeutic category, combinations were presented in Table 5.

Coding with ATC

- If ATC codes at the 5th level cannot be directly matched to the substance, an alternate 4th level code is proposed by searching online [1].

- The 5th level ATC code is proposed when it is available for the combination, otherwise ATC codes are searched for each substance.

- ATC codes for topical use were excluded

Coding with Japan code

- Some vaccines are not available because vaccine is not covered by the pricing list for the national health insurance but by other public support.

- The pricing list is available for medicinal products currently in the market.

Abbreviations:

JGS: Japan Geriatric Society

ATC: Anatomical Therapeutic Chemical

1)WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2017. https://www.whocc.no/atc_ddd_index/ Accessed: Accessed 5 June 2017

Drug classification systems

There are two major global drug classification systems; the Anatomical Therapeutic Classification by the European Pharmaceutical Market Research Association (EPhMRA) [17] and the ATC created by the World Health Organization (WHO) Collaborating Centre for Drug Statistics [14]. Our study used the WHO ATC classification, which has codes at the substance level known as the 5th level.

In Japan, several drug-coding systems exist. The Japan standard commodity classification includes classes for drugs, which appear similar to the 3rd level of the ATC. However, it should be used with caution since it has not been updated since 1990 and, therefore, numerous new drugs are coded as “others.” Based on this system, the National Health Insurance Drug Price List [16, 18] provides 7-digit drug codes at substance level, similar to the ATC 5th level, and 12-digit codes at the product level. In contrast with the ATC process, we extracted the code using the first 7-digit  numeric code from the 12-digit alphanumeric code to represent the substance level.

The selected drugs and the corresponding codes, proposed first by Nomura and Yonekawa, were compared with those formulated separately by the Japanese system vendor, Data Horizon Corporation (https://www.dhorizon.co.jp). Then, the differences were checked and returned to both the authors and the corporation to reach a consensus.

Results

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%20List.pdf and http://docrd.jp/ftp_up/STOPP-J%20List.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.
Table 3

Proposal for drug coding of “List of drugs to be prescribed with special caution” 1)

Therapeutic category/JAN English name

Japan 2)

ATC3)

Nervous system: Overall antipsychotic drugs - Antipsychotic drugs

Aripiprazole Hydrate

1179045

N05AX12

Asenapine Maleate

1179056

N05AH05

Blonanserin

1179048

N05AX

Bromperidol

1179028

N05 AD06

Chlorpromazine Hydrochloride

1171001

N05AA01

Chlorpromazine Phenolphthalinate

1171005

N05AA01

Clocapramine Hydrochloride Hydrate

1179030

N05AX

Clozapine

1179049

N05AH02

Fluphenazine Maleate

1172009

N05AB02

Haloperidol

1179020

N05 AD01

Levomepromazine Maleate

1172014

N05AA02

Mosapramine Hydrochloride

1179035

N05AX10

Nemonapride

1179036

N05AL

Olanzapine

1179044

N05AH03

Oxypertine

1179011

N05AE01

Paliperidone

1179053

N05AX13

Perphenazine

1172006

1172007

N05AB03

Perphenazine Fendizoate

1172004

N05AB03

Perphenazine Maleate

1172013

N05AB03

Perospirone Hydrochloride Hydrate

1179043

N05AX

Pimozide

1179022

N05AG02

Pipamperone Hydrochloride

1179006

N05 AD05

Prochlorperazine Maleate

1172010

N05AB04

Propericiazine (Periciazine)

1172005

N05 AC01

Quetiapine Fumarate

1179042

N05AH04

Risperidone

1179038

N05AX08

Spiperone

1179015

N05 AD

Sulpiride

1179016

2329009

N05AL01

Sultopride Hydrochloride

1179032

N05AL02

Tiapride Hydrochloride

1190004

N05AL03

Timiperone

1179026

N05 AD

Zotepine

1179024

N05AX11

Combination (see Table 5)

