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University of Groningen

Oral adverse effects

Aziz, Yalda; Rademacher, Willem Maria Hubertus; Hielema, Atty; Wishaw, Scott Bradley

Patton; van Diermen, Denise Edwina; de Lange, Jan; Vissink, Arjan; Rozema, Frederik

Reinder

Published in:

Oral diseases

DOI:

10.1111/odi.13680

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

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Publication date:

2020

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Aziz, Y., Rademacher, W. M. H., Hielema, A., Wishaw, S. B. P., van Diermen, D. E., de Lange, J., Vissink,

A., & Rozema, F. R. (2020). Oral adverse effects: drug-induced tongue disorders. Oral diseases.

https://doi.org/10.1111/odi.13680

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Oral Diseases. 2020;00:1–14. wileyonlinelibrary.com/journal/odi  |  1

1 | INTRODUCTION

The global consumption of drugs to treat acute and chronic diseases continues to increase (WHO, 2011). Inevitably, healthcare profes-sionals are frequently confronted with patients using one or more drugs on a daily basis. These drugs can cause several adverse effects in the oral region such as a sensation of oral dryness (xerostomia),

hyposalivation, mucositis and taste disorders (Rademacher et al., 2019). Due to the large number of drugs available and their wide range of adverse effects, it is difficult and time-consuming for healthcare professionals to take all the potential consequences into account during their daily practice. To support oral healthcare pro-fessionals in their decision making, the Journal of Oral Diseases is publishing a series of articles discussing the most frequent adverse

Received: 1 January 2020 

|

  Revised: 21 September 2020 

|

  Accepted: 5 October 2020

DOI: 10.1111/odi.13680 O R I G I N A L A R T I C L E

Oral adverse effects: drug-induced tongue disorders

Yalda Aziz

1,2

 | Willem Maria Hubertus Rademacher

1,2

 | Atty Hielema

3

 |

Scott Bradley Patton Wishaw

3

 | Denise Edwina van Diermen

1

 | Jan de Lange

1,2

 |

Arjan Vissink

4

 | Frederik Reinder Rozema

1,2

1Department of Oral Medicine, Academic

Center for Dentistry Amsterdam (ACTA), Amsterdam, The Netherlands

2Department of Oral Maxillofacial Surgery,

Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

3Department of Medicines Information

Centre, Royal Dutch Pharmacists Association (KNMP), Den Hague, The Netherlands

4Department of Oral Maxillofacial Surgery,

University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence

Yalda Aziz, Department of Oral Medicine, Academic Center for Dentistry Amsterdam (ACTA), Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands.

Email: yalda.aziz@acta.nl

Abstract

Objectives: Due to a worldwide increase in drug consumption, oral healthcare

pro-fessionals are frequently confronted with patients using one or more drugs. A large number of drugs can be accompanied with adverse drug reactions in the orofacial region, amongst others of the tongue. This paper aims to give an overview of drugs that are known to be accompanied with tongue disorders.

Materials and methods: The national drug information database for Dutch

pharma-cists, composed of scientific drug information, guidelines and summaries of product characteristics, was analysed for drug-induced tongue disorders. “MedDRA classifi-cation” and “Anatomical Therapeutic Chemical codes” were used to categorize the disorders.

Results: The database comprises of 1645 drugs of which 121 (7.4%) are documented

to be accompanied with tongue disorders as an adverse effect. Drug-induced tongue disorders are predominantly observed in the following drug categories: “nervous sys-tems,” “anti-infectives for systemic use” and “alimentary tract and metabolism”. The most common drug-induced tongue disorders are glossitis, tongue oedema, tongue discoloration and burning tongue.

Conclusion: Healthcare professionals are frequently confronted with drugs that can

cause tongue disorders. The overview of drugs reported in this article supports clini-cians in their awareness, diagnosis and treatment of drug-induced tongue disorders. K E Y W O R D S

burning tongue, drug-induced tongue disorders, glossitis, tongue oedema, tongue discoloration

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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effects of drugs in the oral region. The first paper discussed drug-in-duced taste disorders (Rademacher et al., 2019). This paper focuses on drug-induced tongue disorders.

Tongue disorders, which are rather frequently observed, can be divided into congenital and acquired tongue disorders. Aglossia, an-kyloglossia, hypoglossia, macroglossia, cleft tongue and glossoptosis are examples of congenital tongue disorders (Mangold et al., 2016). Drug-induced tongue disorders belong to the category acquired tongue disorders.

Several studies have reported cases of drug-induced tongue dis-orders (Alharbi et al., 2018; Balaji et al., 2014; Braggio et al., 2018; Brown, 1949; Gurvits & Tan, 2014; Healy et al., 2004; Hubiche et al., 2013; Kalogirou et al., 2017), but a comprehensive overview of drugs associated with tongue disorders as an adverse effect is not available. Such an overview will support oral healthcare providers in the recognition, diagnosis and eventual treatment of drug-induced tongue disorders.

2 | MATERIALS AND METHODS

An elaborated description of the Materials and Methods used in the current study is described by Rademacher et al. (2019). In short, the data on oral adverse effects of medications were derived from the Informatorium Medicamentorum of the Royal Dutch Pharmacists Association (KNMP), the leading drug information database and reference work for pharmacists in the Netherlands (KNMP, 2019). This database is composed of scientific drug information, guide-lines and summaries of product characteristics. It includes not only entries derived from scientific publications (randomized con-trol trails, observational studies, case reports, etc.), but also data from the Netherlands pharmacovigilance centre LAREB, the Dutch knowledge centre for adverse drug reactions. The Informatorium Medicamentorum is regularly updated with the latest obtainable in-formation from scientific publications, warnings of authorities and summaries of product characteristics of the European Medicines Agency and Medicines Evaluation Board in the Netherlands. The Informatorium Medicamentorum database was last searched on 1 August 2018. All drugs of which was reported that they may cause tongue disorders were extracted from this database. For each drug, the following information was recorded: generic name of the drug, term of the adverse effect, incidence of the adverse effect and Anatomical Therapeutic Chemical (ATC) code of the drug (WHO, 2003). The MedDRA classification was manually applied after the selection of drugs that have been linked to causing tongue disor-ders (MedDRA, 2018a, 2018b). This system categorizes medical terminology in five levels. The “Lowest Level Term (LLT)” and the “Preferred Term (PT)” were used to categorize drug-induced tongue disorders (Rademacher et al., 2019). The most common definitions were used to describe drug-induced tongue disorders. Microsoft® Excel (version 16.16.1) was used to create a database with acquired information on drug-induced tongue disorders. Descriptive statistics were applied where applicable.

