Journal List > J Korean Med Sci > v.35(4) > 1141625

Kim, Kim, Bae, and Kim: Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008–2017

Abstract

Background

Severe and life-threatening drug eruptions include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). One class of medications that has been highly associated with such drug eruptions is antiepileptic drugs (AEDs). We attempt to investigate drug eruptions associated with AEDs as a class, as well as with individual AEDs, in Korea.

Methods

We used the Korea Institute of Drug Safety and Risk Management - Korea Adverse Event Reporting System (KIDS-KAERS) database, a nationwide database of adverse events reports, between January 2008 and December 2017 to investigate the reporting count of all drug eruptions and calculated the ratio of DRESS/SJS/TEN reports for each AED.

Results

Among a total of 2,942 reports, most were of rash/urticaria (2,702, 91.8%), followed by those of DRESS (109, 3.7%), SJS (106, 3.6%), and TEN (25, 0.85%). The common causative AEDs were lamotrigine (699, 23.8%), valproic acid (677, 23%), carbamazepine (512, 17.4%), oxcarbazepine (320, 10.9%), levetiracetam (181, 6.2%), and phenytoin (158, 5.4%). In limited to severe drug eruptions (DRESS, SJS, and TEN; total 241 reports), the causative AEDs were carbamazepine (117, 48.8%), lamotrigine (57, 23.8%), valproic acid (20, 8.3%), phenytoin (15, 6.3%), and oxcarbazepine (10, 4.2%). When comparing aromatic AED with non-aromatic AED, aromatic AEDs were more likely to be associated with severe drug eruption (aromatic AEDs: 204/1,793 versus non-aromatic AEDs: 37/1,149; OR, 3.86; 95% CI, 2.7–5.5). Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5).

Conclusion

Although most cutaneous drug eruptions in this study were rash or urticaria, approximately 8% of reports were of severe or life-threatening adverse drug reactions, such as SJS, TEN, or DRESS. When hypersensitivity skin reactions occurred, aromatic AEDs were associated with 4 fold the risk of SJS/TEN/DRESS compared with non-aromatic AEDs. Our findings further emphasize that high risk AEDs should be prescribed under careful monitoring, and early detection and prompt interventions are needed to prevent severe complications.

INTRODUCTION

Epilepsy is one of the most common neurologic disorders, with a global prevalence of almost 50–60 million people and an annual incidence of 50 per 100,000 persons per year in developed countries.12 Antiepileptic drug (AED) treatment is the most important means of preventing seizures, and two-thirds of patients with epilepsy become seizure free with appropriate pharmacotherapy.3 However, more than 25% of patients discontinue treatment because of adverse effects of the initial AED chosen, and up to one-third are refractory to multiple AEDs; such cases may potentially lead to recurrent adverse drug reactions (ADRs) and drug interactions.4
Adverse skin reactions (ASRs) to drugs occur in up to 8% of the global population and in 2%–3% of hospitalized patients. They occur in 3% of individuals who receive AEDs and are the most common reason for withdrawal of the drugs.5 ASRs are usually mild, appearing in the form of a diffuse, erythematous, maculopapular, pruritic rash or urticaria. However, occasionally they may be severe when occurring as part of the syndromes of erythema multiforme, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). These require immediate AED discontinuation to prevent a fatal outcome.67
The importance of post-marketing surveillance is emphasized because ADRs cannot be fully detected during the premarketing developing process.8 Current trends in pharmacovigilance systems are veering towards patient involvement in the spontaneous reporting of ADRs.9 Several studies for ADRs of AEDs using spontaneous reporting systems have been conducted in other countries, but there are no such studies in Korea.2101112 The aim of our study was to assess the association between ASRs, including SJS, TEN, and DRESS, and AEDs using the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System (KIDS-KAERS) database.