Nervous system: Benzodiazepines

Alprazolam

1124023

N05BA12

Bromazepam

1124020

N05BA08

Brotizolam

1124009

N05CD09

Chlordiazepoxide

1124028

N05BA02

Clorazepate Dipotassium

1124015

N05BA05

Clotiazepam

1179012

N05BA21

Cloxazolam

1124014

N05BA22

Diazepam

1124017

N05BA01

Estazolam

1124001

N05CD04

Ethyl Loflazepate

1124029

N05BA18

Etizolam

1179025

N05BA19

Fludiazepam

1124019

N05BA17

Flunitrazepam

1124008

N05CD03

Flurazepam Hydrochloride

1124002

N05CD01

Flutazolam

1124024

N05BA

Flutoprazepam

1124027

N05BA

Haloxazolam

1124005

N05CD

Lorazepam

1124022

N05BA06

Lormetazepam

1124010

N05CD06

Medazepam

1124021

N05BA03

Mexazolam

1124025

N05BA

Nimetazepam

1124004

N05BA

Nitrazepam

1124003

N05CD02

Oxazolam

1124013

N05BA

Quazepam

1124030

N05CD10

Rilmazafone Hydrochloride Hydrate

1129006

N05CD

Tofisopam

1124026

N05BA23

Triazolam

1124007

N05CD05

Nervous system: Non-benzodiazepines

  

Eszopiclone

1129010

N05CF04

Zolpidem Tartrate

1129009

N05CF02

Zopiclone

1129007

N05CF01

Nervous system: Tricyclic antidepressants

Amitriptyline Hydrochloride

1179002

N06AA09

Amoxapine

1179001

N06AA17

Clomipramine Hydrochloride

1174002

N06AA04

Dosulepin Hydrochloride

1179027

N06AA16

Imipramine Hydrochloride

1174006

N06AA02

Lofepramine Hydrochloride

1174004

N06AA07

Nortriptyline Hydrochloride

1179004

N06AA10

Trimipramine Maleate

1174005

N06AA06

Nervous system: Selective serotonin reuptake inhibitor (SSRI)

Escitalopram Oxalate

1179054

N06AB10

Fluvoxamine Maleate

1179039

N06AB08

Paroxetine Hydrochloride Hydrate

1179041

N06AB05

Sertraline Hydrochloride

1179046

N06AB06

Nervous system: Antiparkinsonian drugs – Anticholinergic drugs

Biperiden Hydrochloride

1162001

N04AA02

Mazaticol Hydrochloride Hydrate

1169004

N04AA10

Piroheptine Hydrochloride

1169003

N04AA

Profenamine Hibenzate

1163002

N04AA05

Profenamine Hydrochloride

1163001

N04AA05

Promethazine Hydrochloride

4413002

R06AD02

D04AA10

Promethazine Hibenzate

4413002

R06AD02

D04AA10

Promethazine Methylenedisalicylate

4413002

R06AD02

D04AA10

Trihexyphenidyl Hydrochloride

1169001

1169002

N04AA01

Systemic hormonal preparations, excl. Sex hormones and insulins: Oral corticosteroids

Betamethasone

2454004

H02AB01

Cortisone Acetate

2452001

H02AB10

Dexamethasone

2454002

D07AB19

H02AB02

Hydrocortisone

2452002

H02AB09

Methylprednisolone

2456003

H02AB04

Prednisolone

2456001

2456002

H02AB06

Triamcinolone

2454003

H02AB08

Combination (see Table 5)

Blood and blood forming organs: Antithrombotic drugs

Acetylsalicylic acid (Aspirin)

1143001

3399007

N02BA01

B01AC06

Apixaban

3339004

B01AF02

Cilostazol

3399002

B01AC23

Clopidogrel Sulfate

3399008

B01AC04

Dabigatran Etexilate Methanesulfonate

3339001

B01AE07

Edoxaban Tosilate Hydrate

3339002

B01AF03

Prasugrel Hydrochloride

3399009

B01AC22

Rivaroxaban

3339003

B01AF01

Ticlopidine Hydrochloride

3399001

B01AC05

Ticagrelor

3399011

B01AC24

Warfarin potassium

3332001

B01AA03

Combination (see Table 5)