3 | RESULTS

The Informatorium Medicamentorum database comprises informa-tion on 1645 drugs with approximately 65,000 unique combinainforma-tions between a drug and an adverse effect as each drug can cause mul-tiple adverse effects. About 2335 (3.5%) of these unique combina-tions enclose adverse effects of medication in the orofacial region.

In total, 121 (7.4%) drugs out of the 1645 drugs have been as-sociated with tongue disorders as adverse drug reaction (Table 1). Drug-induced tongue disorders are predominantly reported in the following drug categories: “nervous systems,” “anti-infectives for systemic use” and “antineoplastic and immunomodulating agents” (Table 2). The most common drug-induced tongue disorders are glossitis, tongue oedema, tongue discoloration and burning tongue.

A wide variety of terminology is found in the literature to de-scribe a particular tongue disorder related to the use of a drug and vice versa. Some of these terms may even overlap each other. As it was not possible to identify the exact definitions that were used to denominate a reported adverse drug reaction by coders, we have chosen to categorize the drug-induced tongue disorders as follows: 1. Alteration in colour of the tongue (glossitis, tongue

discolor-ation, hairy tongue, coated tongue)

2. Increase in volume of the tongue (tongue oedema, hypertrophy of tongue papillae)

3. Alteration in sensitivity of the tongue (burning tongue, dysaesthe-sia of tongue, pruritus of tongue, glossodynia, tongue numbness) 4. Defect of surface of the tongue ( tongue ulceration)

5. Other tongue disorders (tongue irritation, tongue disorders NOS)

TA B L E 1   Number of medications associated with particular

tongue disorders

Adverse effects of medication related to tongue

Number of medication Burning tongue 10 Dysaesthesia of tongue 2 Glossitis 36 Hairy tongue 4

Hypertrophy of tongue papillae 1

Pruritus of tongue 1

Glossodynia 6

Tongue disorders NOS* 5

Coated tongue 4

Irritation of the tongue 2

Tongue oedema 22

Tongue ulceration 4

Tongue discoloration 21

Tongue numbness 3

Total 121

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3.1 | Alteration in colour of the tongue

In total, 36 (2.2% of 1645 drugs) drugs were associated with glossitis (Figure 1) as an adverse drug reaction (Table 1). Glossitis was defined as inflammation of the tongue with loss of filiform papillae, leading to

pain, swelling and erythema (Byrd et al., 2003). It was reported in 10 of the 14 ATC level 1 categories of the ATC classification. The drug cat-egories “anti-infectives for systemic use” (36%) and “nervous systems” (13.9%) contain most medications that have been associated with glos-sitis. Both categories account for almost 50% of drug-induced glosglos-sitis. Drug-induced glossitis is rather “common” in 11.1% (4 out of 36 drugs), “uncommon” in 41.7% (15 out of 36 drugs), “rare” in 30.5% (11 out of 36 drugs) and “very rare” in 11.1% (4 out of 36 drugs) of the drugs. The frequency of occurring of glossitis was not reported for methotrexate.

In the Informatorium Medicamentorum database, 21 drugs (1.28 % of 1645 drugs) were associated with the development of tongue discoloration (Figure 2) as an adverse drug reaction. Tongue discol-oration was defined as pigmentation of the tongue as a result of the drug or its metabolites deposition or by increasing the production of melanin. The discoloration may be blue, brown, grey or black (Rosebush et al., 2019). Tongue discoloration was reported in 7 of the 14 ATC level 1 categories. Tongue discoloration was predomi-nantly reported in the drug categories “anti-infectives for systemic use” (52.4%) and “dermatologicals” (19%). Frequency of drug-in-duced tongue discoloration was “uncommon” in 19% (4 out of 21 drugs), “rare” in 14.3% (3 out of 21 drugs), “very rare” in 47.6% (10 out of 21 drugs) and “unknown” in 19% (4 out of 21 drugs) of the drugs.

Hairy tongue is a transitory and harmless condition character-ized by hypertrophy and prolongation of filiform papillae on the surface of the tongue (Figure 3). The colour of the tongue can vary from yellow to brown or black (Reamy et al., 2010). Hairy tongue as an adverse effect was reported for 4 drugs (0.24% of 1645 drugs). Two of these drugs belong to the drug category “anti-infectives for systemic use.” Coated tongue describes any area of the tongue with a coating on it. Coated tongue as an adverse effect was reported for 4 drugs (0.24% of 1645 drugs). These 4 drugs belong to the drug cat-egories “nervous system,” “anti-infectives for systemic use,” “derma-tologicals” and “alimentary tract and metabolism.” In 3 out 4 drugs is coated tongue a “rare” adverse drug reaction. An overview of all drugs that may alter the colour of the tongue is given in Table 3.

3.2 | Increase in volume of the tongue

Tongue oedema was reported in 22 drugs (1.3% of 1645 drugs). Tongue oedema was defined as swelling of the tongue due to loss of vascular integrity causing extravasation of fluid into interstitial tissue. This adverse effect was mentioned in 9 out of 14 ATC level 1 catego-ries. Occurrence of tongue oedema (Figure 4) was mainly reported in the drug category “nervous systems” (45.5%). Frequency of drug-induced tongue oedema was “common” in 13.6% (3 out of 22 drugs), “uncommon” in 31.8% (7 out of 22 drugs), “rare” in 31.8% (7 out of 22 drugs) and “very rare” in 22.7% (5 out of 22 drugs) of the drugs.

A rare adverse effect of Imipenem is hypertrophy of tongue papillae. Imipenem, belonging to the drug category “anti-infectives for systemic use,” is the only drug that causes this adverse drug re-action. An overview of all drugs that may cause tongue oedema and hypertrophy of tongue papillae is shown in Table 4.

TA B L E 2   Number of drugs associated with tongue disorders per

ATC level 1 category ATC level 1 Category

Drug-induced tongue disorders

Alimentary tract and metabolism 13 Anti-infectives for systemic use 35 Antineoplastic and immunomodulating

agents

11 Antiparasitic products, insecticides and

repellents

0 Blood and blood-forming organs 2 Cardiovascular system 9

Dermatologicals 6

Genitourinary system and sex hormones 1 Musculoskeletal system 2

Nervous system 26

Respiratory system 4

Sensory organs 1

Systemic hormonal preparations, excl. 1

Various 10

Total: 121

F I G U R E 1   Drug-induced median rhomboid glossitis (B.