METHODS

Database, study drugs and ADRs

We reviewed adverse-event reports from the KIDS-KAERS database between January 2008 and December 2017. This adverse event reporting system was first launched in 1988 by the Korea Food and Drug Administration and has collected nationwide spontaneous ADR reports since then. In 2012, the pharmacovigilance activities were transferred to KIDS, which developed KIDS-KAERS database. Suspected drug and adverse event information are reported to KIDS in a form named ‘Individual Case Safety Reports (ICSR)’ using voluntary reporting system by health care workers (doctor, pharmacist or nurse) or general public. Reports are collected via call center, paper forms, the telephone, FAX, e-mail or website. All information received is stored within KIDS-KAERS database as an ICSR. KIDS detects and evaluates signals from cumulated data to generate and provide drug safety information. KAERS database includes adverse event information, drug information, patient and reporter information, and assessment information.
We included 22 AEDs available in Korea with an FDA indication for epilepsy or seizures and classified the drugs into aromatic and non-aromatic AEDs (Table 1).1314 ADRs were coded according to the Preferred Terms (PTs) among World Health Organization Adverse Reaction Terminology (WHO-ART).1516 We conducted searches of the WHO-ART PTs “Rash (0027),” “Urticaria (0044),” “SJS (0042),” “TEN (0014),” and “DRESS (2309).”
Table 1

AEDs evaluated in this study

jkms-35-e17-i001
AEDs (Generic names)
Carbamazepinea Oxcarbazepinea
Clobazam Perampanel
Clonazepam Phenobarbitala
Diazepam Phenytoina
Ethosuximide Pregabalin
Fosphenytoina,b Primidonea
Gabapentin Rufinamidea
Lacosamidea,c Topiramate
Lamotriginea Valproic acid/Divalproex sodium
Levetiracetam Vigabatrin
Lorazepam Zonisamidea
AED = antiepileptic drug.
aAromatic antiepileptic drugs; bFosphenytoin is a prodrug of phenytoin (only intravenous formulation); cLacosamide was launched after 2017 in Korea.
The WHO-Uppsala Monitoring Centre (WHO-UMC) causality assessment system categorizes the evaluation of ADRs into six groups: certain, probable, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable.1517 We included cases where the level of causality category was equal to or above “possible” (“certain,” “probable,” and “possible”). We excluded cases where there was no information on the causality category or where two or more drugs had the same level of causality category.

Statistical analysis

We investigated the reporting count of ASRs for 22 AEDs and calculated the ratio of severe ASRs (DRESS/SJS/TEN) to all ASRs for each AED. Comparisons were made between aromatic AEDs and non-aromatic AEDs for the ratio of DRESS/SJS/TEN to all ASRs using χ2 tests (with 2 × 2 cross tabulation).

Ethics statement

The Institutional Review Board of the National Medical Center of Korea reviewed and approved the study protocol (Approval No. H-1905-102-003). The need for informed consent was waived by the board.

RESULTS

During the study period, a total of 2,942 ASRs caused by AEDs were reported; the demographics of these reports are presented in Table 2. Among the 2,942 reports, 1,450 (49.3%) were of men and 1,456 (49.5%) were of women. Adults (18 years < aged < 65 years; 1,750; 59.5%) were most commonly affected, followed by the elderly (aged ≥ 65 years; 556; 18.9%). The most frequent report source by person was nurses (1,249; 42.5%), followed by doctors (1,000; 34%).
Table 2

Demographics and reporters of adverse skin reactions reports of antiepileptic drugs

jkms-35-e17-i002
Parameters No. of reports %
Gender
Men 1,450 49.3
Women 1,456 49.5
Unknown 36 1.2
Age group, yr
Infant, < 1 33 1.1
Child/adolescent, 1 to 18 459 15.6
Adult, 19 to 64 1,750 59.5
Elderly, ≥ 65 556 18.9
Unknown 144 4.9
Report source by person
Doctor 1,000 34.0
Pharmacist 277 9.4
Nurse 1,249 42.5
Customer 25 0.85
Others/unknown 391 13.3
Total 2,942
Among the total 2,942 reports, most were of rash/urticaria (2,702; 91.8%), followed by those of DRESS (109; 3.7%), SJS (106; 3.6%), and TEN (25; 0.85%) (Table 3). The common causative AEDs were lamotrigine (699; 23.8%), valproic acid (677; 23%), carbamazepine (512; 17.4%), oxcarbazepine (320; 10.9%), levetiracetam (181; 6.2%), and phenytoin (158; 5.4%). Limited to severe ASRs (DRESS, SJS, and TEN; total 241 reports), the common causative AEDs were carbamazepine (117; 48.8%), lamotrigine (57; 23.8%), valproic acid (20; 8.3%), phenytoin (15; 6.3%), and oxcarbazepine (10; 4.2%). When comparing aromatic AEDs with non-aromatic AEDs, aromatic AEDs were more likely to be associated with severe ASRs (aromatic AEDs: 204/1,793 vs. non-aromatic AEDs: 37/1,149; odds ratio [OR], 3.86; 95% confidence interval [CI], 2.7–5.5) (Table 4).
Table 3