Cardiovascular system: Digitalis

Digoxin

2113003

2113004

C01AA05

Metildigoxin

2113005

C01AA08

Cardiovascular system: High-ceiling diuretics

Azosemide

2139008

C03CA

Bumetanide

2139004

C03CA02

Furosemide

2139005

C03CA01

Piretanide

2139007

C03CA03

Torasemide

2139009

C03CA04

Cardiovascular system: Potassium-sparing agents

Eplerenone

2149045

C03DA04

Spironolactone

2133001

C03DA01

Cardiovascular system: Beta blocking agents

Alprenolol Hydrochloride

2123002

C07AA01

Arotinolol Hydrochloride

2123014

C07AA

Bufetolol Hydrochloride

2123006

C07AA

Carteolol Hydrochloride

2123005

2149025

C07AA15

S01ED05

Nadolol

2123015

C07AA12

Nipradilol

2149021

C07AA

S01ED

Pindolol

2123009

2149011

C07AA03

Propranolol Hydrochloride

2123008

2149014

C07AA05

Cardiovascular system: Alpha1 blocking agents

Bunazosin Hydrochloride

2149015

C02CA

Doxazosin Mesilate

2149026

C02CA04

Prazosin Hydrochloride

2149002

C02CA01

Terazosin Hydrochloride Hydrate

2149023

G04CA03

Urapidil

2149020

C02CA06

Respiratory system: H1 receptor antagonists (1st generation)

Alimemazine Tartrate

4413003

R06AD01

Chlorpheniramine Maleate

4419001

4419003

R06AB04

Clemastine Fumarate

4419008

R06AA04

Cyproheptadine Hydrochloride Hydrate

4419005

R06AX02

D-chlorpheniramine Maleate

4419002

R06AB04

Diphenhidramine

4411001

R06AA02

Homochlorcyclizine Hydrochloride

4419006

R06AE

Hydroxyzine Hydrochloride

1179005

N05BB01

Hydroxyzine Pamoate

1179019

N05BB01

Promethazine Hibenzate (relisted)

4413002

R06AD02

Promethazine Hydrochloride (relisted)

4413002

R06AD02

Promethazine Methylenedisalicylate (relisted)

4413002

R06AD02

Combination (see Table 5)

Alimentary tract and metabolism: H2 receptor antagonists

Cimetidine

2325001

A02BA01

Famotidine

2325003

A02BA03

Lafutidine

2325006

A02BA08

Nizatidine

2325005

A02BA04

Ranitidine Hydrochloride

2325002

A02BA02

Roxatidine Acetate Hydrochloride

2325004

A02BA06

Alimentary tract and metabolism: Antiemetic agents

Metoclopramide

2399004

A03FA01

Promethazine Hibenzate (relisted)

4413002

R06AD02

D04AA10

Promethazine Hydrochloride (relisted)

4413002

R06AD02

D04AA10

Promethazine Methylenedisalicylate (relisted)

4413002

R06AD02

D04AA10

Alimentary tract and metabolism: Drugs for constipation

Magnesium Oxide

2344002

2344009

A02AA02

A06AD02

Alimentary tract and metabolism: Biguanides

Buformin Hydrochloride

3962001

A10BA03

Metformin Hydrochloride

3962002

A10BA02

Combination (see Table 5)

Alimentary tract and metabolism: sulfonylureas

Acetohexamide

3961001

A10BB31

Chlorpropamide

3961004

A10BB02

Glibenclamide

3961003

A10BB01

Gliclazide

3961007

A10BB09

Glimepiride

3961008

A10BB12

Glyclopyramide

3961002

A10BB

Tolbutamide

3961006

A10BB03

Combination (see Table 5)

Alimentary tract and metabolism: Alpha glucosidase inhibitors

Acarbose

3969003

A10BF01

Miglitol

3969009

A10BF02

Voglibose

3969004

A10BF03

Combination (see Table 5)

Alimentary tract and metabolism: Thiazoridinediones

Pioglitazone Hydrochloride

3969007

A10BG03

Combination (see Table 5)

Alimentary tract and metabolism: Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Canagliflozin Hydrate

3969022

A10BK02

Dapagliflozin Propylene Glycolate Hydrate

3969019

A10BK01

Empagliflozin

3969023

A10BK03

Ipragliflozin L-proline

3969018

A10BK

Luseogliflozin Hydrate

3969020

A10BK

Tofogliflozin Hydrate

3969021

A10BK

Urologicals: Muscarinic receptor antagonists

Fesoterodine Fumarate

2590015

G04BD11

Imidafenacin

2590013

G04BD

Oxybutynin Hydrochloride

2590005

G04BD04

Propiverine Hydrochloride

2590007

G04BD06

Solifenacin Succinate

2590011

G04BD08

Tolterodine Tartrate

2590012

G04BD07

Musculo-skeletal system: Non-steroidal antiinflammatory drugs (NSAIDs)