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3.3 | Alteration in sensitivity of the tongue

Burning tongue was reported in 10 drugs (0.61% of 1645 drugs) which belong to 5 ATC level 1 categories. Burning tongue was defined as a burning sensation of tongue caused by drugs without specifying the affected region explicitly (Imamura et al., 2019). The appearance of the tongue can be changed, but there is no need for an identi-fiable change in the appearance of the tongue. The drug category “alimentary tract and metabolism” (30%) consists of most drugs that may cause burning tongue. The frequency of burning tongue was

“common” in 30% (3 out of 10 drugs), “uncommon” in 20% (2 out of 10 drugs), “rare” in 10% (1 out of 10 drugs) and “very rare” in 30% (3 out of 10 drugs) of the drugs. The frequency of burning tongue was most frequently (“very common,” 10%) reported for cabozantinib. Dysaesthesia of the tongue is an abnormal unpleasant sensation of the tongue. This adverse effect was reported for metoclopramide and oxaliplatin. These drugs belong to the following drug categories, respectively, “alimentary tract and metabolism” and “antineoplastic and immunomodulating agents.” Numbness of the tongue was de-fined as loss of sensation in the tongue not due to peripheral nerve injury. Numbness of the tongue was reported in 3 drugs from the drug category “nervous system.” The frequency of this adverse drug reaction is uncommon. Pruritus of tongue was defined as an itchy sensation of the tongue as a result of exposure to medications. It was only reported for allergen extracts and was a common side ef-fect of sublingually administrated allergen extracts. Glossodynia was described as burning sensation of the tongue due to an identifiable cause, viz., drugs. Glossodynia was reported in 6 drugs (0.36% of 1645 drugs) in the following drug categories; “anti-infectives for sys-temic use” (33.3%), “antineoplastic and immunomodulating agents” (33.3%), “cardiovascular system” (16.7%) and “various” (16.7%). The frequency of glossodynia was “common” in the drug categories “anti-infectives for systemic use” and “various” (3 out of 6 drugs). In the drug categories “antineoplastic and immunomodulating agents” and "cardiovascular system" was the frequency "very rare" (3 out of 6 drugs). Table 5 gives an overview of all drugs that may cause altera-tion in sensitivity of the tongue.

3.4 | Defect of surface of the tongue

Four drugs are reported to cause ulceration of the tongue (0.30% of 1645 drugs). These drugs belong to the following drug cate-gories: “antineoplastic and immunomodulating agents” (1 drugs), "cardiovascular system" (1 drug) and "nervous system” (2 drugs). The frequency of tongue ulceration was "rare" in 3 out of 4 drugs (Table 6).

3.5 | Other tongue disorders

Unspecified tongue disorders were reported in 5 drugs (0.30% of 1645 drugs) in the following drug categories: “nervous sys-tem” (2 drugs), “antineoplastic and immunomodulating agents” (1 drug), “anti-infectives for systemic use” (1 drug) and “various” (1 drug). The frequency of tongue disorders NOS was “common” in 20% (1 out of 5 drugs), “uncommon” in 40% (2 out of 5 drugs) and “unknown” in 40% (2 out of 5 drugs) of these drugs. Iloprost and cholestyramine were reported to cause irritation of the tongue. They pertain to the drug category, respectively, “blood and blood-forming organs” and “cardiovascular system.” An overview of all drugs that may cause irritation of the tongue and tongue disorders NOS can be found in Table 7.

F I G U R E 2   Chlorhexidine-induced tongue discoloration (B.

Stegenga, 2013). Reprinted with permission

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T A B LE 3  A lte ra tio n i n c ol ou r o f t he t on gu e ( gl os si tis , t on gu e d is co lo ra tio n, h ai ry t on gu e, c oa te d t on gu e) AT C l ev el 1 AT C l ev el 3 G ene ric n am e AT C C od e LL T M ed D R A* Fr eq ue nc y Sp ec ifi c t yp e o f ad mini st ra tio n A LI M EN TA RY T R A C T A N D M ET A B O LIS M ST O MA TO LO G IC AL PR EP A R AT IO N S Tet ra cy cl in e A 01 A B13 G lo ssi tis Ve ry r ar e ( < 0. 01 % ) No t g iv en INTE ST IN A L A NT I-IN FE C TI V ES A m ph ot er ic in B A 07 A A 07 G lo ssi tis U nc omm on (0 .1 -1 % ) A ft er o ra l a dm in is tr at io n D RU G S F O R P EP TI C U LC ER A ND La ns op ra zole A 02B C 03 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en O TH ER A LIM ENT A RY TR A C T A N D M ET A B O LI SM PR O D U C TS B et ain e A 16 A A 06 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en ST O MA TO LO G IC AL PR EP A R AT IO N S Tet ra cy cl in e A 01 A B13 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) A ft er o ra l o r o ro m uc os al ad min is tr at io n INTE ST IN A L A NT I-IN FE C TI V ES Mic on az ol e A 07A C 01 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en ST O MA TO LO G IC AL PR EP A R AT IO N S H yd ro gen p er oxi de A 01 A B 02 H air y t on gu e Fr eq uenc y no t k no wn No t g iv en A NT IE M ET IC S A N D A NT IN A U SE A NT S Pa lo no se tr on A0 4A A0 5 To ngu e c oa te d Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A NT I-IN FE C TI V ES F O R SY ST EM IC U SE B ETA -L A C TA M A NT IB A C TE RI A LS , PE N IC ILLIN S B enz ylp en ic ill in J01 C E01 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en TE TR A C YC LIN ES Min oc yc lin e J0 1A A 08 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A M IN O G LY C O SID E A NT IB A C TE RI A LS Tob ram yc in J01 G B 01 G lo ssi tis U nc omm on (0 .1 -1 % ) In ha la tio n l iq uid O TH ER B ET A -L A C TA M A NT IB A C TE RI A LS C ef tr ia xo ne J0 1D D 04 G lo ssi tis Ve ry r ar e ( < 0. 01 % ) No t g iv en M A C RO LID ES , LIN C O SA M ID ES A N D STR EP TO G R A M IN S Cl ar ithr om yc in J0 1FA 09 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en O TH ER A NT IB A C TE RI A LS Lin ez ol id J0 1X X 08 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en A NT IM YC O TI C S FO R SY ST EM IC U SE Vo ric on az ol e J0 2AC 03 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en O TH ER A NT IB A C TE RI A LS D apt om yc in J01 X X 09 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en D IR EC T A C TIN G A NT IV IR A LS Ra lteg ra vir J0 5A X 08 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en TE TR A C YC LIN ES D ox yc yc lin e J01 A A 02 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en AN TIVI R AL S Tr ifl ur idin e S0 1A D 02 G lo ssi tis U nc omm on (0 .1 -1 % ) In c om bin at io n w ith tipir ac il C A RB A PEN EM S Im ip en em a nd cil as ta tin J01 D H 51 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en (Co nti nue s)