Adverse skin reactions related to AEDs

jkms-35-e17-i003
All AEDs Total Rash/urticaria SJS TEN DRESS
2,942 2,702 (91.8%) 106 (3.6%) 25 (0.85%) 109 (3.7%)
Carbamazepinea 512 395 48 9 60
Clobazam 6 6 0 0 0
Clonazepam 25 25 0 0 0
Diazepam 24 23 0 0 1
Ethosuximide 4 4 0 0 0
Fosphenytoina 27 27 0 0 0
Gabapentin 83 81 2 0 0
Lacosamidea 6 6 0 0 0
Lamotriginea 699 642 34 11 12
Levetiracetam 181 172 2 1 6
Lorazepam 22 20 0 0 2
Oxcarbazepinea 320 310 2 0 8
Perampanel 1 1 0 0 0
Phenobarbitala 47 44 0 0 3
Phenytoina 158 143 10 0 5
Pregabalin 58 56 1 0 1
Primidonea 2 2 0 0 0
Rufinamidea 1 1 0 0 0
Topiramate 64 63 0 0 1
Valproic acid 677 657 6 3 11
Vigabatrin 4 4 0 0 0
Zonisamidea 21 19 1 1 0
AED = antiepileptic drug, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis, DRESS = drug reaction with eosinophilia and systemic symptoms.
aAromatic AEDs.
Table 4

Aromatic AEDs and non-aromatic AEDs for severe adverse skin reactions

jkms-35-e17-i004
Variables Total Rash/urticaria SJS/TEN/DRESS OR (95% CI) P value
Aromatic AEDs 1,793 1,589 204 3.86 (2.7–5.5) < 0.001
Non-aromatic AEDs 1,149 1,112 37 - -
AED = antiepileptic drug, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis, DRESS = drug reaction with eosinophilia and systemic symptoms, OR = odds ratio, CI = confidence interval.
We summarized the WHO-UMC causality categories for AEDs that had more than 30 reported ASRs (Table 5). “Probable/likely” and “possible” were similar for most drugs, but “possible” was markedly more common than “probable/likely” for valproic acid. Death was reported in 7 cases; DRESS was the most commonly reported adverse event (n = 5), and lamotrigine was the most common causative AED (n = 5) (Table 6).
Table 5

Causality categories for each antiepileptic drug (more than 30 reports)

jkms-35-e17-i005
Variables Total Certain Probable/likely Possible
Carbamazepine 512 28 237 247
Gabapentin 83 2 30 51
Lamotrigine 699 31 400 268
Levetiracetam 181 3 94 84
Oxcarbazepine 320 9 177 134
Phenobarbital 47 1 20 26
Phenytoin 158 4 76 78
Topiramate 64 4 31 29
Valproic acid 677 2 233 442
Table 6

Mortality cases from adverse drug reactions of AEDsa

jkms-35-e17-i006
AED Gender Age, yr Adverse drug reactions
Lamotrigine Men 20 DRESS
Lamotrigine Women 21 DRESS
Lamotriginea Men 52 Rash
Lamotrigine Men 33 SJS
Levetiracetam Women Unknown DRESS
Phenytoin Women 28 DRESS
Valproic acid Men 58 DRESS
AED = antiepileptic drug, DRESS = drug reaction with eosinophilia and systemic symptoms, SJS = Stevens-Johnson syndrome.
aRash was not direct cause of death, and patient died from drug-induced hepatitis.