Acemetacin

1145003

M01AB11

Amfenac Sodium Hydrate

1147006

M01AB

Ampiroxicam

1149030

M01 AC

Acetylsalicylic acid (Aspirin) (relisted)

1143001

3399007

N92BA01

B01AC06

Bucolome

1149009

M01AX

Diclofenac Sodium

1147002

M01AB05

S01 BC03

M02AA15

Emorfazone

1148004

N02BG

Etodolac

1149032

M01AB08

Flufenamate Aluminum

1141004

M01AG03

Flurbiprofen

1149011

M01AE09

M02AA19

Ibuprofen

1149001

M01AE01

Indometacin

1145001

1145002

C01EB03

M01AB01

M02AA23

Indomethacin Farnesil

1145005

M01AB01

Lornoxicam

1149036

M01 AC05

Loxoprofen Sodium Hydrate

1149019

M01AE

M02AA

Mefenamic Acid

1141005

M01AG01

Meloxicam

1149035

M01 AC06

Mofezolac

1149033

M01AX

Nabumetone

1149027

M01AX01

Naproxen

1149007

M01AE02

Oxaprozin

1149026

M01AE12

Piroxicam

1149017

M01 AC01

M02AA07

S01 BC06

Pranoprofen

1149010

S01 BC09

Proglumetacin Maleate

1145004

M01AB14

Sulindac

1149015

M01AB02

Tiaprofenic Acid

1149025

M01AE11

Tiaramide Hydrochloride

1148001

N02BG

Zaltoprofen

1149029

M01AE

Combination (See Table 5)

Japanese version available at http://www.jpn-geriat-soc.or.jp/tool/xls/list_03.xlsx or http://www.jpn-geriat-soc.or.jp/tool/pdf/list_02.pdf

ATC: Anatomical Therapeutic Chemical Classification System

JAN: Japanese Accepted Names for Pharmaceuticals

Japan: the first 7-digit numbers of the code of the Japanese drug price list

1)Drugs that had been previously approved but do not currently being marketed are excluded. The list includes long-term oral use drugs as a general rule, except self-injection insulin, according to the guidelines (Japan Geriatric Society. Guidelines for Medical Treatment and its Safety in the elderly 2015 (In Japanese). Toyko, Medical View Co., Ltd. 2015)

2)A different base adduct may or may not require different codes in Japan; hydroxyzine (1179005 for hydrochloride, 1179019 for pamoate) or promethazines (4413002)

3)ATC codes for topical use were excluded, e.g. A07EA Corticosteroids acting locally, D04AA Antihistamines for topical use; defined daily dose (DDD) are not available for most of those

4)The guidelines distinguish sulpiride and sultopride from other antipsychotic drugs

5)The guidelines distinguish acetyhlsalicylic acid (aspirine) from other antithrombotic drugs

6)The guidelines distinguish oxybutynin from other muscarinic receptor antagonists

7)The guidelines does not have metildigoxin (oral), however it is marketed and added to the Table 3 from molecular based perspectives

Table 4

Proposal for drug coding of “List of drugs to consider starting” 1)

Therapeutic category/JAN English name

Japan 2)

ATC 2)

Antiparkinson drugs

 Combination (see Table 5)

  

Vaccine: Influenza

 Influenza HA Vaccine (A/B)

NA

J07BB02

 Adsorbed Influenza Virus Vaccine (H5N1)

NA

J07BB02

Vaccine: Pneumococcal

 Pneumococcal Polysaccharide Conjugate Vaccine(adsorbed)

631140G

J07AL52

 Pneumococcus Vaccine

6311400

J07AL01

Cardiovascular system: Angiotensin conversion enzyme (ACE) inhibitor

 Alacepril

2144003

C09AA

 Benazepril Hydrochloride

2144007

C09AA07

 Captopril

2144001

C09AA01

 Cilazapril Hydrate

2144005

C09AA08

 Delapril Hydrochloride

2144004

C09AA12

 Enalapril Maleate

2144002

C09AA02

 Imidapril Hydrochloride

2144008

C09AA16

 Lisinopril Hydrate

2144006

C09AA03

 Perindopril Erbumine

2144012

C09AA04

 Quinapril Hydrochloride

2144010

C09AA06

 Temocapril Hydrochloride

2144009

C09AA14

 Trandolapril

2144011

C09AA10

Cardiovascular system: Angiotensin receptor blocker (ARB)

