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Published in: Clinical Drug Investigation 4/2019

01-04-2019 | Antiepileptic Drugs | Original Research Article

Adverse Cutaneous Drug Reactions Associated with Old- and New- Generation Antiepileptic Drugs Using the Japanese Pharmacovigilance Database

Authors: Keiko Hosohata, Ayaka Inada, Saki Oyama, Iku Niinomi, Tomohito Wakabayashi, Kazunori Iwanaga

Published in: Clinical Drug Investigation | Issue 4/2019

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Abstract

Background and Objective

Adverse cutaneous drug reactions associated with antiepileptic drugs (AEDs) are a serious problem in the clinical setting. New-generation AEDs have been reported to be better tolerated than old-generation forms; however, information about the risks of adverse cutaneous drug reactions to new-generation AEDs is limited.

Objective

The purpose of this study was to clarify the association of AEDs with adverse cutaneous drug reactions using a spontaneous reporting database.

Methods

We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analyzed. Based on reports of all adverse events, we obtained 4805 reports of adverse cutaneous drug reactions associated with AEDs, and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for drug rash, Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

Results

Individual AEDs had variable signals for drug rash, SJS, and TEN. The strongest signals were detected for drug rash caused by lamotrigine (ROR 9.18, 95% CI 8.65–9.74), SJS caused by zonisamide (ROR 9.85, 95% CI 8.23–11.78), and TEN caused by phenobarbital (ROR 14.08, 95% CI 11.28–17.57).