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AT C l ev el 1 AT C l ev el 3 G ene ric n am e AT C C od e LL T M ed D R A* Fr eq ue nc y Sp ec ifi c t yp e o f ad mini st ra tio n B ETA -L A C TA M A NT IB A C TE RI A LS , PE N IC ILLIN S Ph en et icilli n J0 1C E0 5 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en TE TR A C YC LIN ES D em ecl oc ycl in e J01 A A 01 Ton gu e d is co lor at ion Fr eq uenc y no t k no wn No t g iv en TE TR A C YC LIN ES Min oc yc lin e J0 1A A 08 Ton gu e d is co lor at ion Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en B ETA -L A C TA M A NT IB A C TE RI A LS , PE N IC ILLIN S A m ox icilli n J0 1C A 04 Ton gu e d is co lor at ion U nc omm on (0 .1 -1 % ) No t g iv en D IR EC T A C TIN G A NT IV IR A LS Rib av irin J0 5A P0 1 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en M A C RO LID ES , LIN C O SA M ID ES A N D STR EP TO G R A M IN S Cl ar ithr om yc in J0 1FA 09 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) A ft er i nt ra ve no us ad min is tr at io n M A C RO LID ES , LIN C O SA M ID ES A N D STR EP TO G R A M IN S A zit hro m yc in J0 1FA 10 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en O TH ER A NT IB A C TE RI A LS Lin ez ol id J0 1X X 08 Ton gu e d is co lor at ion U nc omm on (0 .1 -1 % ) No t g iv en TE TR A C YC LIN ES D ox yc yc lin e J01 A A 02 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en C A RB A PEN EM S Im ip en em a nd cil as ta tin J01 D H 51 Ton gu e d is co lor at ion Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en SU LP H O N A M ID ES A N D TR IM ETH O PR IM Sulp ha m et ho xaz ol e an d t rim et ho pr im J01 EE01 Ton gu e d is co lor at ion Fr eq uenc y no t k no wn No t g iv en D IR EC T A C TIN G A NT IV IR A LS D ar una vi r J0 5A E10 To ngu e c oa te d Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en C O M B IN AT IO N O F A NT IB A C TE RI A LS C omb in at ion o f ant ib ac te ria ls J0 1R A H air y t on gu e Ve ry r ar e ( < 0. 01 % ) In c om bi na tio n w ith am ox icilli n SU LP H O N A M ID ES A N D TR IM ETH O PR IM Sulp ha m et ho xaz ol e an d t rim et ho pr im J01 EE01 H air y t on gu e Fr eq uenc y no t k no wn No t g iv en A NT IN EO PL A ST IC IM M U N O M O D U LA TIN G A N D A G EN TS IM M U N O ST IM U LA NT S Pe gi nt er fe ro n a lfa -2 a L0 3A B11 G lo ssi tis C omm on (1 -1 0% ) No t g iv en IM M U N O ST IM U LA NT S Pe gi nt er fe ro n a lfa -2 b L0 3A B10 G lo ssi tis C omm on (1 -1 0% ) No t g iv en O TH ER A NT IN EO PL A ST IC AG EN TS Ti vo za nib L01 X E3 4 G lo ssi tis C omm on (1 -1 0% ) No t g iv en A NT IM ET A B O LI TE S M et ho tr ex ate L01 B A 01 G lo ssi tis Fr eq uenc y no t k no wn No t g iv en IM M U N O ST IM U LA NT S Pe gi nt er fe ro n a lfa -2 b L0 3A B10 Ton gu e d is co lor at ion Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en C A RD IO VA SC UL A R SY ST EM A C E I N H IB IT O RS , P LA IN C ap to pr il C 09A A 01 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en T A B LE 3  (Co nti nue d) (Co nti nue s)

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AT C l ev el 1 AT C l ev el 3 G ene ric n am e AT C C od e LL T M ed D R A* Fr eq ue nc y Sp ec ifi c t yp e o f ad mini st ra tio n A C E I N H IB IT O RS , P LA IN En al ap ril C 09A A 02 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A C E I N H IB IT O RS , P LA IN Ra mip ril C 09A A 05 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A C E I N H IB IT O RS , P LA IN Q uin ap ril C 09A A 06 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A N TI A D RE N ER G IC A G EN TS , C ENTR A LL Y A C TIN G Me th yldo pa (le vo ro ta tor y) C 02 A B 01 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en D ERMA TO LO G IC AL S A N TI FU N G A LS F O R T O PI C A L U SE K et oc onaz ol e D 01 A C 08 Ton gu e d is co lor at ion Fr eq uenc y no t k no wn No t g iv en C H EM O TH ER A PE U TI C S F O R TO PI C A L U SE M et ro nid az ol e D 06 BX 01 Ton gu e d is co lor at ion Fr eq uenc y no t k no wn A ft er c ut an eo us u se C H EM O TH ER A PE U TI C S F O R TO PI C A L U SE M et ro nid az ol e D 06 BX 01 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en PR O TE C TI V ES A G A IN ST U V-R A D IA TI ON A fa mel ano tide D 02 B B 02 Ton gu e d is co lor at ion U nc omm on (0 .1 -1 % ) No t g iv en C H EM O TH ER A PE U TI C S F O R TO PI C A L U SE M et ro nid az ol e D 06 BX 01 To ngu e c oa te d Fr eq uenc y no t k no wn No t g iv en C H EM O TH ER A PE U TI C S F O R TO PI C A L U SE M et ro nid az ol e D 06 BX 01 H air y t on gu e Fr eq uenc y no t k no wn No t g iv en G EN IT O U RI N A RY S YS TE M A N D S EX H O RM O N ES O TH ER G YN AE C O LO G IC AL S Feno ter ol G 02C A 03 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) In c om bi na tio n w ith ip ra tr opi um MU SC UL O SK EL ET A L SY ST EM A NT I-IN FL A M M AT O RY A N D A NT IR H EU M AT IC PR ODUC TS , N ON -S TE RO ID S D ic lo fe na c M 01 A B 05 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) A ft er s ys te m ic u se D RU G S A FF EC TI N G B O N E S TR U C TU RE A N D M IN ER A LI ZA TI O N Ri se dr on ic a cid M 05 B A 07 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en N ER V O U S S YS TE M A NT IE PILE PT IC S C ar bam az ep ine N 03 A F0 1 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A NT ID EP RE SSA NT S Se rtr al in e N 06 A B 06 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en A NT IMI G R A IN E PR EP A R AT IO N S El et rip ta n N 02 CC 06 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en PS YC H O ST IM U LA NT S, A G EN TS U SE D F O R A D H D A N D N O O TR O PI C S M od af in il N 06 B A 07 G lo ssi tis U nc omm on (0 .1 -1 % ) No t g iv en AN AE ST H ET IC S, L O C AL M epi va ca in e N 01B B 03 G lo ssi tis Ve ry r ar e ( < 0. 01 % ) No t g iv en A NT ID EP RE SSA NT S A mi tr ip ty lin e N 06 A A0 9 Ton gu e d is co lor at ion Ve ry r ar e ( < 0. 01 % ) No t g iv en D RU G S U SE D I N A D D IC TI V E D IS OR D ER S V are nic lin e N 07 B A 03 To ngu e c oa te d Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en T A B LE 3  (Co nti nue d) (Co nti nue s)