 Azilsartan

2149048

C09CA09

 Candesartan Cilexetil

2149040

C09CA06

 Irbesartan

2149046

C09CA04

 Olmesartan Medoxomil

2149044

C09CA08

 Telmisartan

2149042

C09CA07

 Valsartan

2149041

C09CA03

 Losartan Potassium

2149039

C09CA01

 Coombination (See Table 5)

  

Cardiovascular system: Lipid modifying agents (Statine)

 Atorvastatin Calcium Hydrate

2189015

C10AA05

 Fluvastatin Sodium

2189012

C10AA04

 Pitavastatin Calcium Hydrate

2189016

C10AA08

 Pravastatin Sodium

2189010

C10AA03

 Rosuvastatin Calcium

2189017

C10AA07

 Simvastatin

2189011

C10AA01

 Coombination (See Table 5)

  

Urologicals: Drugs for benign prostatic hypertrophy (selective alpha-1 blockers)

 Naftopidil

2590009

G04CA

 Silodosin

2590010

G04CA04

 Tamsulosin Hydrochloride

2590008

G04CA02

Antineoplastic and immunomodulating agents: Drugs for rheumatoid arthritis

 Actarit

1149031

M01CX

 Auranofin

4420001

M01CB03

 Bucillamine

4420002

M01CC02

 Iguratimod

3999031

M01CX

 Leflunomide

3999020

L04AA13

 Lobenzarit Sodium

1149020

M01CX

Methotrexate

4222001

3999016

L01BA01

L04AX03

 Mizoribine

3999002

L04AX

 Salazosulfapyridine

6219001

A07EC01

 Tofacitinib Citrate

3999034

L04AA29

ATC: Anatomical Therapeutic Chemical Classification System

JAN: Japanese Accepted Names for Pharmaceuticals

1)Drugs that had been previously approved but do not currently being marketed are excluded. The list includes long-term oral use drugs as a general rule, except self-injection insulin, according to the guidelines (Japan Geriatric Society. Guidelines for Medical Treatment and its Safety in the elderly 2015 (In Japanese). Toyko, Medical View Co., Ltd. 2015.)

2)the first 7-digit numbers of the code of the Japanese drug price list.A different base adduct may or may not require different codes in Japan; hydroxyzine (1179005 for hydrochloride, 1179019 for pamoate) or promethazines (4413002).

3)ATC codes for topical use were excluded, e.g. A07EA Corticosteroids acting locally, D04AA Antihistamines for topical use; defined daily dose (DDD) are not available for most of those.

Table 5

Proposal for coding the combination drugs of “List of drugs to be prescribed with special caution” and “List of drugs to consider starting”

Combination drugs (substance name in JAN)

Japan 1)

ATC2)

“List of drugs to be prescribed with special caution”

Chlorpromazine Hydrochloride

Phenobarbital *

Promethazine Hydrochloride

1179100

1179101

R06AD52 promethazine, combinations or N05AA01 chlorpromazine and R06AD02 promethazine

tia

Aluminum Glycinate *

Magnesium Carbonate *

1143010

3399100

N02BA51 acetylsalicylic acid, combinations excl. Psycholeptics

Acetylsalicylic acid (aspirin)

Clopidogrel Sulfate

3399101

N02BA51 acetylsalicylic acid, combinations excl. Psycholeptics or B01AC06 acetylsalicylic acid and B01AC04 clopidogrel

Acetylsalicylic acid (aspirin)

Lansoprazole *

3399102

B01AC56 acetylsalicylic acid, combinations with proton pump inhibitors

Metformin Hydrochloride

Pioglitazone Hydrochloride

3969100

A10BD05 metformin and pioglitazone

Glimepiride

Pioglitazone Hydrochloride

3969101

A10BD06 glimepiride and pioglitazone

Mitiglinide

Voglibose

3969102

A10BD Combinations of oral blood glucose lowering drugs or A10BX08 mitiglinide and A10BF03 voglibose

Pioglitazone

Alogliptin*

3969103

A10BD09 pioglitazone and alogliptin

Metformin

Vildagliptin*

3969104

A10BD08 metformin and vildagliptin

Alogliptin*

Metformin

3969105

A10BD13 metformin and alogliptin

“List of drugs to consider starting”