DISCUSSION

In this study, we investigated hypersensitivity skin reactions to AEDs using pharmacovigilance data in Korea. In large, accessible, nationwide drug safety databases, comprehensive information on adverse drug events had been collated, and thus the study design was suitable for the evaluation of rare but very serious adverse drug events.2
In the present study, we identified that most ASRs associated with AEDs are benign rash or urticaria (91.8%), but severe or fatal skin reactions were not rare, occurring in up to approximately 8% of cases. The common causative AEDs were lamotrigine, valproic acid, carbamazepine, oxcarbazepine, levetiracetam, and phenytoin. In case of AED-related ASRs, aromatic AEDs were found to be associated more frequently with severe or fatal skin reactions than non-aromatic AEDs, with an OR of 3.86. The results of the present study are similar to the results of earlier studies except that there were few reports related to zonisamide (21; 0.7%) in the present study218 A recent study on severe cutaneous adverse reactions to AEDs in Korean hospitalized patients showed similar results.19
The modified version of the WHO classification distinguishes the toxic and adverse effects of AEDs into five types: acute, related to the pharmacological properties of the drug (type A); idiosyncratic (type B); chronic (type C); delayed (type D); and secondary to drug interactions (type E).20 Skin rashes and severe mucocutaneous reactions (DRESS, SJS, and TEN) belong to type B adverse effects. They are related to individual vulnerability (immunological, genetic, or other mechanism) and are unpredictable, with high morbidity and mortality rates.20 ASRs are the most common idiosyncratic reactions to AEDs and occur in 5%–15% of individuals who receive AEDs.6 In a meta-analysis of Chinese patients, AEDs were found to be the second most common causative drugs associated with severe ASRs.21 Carbamazepine was also reported as the second causative drug of severe cutaneous adverse reactions in Korea.19 Moreover, in relief system for ADRs, AEDs are one of the most common causative drugs; in 2018, all 18 reports related to AEDs were due to severe ASRs (SJS, TEN, and DRESS).2223
Many investigations of genomic contributions that modulate the risk of developing AED-induced hypersensitivity reactions have revealed significant associations with genes encoding the human leukocyte antigen (HLA) alleles.24 Pharmacogenomics studies have identified a striking association between the HLA-B*15:02 allele and carbamazepine-induced SJS/TEN in the Han Chinese population.25 The frequency of the HLA-B*15:02 allele is substantially lower among European Caucasians (about 0.001%) and higher in Asian populations (1.6%–11%).26 In addition to HLA-B*15:02, the association between several other HLA types (HLA-A*31:01, HLA-B*15:11, and HLA-A*24:02) and AED-induced ASRs has also been reported in Korean populations.24
In this study, a total of six AEDs (lamotrigine, valproic acid, carbamazepine, oxcarbazepine, levetiracetam, and phenytoin) had reports of more than 100 ASRs, and among them, four AEDs are aromatic AEDs, which contain an aromatic ring in their chemical structure. In addition, the risk of severe ASRs was significantly higher with aromatic AED use than with that of non-aromatic AEDs. These results are similar to those of previous studies.12162728 One of the main hypotheses explaining this observation is that AEDs containing an aromatic ring in their chemical structure can form an arene-oxide intermediate.1328 This chemically reactive product may become immunogenic through interactions with proteins or cellular macromolecules in accordance with the hapten hypothesis, suggesting that this structural commonality between AEDs may be responsible for hypersensitivity reactions.13 Another argument supporting this hapten hypothesis is the rate of cross sensitivity that has been reported among patients using aromatic AEDs, which has been reported to be as high as 80%–87%.28 Identification of genetic polymorphisms that predispose to AED-induced skin reactions and the subsequent avoidance of AED treatment could help to prevent life-threatening events.28
Our results showed that valproic acid (a non-aromatic AED) was the second most commonly reported drug (677; 23%). This finding is different from that of previous retrospective studies of epilepsy patients but similar to that of a pharmacovigilance study using spontaneous reporting.2716 Valproic acid was the most frequently prescribed AED in Korea based on the 2007 databases of National Health Insurance.29
Valproic acid is an FDA-approved drug to treat manic or mixed episodes associated with bipolar disorder, and migraine as well as seizure. It is also used for treating neuropathic pain, fibromyalgia, and behavioral symptoms in dementia.3031 As the pharmacovigilance study includes not only epilepsy but also other diseases, it is likely that the frequency of adverse events is relatively high. In addition, considering that it was relatively common for valproic acid to belong to the “possible” causality category, the possibility of an exaggerated number of ASRs for it cannot be excluded.
In case of zonisamide, the number of reports was low in contrast to that in previous studies.2716 In Korea, zonisamide is available only as a single original drug, and although it seems that the low number of prescriptions is one of the reasons for low adverse event reports, further investigation is needed to confirm this.
Several serious limitations of our study should be noted. First, we were unable to calculate the reporting ORs due to the data characteristics of single category adverse events. We were also unable to calculate the true incidence rates due to the lack of total number of patients receiving the drugs of interest.2 Second, adverse event reports of this study might have been underreported because the KIDS-KD is a spontaneous adverse event reporting system.8 Especially, a reporting bias can be influenced by severity of adverse events. The chance of reporting would be higher in patients with serious skin reactions such as SJS, TEN and DRESS, and lower in patients with simple rash or urticaria. Therefore, the proportion of serious skin reactions (241/2,942 in this study) might have been over-estimated or exaggerated. In addition, this voluntary reporting database nature results in several limitations such as a lack of central quality control by expert panels and many missing or lacking clinical data (e.g., age, gender, indications, etc.).3 As ADR reports in the KIDS-KAERS were anonymized, additional information could not be assessed.32
The present study found that various AEDs are associated with cutaneous ADRs. Although most cutaneous drug reactions were benign, certain AEDs were associated with a higher risk of severe cutaneous drug reactions such as SJS, TEN, or DRESS. Our findings support previous evidence that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains AED-associated cutaneous drug reactions. High risk AEDs should be prescribed under careful monitoring, and early detection and prompt intervention are needed to prevent severe complications.