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4 | DISCUSSION

Drug-induced tongue disorders were reported in 7.4% (121/1645) of the drugs used in the Netherlands. It was reported in all ATC level 1 drug categories except the drug category “antiparasitic products, insecticides and repellents.” We assume that many oral health-care providers are confronted with patients that suffer from drug-induced tongue disorders. Patients using drug from the categories “anti-infectives for systemic use” and “nervous system” are more likely to endure drug-induced tongue disorders.

As far as we know, this is the first article that gives a compendi-ous overview of drug-induced tongue disorders. Most of the articles on this topic are case reports on one particular drug and adverse drug reaction. Till date, there is no study performed that gives a complete overview of drugs that cause tongue disorders. An im-portant note is that the adverse effects reported in our study are not just derived from randomized controlled trials, which bears the hazard of underreporting, but from a mixture of clinical studies and case reports. Furthermore, the data on adverse effects are also ex-tracted from scientific drug information, guidelines and summaries of product characteristics as well as that our study contains entries from LAREB. As the information on adverse drug effects originates from different sources, the hazard of underreporting and inaccurate reporting is minimized in this study.

The drug-induced tongue disorders reported in the literature are often not well-defined or a wide range of terminology is used to de-scribe a particular disorder and vice versa. For example, the term glossitis indicates a variety of tongue diseases. Depending upon the underlying cause and symptoms, it can refer to atrophic glossitis or median rhomboid glossitis or benign migratory glossitis or herpetic geometric glossitis, etc. Moreover, tongue conditions like candidiasis or tongue soreness caused by burning mouth syndrome can easily be labelled as glossitis due to their broadly similar clinical presentation and symptoms. As it is not possible to identify the exact definitions of the reported adverse drug reactions, we opted to describe tongue

AT C l ev el 1 AT C l ev el 3 G ene ric n am e AT C C od e LL T M ed D R A* Fr eq ue nc y Sp ec ifi c t yp e o f ad mini st ra tio n RE SP IR AT O RY S YS TE M O TH ER D RU G S F O R O B ST RU C TI V E A IR W AY D IS EA SE S, IN H A LA NT S Ti ot ro pi um b ro mid e R0 3BB 04 G lo ssi tis Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en SE NS O RY O RG A NS O PH TH AL M O LO G IC AL S B et ax ol ol S0 1E D 02 G lo ssi tis Ve ry r ar e ( < 0. 01 % ) No t g iv en VA RIO U S A LL ER G EN S A lle rg en e xt ra ct s V 01 A A G lo ssi tis C omm on (1 -1 0% ) A ft er s ub lin gu al ad min is tr at io n V 01 A A 02 A LL O TH ER T H ER A PE U TI C PR O D U C TS Su cr of er ric ox yh yd ro xi de V 03 A E0 5 Ton gu e d is co lor at ion U nc omm on (0 .1 -1 % ) A ft er o ra l o r o ro m uc os al ad min is tr at io n D ef in iti on s: *G lo ss iti s w as d ef in ed a s i nf la m m at io n o f t he t on gu e w ith l os s o f f ili fo rm p ap ill ae , l ea di ng t o p ai n, s w el lin g a nd e ry th em a. *T on gu e d is co lo ra tio n w as d ef in ed a s p ig m en ta tio n o f t he t on gu e a s a r es ul t o f t he d ru g o r i ts m et ab ol ite d ep os iti on o r b y i nc re as in g t he p ro du ct io n o f m el an in . *H ai ry t on gu e i s a t ra ns ito ry a nd h ar m le ss c on di tio n c ha ra ct er ize d b y hy pe rt ro phy a nd p ro lo ng at io n o f f ili fo rm p ap ill ae o n t he s ur fa ce o f t he t on gu e. *C oa te d t on gu e d es cr ib es a ny a re a o f t he t on gu e w ith a c oa tin g o n i t. T A B LE 3  (Co nti nue d)