Entacapone *

Carbidopa Hydrate

Levodopa

1169102

N04BA03 levodopa, decarboxylase inhibitor and COMT inhibitor

Carbidopa Hydrate *

Levodopa

1169101

N04BA02 levodopa and decarboxylase inhibitor

Benserazide Hydrochloride *

Levodopa

1169100

N04BA02 levodopa and decarboxylase inhibitor

Azilsartan

Amlodipine Besilate

2149121

C09CA09 azilsartan medoxomil and C08CA01 amlodipine

Azelnidipine

Olmesartan Medoxomil

2149115

C08C selective calcium channel blockers with mainly vascular effects and C09CA08 olmesartan medoxomil

Amlodipine Besilate

Irbesartan

2149118

C09DB05 irbesartan and amlodipine

Amlodipine Besilate

Candesartan Cilexetil

2149116

C09DB07 candesartan and amlodipine

Amlodipine Besilate

Telmisartan

2149117

C09DB04 telmisartan and amlodipine

Amlodipine Besilate

Valsartan

2149114

C09DB01 valsartan and amlodipine

Irbesartan

Trichlormethiazide

2149119

C09DA04 irbesartan and diuretics

Candesartan Cilexetil

Hydrochlorothiazide

2149111

C09DA06 candesartan and diuretics

Cilnidipine

Valsartan

2149120

C08CA14 cilnidipine and C09CA03 valsartan

Termisartan

Hydrochlorothiazide

2149113

C09DA07 telmisartan and diuretics

Valsartan

Hydrochlorothiazide

2149112

C09DA03 valsartan and diuretics

Hydrochlorothiazide

Losartan Potassium

2149110

C09DA01 losartan and diuretics

Atorvastatin Calcium Hydrate

Amlodipine Besilate

2190101

2190102 2190103 2109104

C10BX03 atorvastatin and amlodipine

ATC: Anatomical Therapeutic Chemical Classification System

JAN: Japanese Accepted Names for Pharmaceuticals

1)The first 7-digit numbers of the code of the Japanese drug price list. The drugs with a different compounding ratio of active substances need different codes in the National Health Insurance Drug Price Standard in Japan. For example, there are bland medicinal products with acetylsalicylic acid 330 mg for anti-inflammatory use (1143010) and 81 mg for antiplatelet (3399100)

2)Some combination drugs have individual ATC codes

* Substances are excepted from the STOPP-J list (Table 3and 4)

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.

Discussion

Identification and application of STOPP-J drug substances

The efforts to reduce inappropriate drug use in elderly patients are likely to have a substantial impact on reducing drug-related morbidity. One major required step is a change in the prescription behavior of physicians, which is influenced by their knowledge and alert systems involving pharmacists, computerized reminders [19], and promotional information from pharmaceutical companies [20]. The current JGS guidelines provide concept and review steps for prescribing to the elderly but do not fully detail specific substances. Thus, our computerized database of standard drug substances, reflecting the STOPP-J with a corresponding coding system, will provide an efficient way to improve physician knowledge about medication for the elderly.

This study revealed that some substances approved in Japan were omitted from the ATC classification system, which was also reported by Groot et al. [8] in reference to the STOPP/START. This may occur when a drug is marketed in Japan only, and the substance or combination is not registered with the WHO Collaborating Center for Drug Statistics. When other countries have the same situation, it would also be necessary to set up the framework to ask the WHO Collaboration Center to include medicinal substances limited to them. This would enhance ATC completeness. To support ATC users, the Uppsala Monitoring Center/WHO Collaborating Centre for International Drug Monitoring does provide the WHO Drug Global with drug information, including Japanese approved drugs and referencing ATC codes at the 5th level, for global pharmacovigilance [21]. Their service supports linking Japanese substances with the ATC, and major global companies use this service for internal databases. It is important to make ATC codes useful in pharmacovigilance and pharmacoepidemiology studies for all Japanese and worldwide drugs and create an official framework to register new substance as soon as possible. This would facilitate drug safety monitoring by pharmaceutical companies and the review of drugs at the class and substance levels. We excluded some medicinal products from the first listing step of the drug indication categories. This paradoxically suggests that researchers run the risk of including appropriately prescribed drugs when extracting data from the drug classification systems.