Notes

Disclosure The authors have no potential conflicts of interest to disclose.

Author Contributions

  • Conceptualization: Kim DW.

  • Data curation: Kim HK, Kim DY.

  • Formal analysis: Kim HK, Bae EK.

  • Investigation: Kim HK, Kim DY, Bae EK.

  • Methodology: Kim HK, Bae EK, Kim DW.

  • Supervision: Kim DW.

  • Validation: Kim HK.

  • Writing - original draft: Kim HK.

  • Writing - review & editing: Kim HK, Kim DW.

References

1. Kothare SV. Epidemiology: Practical Epilepsy. 1st ed. New York, NY: Demosmedical;2016.
2. Hosohata K, Inada A, Oyama S, Niinomi I, Wakabayashi T, Iwanaga K. Adverse cutaneous drug reactions associated with old- and new-generation antiepileptic drugs using the Japanese pharmacovigilance database. Clin Drug Investig. 2019; 39(4):363–368.
pmid
3. Bauer D, Quigg M. Optimizing management of medically responsive epilepsy. Continuum (Minneap Minn). 2019; 25(2):343–361.
crossref pmid
4. Mohanraj R, Brodie MJ. Pharmacological outcomes in newly diagnosed epilepsy. Epilepsy Behav. 2005; 6(3):382–387.
crossref pmid
5. Błaszczyk B, Lasoń W, Czuczwar SJ. Antiepileptic drugs and adverse skin reactions: An update. Pharmacol Rep. 2015; 67(3):426–434.
crossref pmid
6. Tatum WO. Antiepileptic drugs: adverse effects and drug interactions. Continuum (Minneap Minn). 2010; 16(3):136–158.
pmid
7. Arif H, Buchsbaum R, Weintraub D, Koyfman S, Salas-Humara C, Bazil CW, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology. 2007; 68(20):1701–1709.
crossref pmid
8. Soukavong M, Kim J, Park K, Yang BR, Lee J, Jin XM, et al. Signal detection of adverse drug reaction of amoxicillin using the Korea adverse event reporting system database. J Korean Med Sci. 2016; 31(9):1355–1361.
crossref pmid pmc
9. Inácio P, Cavaco A, Airaksinen M. The value of patient reporting to the pharmacovigilance system: a systematic review. Br J Clin Pharmacol. 2017; 83(2):227–246.
crossref
10. Bohn J, Kortepeter C, Muñoz M, Simms K, Montenegro S, Dal Pan G. Patterns in spontaneous adverse event reporting among branded and generic antiepileptic drugs. Clin Pharmacol Ther. 2015; 97(5):508–517.
crossref pmid
11. Chaabane A, Fadhel NB, Chadli Z, Romdhane HB, Fredj NB, Boughattas NA, et al. Association of non-immediate drug hypersensitivity with drug exposure: a case control analysis of spontaneous reports from a Tunisian pharmacovigilance database. Eur J Intern Med. 2018; 53:40–44.
crossref pmid
12. Ordoñez L, Salgueiro E, Jimeno FJ, Manso G. Spontaneous reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with antiepileptic drugs. Eur Rev Med Pharmacol Sci. 2015; 19(14):2732–2737.
pmid
13. Handoko KB, van Puijenbroek EP, Bijl AH, Hermens WA, Zwart-van Rijkom JE, Hekster YA, et al. Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring. Drug Saf. 2008; 31(8):695–702.
pmid
14. Fong MK, Sheng B. DRESS syndrome: a case of cross-reactivity with lacosamide? Epilepsia Open. 2017; 2(2):273–275.
crossref pmid pmc
15. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000; 356(9237):1255–1259.