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T A B LE 4  In cr ea se i n v ol um e o f t he t on gu e ( to ng ue o ed em a, h yp er tr op hy o f t on gu e p ap ill ae ) AT C l ev el 1 AT C l ev el 3 G ene ric n am e AT C C od e LL T M ed D R A* Fr eq ue nc y Sp ec ifi c t yp e o f a dm in is tr at io n A LI M EN TA RY T R A C T A N D M ET A B O LIS M O TH ER A LI M EN TA RY T R A C T A N D M ET A B OL IS M P RODUC TS Id ur su lfas e A 16 A B 09 To ngu e o edem a C omm on (1 -1 0% ) No t g iv en A NT I-IN FE C TI V ES F O R SY ST EM IC U SE O TH ER B ET A -L A C TA M A NT IB A C TE RI A LS C ef az ol in J0 1D B 04 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A NT IM YC O TI C S FO R SY STE M IC U SE Vo ric on az ol e J0 2AC 03 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en A NT IM YC O TI C S FO R SY STE M IC U SE Po sa co na zole J0 2AC 04 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en C A RB A PEN EM S Im ip en em a nd cil as ta tin J01 D H 51 H yp er tr op hy o f t on gu e pap ill ae Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A NT IN EO PL A ST IC A N D IM M U N O M O D U LA TIN G AG EN TS H O RM O N E A N TA G O N IS TS A N D REL AT ED A G EN TS Enz al ut amid e L0 2B B 04 To ngu e o edem a Ve ry r ar e ( < 0. 01 % ) No t g iv en BL O O D AN D BL O O D -FO RM IN G O RG A N S V IT A M IN K A N D O TH ER H A EMO ST AT IC S El tr omb opa g B 02 BX 05 To ngu e o edem a C omm on (1 -1 0% ) In c as e o f p at ie nt s w ith i m m un e thr omb oc yt op en ic p ur pu ra or ap la st ic an ae m ia C A RD IO VA SC UL A R SY ST EM A C E I N H IB IT O RS , P LA IN Fo si no pri l C 09 A A 09 To ngu e o edem a Ve ry r ar e ( < 0. 01 % ) No t g iv en N ER V O U S S YS TE M A NT ID EP RE SSA NT S A mi tr ip ty lin e N 06 A A0 9 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en A NT ID EP RE SSA NT S D ox ep in N 06 A A1 2 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A NT ID EP RE SSA NT S N or tr ip ty lin e N 06 A A 10 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en H YP N O TI C S A N D S ED AT IV ES M ela to nin N0 5C H0 1 To ngu e o edem a Ve ry r ar e ( < 0. 01 % ) No t g iv en A NT IM IG R A IN E PR EP A R AT IO N S Ri za tr ip ta n N 02 CC 04 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en A NT IE PILE PT IC S Preg ab al in N 03 A X16 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en D O PA MIN ER G IC A G ENT S Rot ig ot in e N 04B C 09 To ngu e o edem a U nc omm on (0 .1 -1 % ) In c ase o f P ar ki ns on ’s d ise ase D O PA MIN ER G IC A G ENT S Rot ig ot in e N 04B C 09 To ngu e o edem a C omm on (1 -1 0% ) Fo r r es tle ss l eg s A NT IP SY C H O TI C S Pa lip er id on e N 05A X1 3 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en AN AE ST H ET IC S, L O C AL M epi va ca in e N 01B B 03 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en RE SP IR AT O RY S YS TE M AD RE N ER G IC S, IN H AL AN TS In da cate ro l R0 3A C1 8 To ngu e o edem a U nc omm on (0 .1 -1 % ) No t g iv en SY ST EM IC H O RMO N A L PR EP A R AT IO N S, E XC L. A NT IP A R ATH YR O ID A G ENT S C al ci to nin (s alm on sy nt het ic ) H 05 B A 01 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en VA RIO U S M A G N ET IC R ES O N A N C E IM A G IN G C O NTR A ST M ED IA G ado ter ido l V 08 C A 04 To ngu e o edem a Ra re ( ≥ 0 .0 1% a nd < 0 .1 % ) No t g iv en A LL O TH ER T H ER A PE U TI C PR O D U C TS Pa life rm in V 03 A F0 8 To ngu e o edem a Ve ry r ar e ( < 0. 01 % ) No t g iv en A LL ER G EN S A lle rg en e xt ra ct s V 01 A AV 01 A A 02 To ngu e o edem a Ve ry r ar e ( < 0. 01 % ) A ft er s ub cu ta ne ou s a dm in is tr at io n *D ef in iti on : s w el lin g o f t he t on gu e d ue t o l os s o f v as cu la r i nt eg rit y c au sin g e xt ra va sa tio n o f f lu id i nt o i nt er st iti al t iss ue .

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T A B LE 5  A lte ra tio n i n s en si tiv ity o f t he t on gu e (b ur ning tong ue , dy sae st he sia o f t ong ue , p ru rit us o f t ong ue , g lo ss ody ni a, tong ue n um bn es s) AT C l ev el 1 AT C l ev el 3 G en er ic na m e AT C C od e LL T Med D R A* Fr eq uen cy Sp ec ifi c t yp e o f ad minis tr at io n A LI M EN TA RY T R A C T A N D ME TA B O LIS M INTE STIN A L A NTI -IN FE C TI V ES C ol is tin A 07A A 10 B ur ni ng to ng ue Ve ry r ar e ( < 0.0 1% ) A ft er in ha la tio n A NTIP RO PU LS IV ES Lo pe ra m id e A0 7D A0 3 B ur ni ng to ng ue Ra re ( ≥ 0 .0 1% an d < 0 .1 % ) No t g iv en ST O M AT O LO G IC AL P RE PAR AT IO N S C hlo rhe xi di ne A 01 A B 03 B ur ni ng to ng ue Ve ry r ar e ( < 0.0 1% ) No t g iv en PR O PU LS IV ES M et oc lo pr am id e A0 3F A0 1 D ys ae st he si a o f to ng ue Fr eq uenc y no t kno wn No t g iv en A NTI -IN FE C TI V ES F O R SY STE MI C US E B ET A -L A C TAM AN TI B A C TE RIAL S, PE N IC ILLIN S Ph en et icilli n J01 C E0 5 G los so dy ni a Ve ry r ar e ( < 0.0 1% ) No t g iv en SU LP H O N A M ID ES A N D TR IME TH O PR IM Tri m et ho pri m J01 EA 01 G los so dy ni a Ve ry r ar e ( < 0.0 1% ) No t g iv en A NTIN EO PL A STI C A N D IM MU N O M O DU LA TI N G AG EN TS O TH ER A NTIN EO PL A STI C A G ENT S C ab oz an tin ib L0 1X E26 B ur ni ng to ng ue Ve ry c omm on (≥ 10 % ) No t g iv en O TH ER A NTIN EO PL A STI C A G ENT S O xa lip la tin L01 X A 03 D ys ae st he si a o f to ng ue Fr eq uenc y no t kno wn No t g iv en O TH ER A NTIN EO PL A STI C A G ENT S So raf en ib L01 X E0 5 G los so dy ni a C omm on (1 -1 0% ) No t g iv en O TH ER A NTIN EO PL A STI C A G ENT S Su nit ini b L01 X E0 4 G los so dy ni a C omm on (1 -1 0% ) No t g iv en C ARD IO VA SC U LAR S YS TE M A N TI A D RE N ER G IC A G EN TS , C EN TR A LL Y A C TIN G Me th yld op a (lev or ot at or y) C 02 A B 01 G los so dy ni a Ve ry r ar e ( < 0.0 1% ) No t g iv en N ER V O U S S YS TE M A NTIMI G R A IN E PR EP A R ATI O N S Su ma tr ip ta n N 02C C 01 B ur ni ng to ng ue C omm on (1 -1 0% ) No t g iv en A NTIE PILE PTI C S To pi ra m ate N 03 A X11 B ur ni ng to ng ue U nc omm on (0 .1 -1 % ) No t g iv en A N A ES TH ETI C S, L O C A L Ro pi va ca in e N 01B B 09 N um bn es s o f to ng ue U nc omm on (0 .1 -1 % ) No t g iv en A N A ES TH ETI C S, L O C A L B upi va ca in e N 01 B B 01 N um bn es s o f to ng ue U nc omm on (0 .1 -1 % ) No t g iv en A N A ES TH ETI C S, L O C A L Pr ilo ca in e N 01B B 04 N um bn es s o f to ng ue U nc omm on (0 .1 -1 % ) No t g iv en RE SP IR AT O RY S YS TE M AD RE N ER G IC S, IN H AL AN TS Sa lb ut am ol R0 3AC 02 B ur ni ng to ng ue C omm on (1 -1 0% ) A ft er in ha la tio n TH RO AT P RE PA R ATI O N S Fl ur bip ro fe n M 01 A E0 9 B ur ni ng to ng ue U nc omm on (0 .1 -1 % ) No t g iv en VARI O U S A LL ER G EN S A ller gen e xt rac ts V 01 A AV 01 A A 02 B ur ni ng to ng ue Ve ry r ar e ( < 0.0 1% ) A ft er s ub cu ta ne ou s ad min is tr at io n (Co nti nue s)

