Elsevier

Epilepsy Research

Volume 124, August 2016, Pages 12-15
Epilepsy Research

Levetiracetam-induced cutaneous adverse drug reactions were not associated with HLA genes in a small sample of Chinese patients with epilepsy

https://doi.org/10.1016/j.eplepsyres.2016.04.008Get rights and content

Highlights

  • The onset of skin rash occurred within 4 weeks of levetiracetam exposure.

  • The mean latency to skin rash from levetiracetam exposure was (15.67 ± 5.41) days.

  • Our study failed to show any potential link between HLA alleles and LEV-induced cADRs in Han Chinese.

Abstract

Purpose

This study aimed to evaluate the clinical characteristics of levetiracetam (LEV)-induced cutaneous adverse drug reactions (cADRs) and to explore its possible genetic association with the human leukocyte antigen (HLA) genes.

Methods

Nine cases with LEV-induced cADRs were recruited. Demographic and clinical information of these cases was summarized. Additionally, cases were matched with LEV-tolerant controls (1:4). High-resolution HLA class I and class II genotyping was performed for each participant. The allele frequencies between the cases and controls were compared.

Results

All LEV-induced cADRs were mild skin rashes which occurred within 28 days of LEV exposure. The mean latency from LEV exposure to skin rash was (15.67 ± 5.41) days (ranging 6–27). The carrier rates of the two alleles, HLA-DRB1*0405 and HLA-DQB1*0401, were higher in cases compared with controls (the same P = 0.036, OR = 13.875, 95% CI: 1.273-151.230). The association between the HLA-C*0304 allele and LEV-induced cADRs was boundary (P = 0.05, OR = 5.2, 95% CI: 1.086-24.897). However, the above-mentioned HLA alleles didn’t reach statistical significance after multiple comparisons.

Conclusions

Safety monitoring was necessary within four weeks after the initiation of LEV treatment, although it has been regarded as a safe antiepileptic drug. Our study failed to show any potential link between HLA alleles and LEV-induced cADRs in Han Chinese. Further studies are needed to clarify the genetic and immunological mechanisms of LEV-induced cADRs.

Introduction

Levetiracetam (LEV) was first approved by United States Food and Drug Administration (US FDA) in December 1999 and proved to be effective in both partial and generalized epilepsy syndromes either as adjunctive treatment or monotherapy (Berkovic et al., 2007, French and Pedley, 2008). Unlike other antiepileptic drugs (AEDs), LEV has unique structural feature, novel antiepileptic mechanism and also fewer adverse side effects. One of the most common adverse reactions, AEDs-induced cutaneous adverse drug reactions (cADRs), has been less reported in LEV. To the best of our knowledge, only some scattered case reports of LEV-induced cADRs can be retrieved. The clinical characteristics and genetic mechanisms of LEV-induced cADRs have been unclear.

Recent advances in pharmacogenomics of AEDs may bring us some inspirations. Accumulated evidence confirmed the closely association between some AEDs-induced cADRs and the human leukocyte antigen (HLA) genes. Several important biological markers, including HLA-B*1502 allele (Chung et al., 2004) and HLA-A*3101 allele (McCormack et al., 2011), have been found to have outstanding predictive value for specific AEDs-induced cADRs in different populations. In the present study, we investigated the clinical features of nine epilepsy patients who experienced LEV-induced cADRs and exploratorily examine the possible association of the HLA genes with the risk of LEV-induced cADRs in Chinese Han populations.

Section snippets

Patients

Nine cases with LEV-induced cADRs from epilepsy center of West China Hospital (8 from outpatient clinic and 1 from the ward) were included between September 2011 and December 2014. The diagnostic criteria for the patient group were: subjects who developed LEV-induced maculopapular exanthema (MPE) after taking LEV for less than eight weeks. Patients who developed MPE after simultaneously use of other suspicious drugs were excluded. Other common causes of cADRs including over-the-counter drugs,

Clinical characteristics

Nine epileptic patients (6 male, 3 female) with LEV-induced cADRs and 36 LEV-tolerant controls were included. LEV was taken as monotherapy for epilepsy in four patients while as adjunctive treatment in the rest. All of the skin rashes were confirmed as MPE. Routine laboratory examination and temperature were normal. Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), were not observed. All nine patients had the rashes

Discussion

LEV, a new generation antiepileptic drug, with novel anticonvulsive mechanism (Hovinga, 2001), is structurally similar to piracetam which is one of the most common nootropic drugs, but different from other currently marketed AEDs. LEV is characterized with insignificant drug interactions and favorable tolerability and safety profile (Lo et al., 2011, Lyseng-Williamson, 2011). The reported adverse effects profile of LEV include somnolence, headache, asthenia, fatigue, dizziness, behavioural

Disclosure

None of the authors has any conflict of interest to disclose.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81171301). We thank all subjects who participated in this study.

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These authors contributed equally to this work.

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