crossref pmid
16. World Health Organization. International Monitoring of Adverse Reactions to Drugs: Adverse Reaction Terminology. Uppsala: WHO Collaborating Centre for International Drug Monitoring;1992.
17. World Health Organization. The use of the WHO-UMC system for standardised case causality assessment. Accessed August 7, 2019. https://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en.
18. Borrelli EP, Lee EY, Descoteaux AM, Kogut SJ, Caffrey AR. Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: an analysis of the US Food and Drug Administration Adverse Event Reporting System. Epilepsia. 2018; 59(12):2318–2324.
crossref pmid pmc
19. Park CS, Kang DY, Kang MG, Kim S, Ye YM, Kim SH, et al. Severe cutaneous adverse reactions to antiepileptic drugs: a nationwide registry-based study in Korea. Allergy Asthma Immunol Res. 2019; 11(5):709–722.
crossref pmid pmc
20. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012; 11(9):792–802.
crossref pmid
21. Deng Q, Fang X, Zeng Q, Lu J, Jing C, Huang J. Severe cutaneous adverse drug reactions of Chinese inpatients: a meta-analysis. An Bras Dermatol. 2017; 92(3):345–349.
crossref pmid pmc
22. Korea Institute of Drug Safety & Risk Management. Accessed October 6, 2019. https://karp.drugsafe.or.kr/frt/bbs/EgovFrontNotice.do?bbsId=BBSMSTR_000000000052.
23. Yang MS. Relief system for adverse drug reactions in Korea. Korean J Med. 2018; 93(1):5–13.
crossref
24. Mullan KA, Anderson A, Illing PT, Kwan P, Purcell AW, Mifsud NA. HLA-associated antiepileptic drug-induced cutaneous adverse reactions. HLA. 2019; 93(6):417–435.
crossref pmid
25. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004; 428(6982):486.
pmid
26. Fricke-Galindo I, Jung-Cook H, LLerena A, López-López M. Pharmacogenetics of adverse reactions to antiepileptic drugs. Neurologia. 2018; 33(3):165–176.
crossref pmid
27. Guvenir H, Dibek Misirlioglu E, Civelek E, Toyran M, Buyuktiryaki B, Ginis T, et al. The Frequency and Clinical Features of Hypersensitivity Reactions to Antiepileptic Drugs in Children: A Prospective Study. J Allergy Clin Immunol Pract. 2018; 6(6):2043–2050.
crossref pmid
28. Wang XQ, Shi XB, Au R, Chen FS, Wang F, Lang SY. Influence of chemical structure on skin reactions induced by antiepileptic drugs--the role of the aromatic ring. Epilepsy Res. 2011; 94(3):213–217.
crossref pmid
29. Lee SY, Jung KY, Lee IK, Yi SD, Cho YW, Kim DW, et al. Prevalence of treated epilepsy in Korea based on national health insurance data. J Korean Med Sci. 2012; 27(3):285–290.
crossref pmid pmc
30. Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011; (10):CD009183.
crossref
31. Dolder CR, Nealy KL, McKinsey J. Valproic acid in dementia: does an optimal dose exist? J Pharm Pract. 2012; 25(2):142–150.
pmid
32. Park KH, Lee SC, Yuk JE, Kim SR, Lee JH, Park JW. Eperisone-induced anaphylaxis: pharmacovigilance data and results of allergy testing. Allergy Asthma Immunol Res. 2019; 11(2):231–240.
crossref pmid