When the Beers criteria were applied to studies on Japanese elderly patients, hospitalization risk was higher in potentially inappropriate medication users [12] and, in contrast, no association was observed between potentially inappropriate medication use and adverse outcomes [13]. The study using STOPP and START addressed the notion that potentially inappropriate prescribing increased healthcare utilization [22]. Although some drug utilization studies have been reported on the STOPP-J, the future applications of our results to pharmacoepidemiologic clinical studies are worth considering in Japan, similar to a previous study using the Beers criteria in Japan [12, 13]. The use of large databases has become more sophisticated, and 13 Japanese healthcare databases are acknowledged by other entities [23] (e.g., JMDC Claims Database® [24], which provides the names and ATC codes of drugs prescribed from 2005). Some unlisted domestic databases also exist, including the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which maintain data records from April 2013 provided by the ministry [25]. Currently, no ATC codes are available in the NDB, but the National Health Insurance Drug Price List codes are provided and, therefore, our proposed codes can be used. Another database is the Japanese Adverse Drug Event Report database (JADER), which records spontaneous reports of adverse events to the regulatory agency and lists drug names in plain text, without codes [26]. MID-NET is another prospective database, which was launched in April 2018 by the regulatory agency [27]. It is noteworthy that global comparisons based on the guidelines for medication in the elderly would be complicated or difficult to analyze because substances and their corresponding codes vary.

Currently, there are many therapeutic guidelines and principles for the proper use of medicines, and different definitions are presented worldwide or even in certain countries. Since those guidelines are to be updated periodically in several years, the guidelines propose their philosophies and examples, without identification of drugs. Therefore, interpretation and practice tend to vary by users. When adopting the guidelines, it is important to first define drugs of interest at the component molecule level; however, papers that do not identify the studied drug names might exist. In this research, with reference to the research method of Groot et al. [8] of Ireland, we presented concrete pharmaceutical molecules intended by the STOPP-J proposed by the JGS and proposed corresponding drug codes to be widely used in Japan. The results of this research are expected to be helpful in designing research and validating the actual condition of medical service at a clinical institute. Another important application is to import the drug code list into electronic prescription systems and health information systems so that the system can aid physicians in prescribing cautiously. This application is expected to be used in practice in the near future.

Limitations of using the list

This study was limited to Japanese drugs for internal use, except insulin, because the JGS guidelines focus on the long-term use of drugs to promote appropriate medications and avoid systemic adverse events in the elderly. The study also excluded drugs mainly used for short-term treatments of less than 1 month, e.g., antipyretics. In addition, based on the JGS, the target population in our list comprised patients older than 75 years who are with or without frailty, which is quite different from other guidelines. The drug list would be useful in research to understand the status of drug prescribing or hypothesize about the trends in total drug use and polypharmacy. However, more information such as dosage regimens and comorbidities is normally required to answer clinical questions. Users also need to consider how to interpret the output. For example, the alerted drug should be able to be monitored or stopped for individual patients. Because the JGS tool is not meant to be a prescription rule, but rather provides information to support physicians’ judgment when prescribing, the dosage regimen and underlying diseases should be mentioned. Lastly, a periodic update of the list is critical for efficient use in practice.

This was the first challenge to identify the STOPP-J substances to be coded. Some difficulties were found through the work in the interpretation of the STOPP-J, for example, insulins, and healthcare data users may misunderstand what the guidelines really proposed. In addition, new medicines need to be timely evaluated to determine whether they should be prescribed with special caution or considered for medication.

Conclusion

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.

Declarations

Acknowledgements

The authors would like to thank JAPIC for their support in extracting drug names, Data Horizon Corporation and Shigeki Zeniya for coding assistance, and Yasuyuki Matsushita and Yoko Yoshimoto for sharing their knowledge on drug coding by Japanese pharmaceutical companies.

Availability of data and materials

All the data generated or analyzed during this study are included in this published article (and its supplementary information files).

Authors’ contributions

AKI, K and I are members of the JGS and selected substances from prescribers’ view point. AKA and N selected substances from the viewpoint of pharmaceuticals data management and supervised Y who searched the codes corresponding to substances. N was a major contributor to writing the manuscript. All authors read and approved the final manuscript.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
(2)
Department of Geriatric Medicine, the University of Tokyo, Tokyo, Japan
(3)
Public Health and Epidemiology, Meiji Pharmaceutical University, Tokyo, Japan

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