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AT C l ev el 1 AT C l ev el 3 G en er ic na m e AT C C od e LL T Med D R A* Fr eq uen cy Sp ec ifi c t yp e o f ad minis tr at io n A LL ER G EN S A ller gen e xt rac ts V 01 A AV 01 A A 02 B ur ni ng to ng ue C omm on (1 -1 0% ) A ft er s ub lin gu al ad min is tr at io n A LL ER G EN S A ller gen e xt rac ts V 01 A A To ng ue p ru rit us C omm on (1 -1 0% ) A ft er s ub lin gu al ad min is tr at io n A LL ER G EN S A ller gen e xt rac ts V 01 A A G los so dy ni a C omm on (1 -1 0% ) A ft er s ub lin gu al ad min is tr at io n D ef in itio ns : *B ur ni ng s en sa tio n o f t on gu e c au se d b y d ru gs . *D ys ae st he sia o f t he ton gue is a n a bn or m al u np le as an t s en sa tion o f t he ton gue . *P ru rit us o f t on gu e i s a s a n i tc hy s en sa tio n o f t he t on gu e. *G lo ss ody ni a i s a b ur ni ng sen sa tio n o f t he to ng ue . *N um bn es s o f t he t on gu e i s a l os s o f s en sa tio n i n t he t on gu e. T A B LE 5  (Co nti nue d) T A B LE 6  D ef ec t o f s ur fa ce o f t he t on gu e ( t on gu e u lc er at io n) AT C l ev el 1 AT C l ev el 3 G en er ic na m e AT C C od e LL T Med D R A* Fr eq uen cy Sp ec ifi c t yp e o f a dm in is tr at io n A NTIN EO PL A STI C IMM U N O M O D U LA TIN G A N D A G EN TS IM M U N O SU PP RE SSA N TS al em tu zu ma b L0 4A A3 4 To ng ue u lc er at io n Fr eq uenc y no t kno wn In c as e o f p at ie nt s w ith B -c el l c hr on ic l ym ph oc yt ic leu kae m ia C ARD IO VA SC U LAR S YS TE M VA SO D IL AT O RS U SE D I N C A RDI A C DI SE A SE S Nic or an di l C 01 D X16 To ng ue u lc er at io n Ra re ( ≥ 0 .0 1% an d < 0 .1 % ) No t g iv en N ER V O U S S YS TE M H YP N O TI C S A N D S ED AT IV ES M ela to nin N0 5C H0 1 To ng ue u lc er at io n Ra re ( ≥ 0 .0 1% an d < 0 .1 % ) No t g iv en A N TI D EP RE SSA N TS Se rtr al in e N 06 A B 06 To ng ue u lc er at io n Ra re ( ≥ 0 .0 1% an d < 0 .1 % ) No t g iv en

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disorders using the most common definitions. Furthermore, to as-sure data uniformity we standardized the data by using the ATC and MedDRA classification. The use of ATC and MedDRA classification makes our data internationally applicable. As mentioned in the first article of this series, it is recommended to use MedDRA classifica-tion for homogenous data collecclassifica-tion. We assume that it will improve recording of adverse drug reactions in the future. As discussed in the first article, there will be drugs that are not mentioned in this paper due to difference in local law and regulations on drug per country. But most of the drugs mentioned in this study are available in European countries.

In the recent years, several studies have reported cases of drug-induced tongue disorders. Drugs like angiotensin-converting enzyme (ACE) inhibitors(Leung et al., 2012; Stallone et al., 2004), non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and certain antibiotics are reported to cause angioedema of the lips, tongue and face. About 25%-40% of angioedema in orofacial region are induced by ACE inhibitors. Perindopril is one of the ACE inhibitors that is often associated with angioedema of the lips and tongue. The un-derlying mechanism for ACE inhibitor-induced angioedema is the enzymatic inhibition of bradykinin degradation (Alharbi et al., 2018). Early recognition of drug-induced tongue oedema is important as it can be a life-threatening condition. In this study, tongue oedema was reported in 22 drugs, mainly in the drug category “nervous systems” (45.5%). Fosinopril was the only ACE inhibitor that was reported to cause tongue oedema. Contrary to expectations, the frequency of fosinopril-induced tongue oedema was very rare (˂0.01%). This dis-crepancy could be explained by the fact that other studies report on all cases of ACE inhibitor-induced angioedema in the orofacial region. They do not subdivide the orofacial angioedema into differ-ent categories. In this study, however, the focus lied solely on the tongue oedema.

Drugs such as tetracycline, penicillins, anticholinergics and linezolid are reported to cause black hairy tongue (Balaji et al., 2014; Braggio et al., 2018; Gurvits & Tan, 2014; Reamy et al., 2010). Beside the colour black, hairy tongue can also be yellow, green, blue, brown or even colourless. Generally, no treatment is necessary for this condition as it is predominantly asymptom-atic. The pathophysiology of drug-induced black hairy tongue is still unknown. In this study, hairy tongue as an adverse effect was reported for 4 drugs: metronidazole, hydrogen peroxide, antibi-otics in combination with amoxicillin and sulphamethoxazole and trimethoprim. On the other hand, 21 drugs were associated with the development of tongue discoloration as an adverse drug reac-tion. As expected, most of the drugs were antibiotics. The differ-ence is likely due to categorizing the tongue disorders by using the MedDRA classification and ATC codes. In order to collect homog-enous data on adverse drug reactions, MedDRA classification is recommended to be used.

The occurrence of severe glossitis after administration of sulphanilamide and sulphathiazole has been reported in the lit-erature. The underlying mechanism for glossitis in those cases was avitaminoses without apparent cause (Brown, 1949). In the

T A B LE 7  O ther to ngu e d iso rder s (tong ue ir rit at ion , t ong ue d isor der s N O S) AT C l ev el 1 AT C l ev el 3 G en er ic na m e AT C C od e LL T Med D R A* Fr eq uen cy Sp ec ifi c t yp e o f ad minis tr at io n A NTI -IN FE C TI V ES F O R SY STE MI C US E SU LP H O N A MID ES A N D TR IME TH O PR IM Sul pha m et ho xaz ol e an d tri m et ho pri m J01 EE01 To ng ue d is or der N OS Fr eq uenc y no t kno wn No t g iv en A NTIN EO PL A STI C A N D IM MU N O M O DU LA TI N G A G EN TS H O RM O N ES A N D R EL AT ED A G EN TS Le up ro re lin L02 A E02 To ng ue d is or der N OS C omm on (1 -1 0% ) No t g iv en B LO O D A N D B LO O D -F O RM IN G O RG A N S A NTI TH RO MB O TI C A G ENT S Ilo pros t B 01 A C11 To ng ue ir rit at io n C omm on (1 -1 0% ) A ft er in ha la tio n C ARD IO VA SC U LAR S YS TE M LI PI D M O D IF YI N G A G EN TS , P LA IN C ho le st yr amin e C10 A C 01 To ng ue ir rit at io n Ve ry r ar e (< 0.0 1% ) No t g iv en N ER V O U S S YS TE M A N TI D EP RE SSA N TS Imip ra min e N 06A A 02 To ng ue d is or der N OS Fr eq uenc y no t kno wn No t g iv en A N TI D EP RE SSA N TS Se rtr al in e N 06 A B 06 To ng ue d is or der N OS U nc omm on (0 .1 -1 % ) No t g iv en VARI O U S A LL ER G EN S A ller gen e xt rac ts V 01 A A To ng ue d is or der N OS U nc omm on (0 .1 -1 % ) A ft er s ub lin gu al ad min is tr at io n *T on gue d iso rde r N O S: ton gue d isor de r n ot o the rw ise sp ec ifi ed .

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present study, glossitis was one of the most frequent adverse ef-fects of drugs. The drug categories “anti-infectives for systemic use” and “nervous systems” contained most of the medications that can induce glossitis. Nonetheless, both medications are not mentioned in the drug category “anti-infectives for systemic use.” The reason could be difference in local law and regulations on drug per country. Both antibiotics are not registered in the “far-macotherapeutisch kompas.” Far“far-macotherapeutisch kompas is an online database in Dutch (FK, 2019) which consist all the med-ications registered with the Medicines Evaluation Board of the Netherlands. In addition, it also consists drugs that are registered in European Medicines Agency.

Antirheumatic drugs such as leflunomide are reported to cause ulcers in the tongue (Kalogirou et al., 2017). Tongue ulcers are also associated with nicorandil use. The pathophysiology of nicorandil-in-duced tongue ulcers is still unclear (Healy et al., 2004). These ulcers usually heal after the discontinuation of the drugs. In the present study, four drugs were reported to cause ulceration of the tongue: alemtuzumab, nicorandil, melatonin and sertraline. Contrary to the literature, tongue ulceration was not reported for leflunomide. Our study might underreport some adverse drug reactions compared to another studies which are not based on MedDRA classification. The LLT term used to categorize the drug-induced tongue disorders is very specific. According to the farmacotherapeutisch kompas, an ad-verse effect of leflunomide is ulcers in the mouth which is unspecific compared to tongue ulceration.

5 | CONCLUSION

The growing use of drugs is accompanied by a more frequent observation of tongue disorders that may have been induced by the use of drugs. As mentioned before, a wide variety of, partly overlapping, terminology is found in the literature to describe a particular tongue disorder related to the use of a drug and vice versa. The terminology used in this paper might help to bring the terminology used in pharmacology and oral medicine more in line. The overview of drugs reported in this paper helps oral healthcare workers in the recognition, diagnosis and eventual treatment of drug-induced tongue disorders.

AUTHOR CONTRIBUTIONS

Yalda Aziz: Data curation; Validation; Visualization; Writing-original

draft; Writing-review & editing. Willem Rademacher: Data curation; Investigation; Methodology; Validation. Atty Hielema: Methodology; Resources. Scott Bradley Patton Wishaw: Methodology; Resources.

Denise van Diermen: Supervision. Jan de Lange: Supervision. Arjan Vissink Supervision, Writing-review & editing. Frederik Rozema

Conceptualization, Methodology, Supervision, Writing-review & editing.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the Royal Dutch Pharmacist Association for providing access to Informatorium Medicamentorum.

PEER RE VIEW

The peer review history for this article is available at https://publo ns.com/publo n/10.1111/odi.13680.

ORCID

Yalda Aziz https://orcid.org/0000-0002-1847-6264 Arjan Vissink https://orcid.org/0000-0003-2581-4361 REFERENCES

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How to cite this article: Aziz Y, Rademacher WMH, Hielema

A, et al. Oral adverse effects: drug-induced tongue disorders.

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