Conclusion

There are clear differences in the risk of cutaneous reactions among AEDs, and further studies are needed to confirm these findings.
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Literature
1.
go back to reference Van de Vel A, Cuppens K, Bonroy B, Milosevic M, Jansen K, Van Huffel S, et al. Non-eeg seizure-detection systems and potential sudep prevention: state of the art. Seizure. 2013;22:345–55.CrossRefPubMed Van de Vel A, Cuppens K, Bonroy B, Milosevic M, Jansen K, Van Huffel S, et al. Non-eeg seizure-detection systems and potential sudep prevention: state of the art. Seizure. 2013;22:345–55.CrossRefPubMed
2.
go back to reference Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: a systematic review and meta-analysis. Neurology. 2011;77:1005–12.CrossRefPubMedPubMedCentral Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: a systematic review and meta-analysis. Neurology. 2011;77:1005–12.CrossRefPubMedPubMedCentral
3.
go back to reference Kowski AB, Weissinger F, Gaus V, Fidzinski P, Losch F, Holtkamp M. Specific adverse effects of antiepileptic drugs–a true-to-life monotherapy study. Epilepsy Behav. 2016;54:150–7.CrossRefPubMed Kowski AB, Weissinger F, Gaus V, Fidzinski P, Losch F, Holtkamp M. Specific adverse effects of antiepileptic drugs–a true-to-life monotherapy study. Epilepsy Behav. 2016;54:150–7.CrossRefPubMed
4.
5.
go back to reference Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology. 2009;72:1223–9.CrossRefPubMedPubMedCentral Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology. 2009;72:1223–9.CrossRefPubMedPubMedCentral
6.
go back to reference Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68:402–8.CrossRefPubMed Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68:402–8.CrossRefPubMed
7.
go back to reference Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. Allopurinol is the most common cause of Stevens–Johnson Syndrome and toxic epidermal necrolysis in europe and israel. J Am Acad Dermatol. 2008;58:25–32.CrossRefPubMed Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et al. Allopurinol is the most common cause of Stevens–Johnson Syndrome and toxic epidermal necrolysis in europe and israel. J Am Acad Dermatol. 2008;58:25–32.CrossRefPubMed
8.
go back to reference Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia. 2015;56:450–9.CrossRefPubMed Werhahn KJ, Trinka E, Dobesberger J, Unterberger I, Baum P, Deckert-Schmitz M, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia. 2015;56:450–9.CrossRefPubMed
9.
go back to reference Trinka E, Giorgi L, Patten A, Segieth J. Safety and tolerability of zonisamide in elderly patients with epilepsy. Acta Neurol Scand. 2013;128:422–8.CrossRefPubMed Trinka E, Giorgi L, Patten A, Segieth J. Safety and tolerability of zonisamide in elderly patients with epilepsy. Acta Neurol Scand. 2013;128:422–8.CrossRefPubMed
10.
go back to reference Mahe J, de Campaigno EP, Chene AL, Montastruc JL, Despas F, Jolliet P. Pleural adverse drugs reactions and protein kinase inhibitors: identification of suspicious targets by disproportionality analysis from Vigibase. Br J Clin Pharmacol. 2018;84(10):2373–83.CrossRefPubMed Mahe J, de Campaigno EP, Chene AL, Montastruc JL, Despas F, Jolliet P. Pleural adverse drugs reactions and protein kinase inhibitors: identification of suspicious targets by disproportionality analysis from Vigibase. Br J Clin Pharmacol. 2018;84(10):2373–83.CrossRefPubMed
11.
go back to reference Mendes D, Alves C, Batel-Marques F. Safety profiles of adalimumab, etanercept and infliximab: a pharmacovigilance study using a measure of disproportionality in a database of spontaneously reported adverse events. J Clin Pharm Therap. 2014;39:307–13.CrossRef Mendes D, Alves C, Batel-Marques F. Safety profiles of adalimumab, etanercept and infliximab: a pharmacovigilance study using a measure of disproportionality in a database of spontaneously reported adverse events. J Clin Pharm Therap. 2014;39:307–13.CrossRef
12.
go back to reference Hosohata K, Inada A, Oyama S, Furushima D, Yamada H, Iwanaga K. Surveillance of drugs that most frequently induce acute kidney injury: a pharmacovigilance approach. J Clin Pharm Therap. 2019;44(1):49–53.CrossRef Hosohata K, Inada A, Oyama S, Furushima D, Yamada H, Iwanaga K. Surveillance of drugs that most frequently induce acute kidney injury: a pharmacovigilance approach. J Clin Pharm Therap. 2019;44(1):49–53.CrossRef
13.
go back to reference Gosho M. Risk of hypoglycemia after concomitant use of antidiabetic, antihypertensive, and antihyperlipidemic medications: a database study. J Clin Pharmacol. 2018;58(10):1324–31.CrossRefPubMed Gosho M. Risk of hypoglycemia after concomitant use of antidiabetic, antihypertensive, and antihyperlipidemic medications: a database study. J Clin Pharmacol. 2018;58(10):1324–31.CrossRefPubMed
14.
go back to reference Hosohata K, Matsuoka E, Inada A, Oyama S, Niinomi I, Mori Y, et al. Differential profiles of adverse events associated with mycophenolate mofetil between adult and pediatric renal transplant patients. J Int Med Res. 2018;46(11):4617–23.CrossRefPubMedPubMedCentral Hosohata K, Matsuoka E, Inada A, Oyama S, Niinomi I, Mori Y, et al. Differential profiles of adverse events associated with mycophenolate mofetil between adult and pediatric renal transplant patients. J Int Med Res. 2018;46(11):4617–23.CrossRefPubMedPubMedCentral
15.
go back to reference Oyama S, Hosohata K, Inada A, Niinomi I, Mori Y, Yamaguchi Y, et al. Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database. Therap Clin Risk Manag. 2018;14:1599–604.CrossRef Oyama S, Hosohata K, Inada A, Niinomi I, Mori Y, Yamaguchi Y, et al. Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database. Therap Clin Risk Manag. 2018;14:1599–604.CrossRef
16.
go back to reference Kose E. Adverse drug event profile associated with pregabalin among patients with and without cancer: analysis of a spontaneous reporting database. J Clin Pharm Therap. 2018;43:543–9.CrossRef Kose E. Adverse drug event profile associated with pregabalin among patients with and without cancer: analysis of a spontaneous reporting database. J Clin Pharm Therap. 2018;43:543–9.CrossRef
17.
go back to reference Anzai T, Takahashi K, Watanabe M. Adverse reaction reports of neuroleptic malignant syndrome induced by atypical antipsychotic agents in the Japanese Adverse Drug Event Report (JADER) database. Psychiatry Clin Neurosci. 2019;73(1):27–33.CrossRef Anzai T, Takahashi K, Watanabe M. Adverse reaction reports of neuroleptic malignant syndrome induced by atypical antipsychotic agents in the Japanese Adverse Drug Event Report (JADER) database. Psychiatry Clin Neurosci. 2019;73(1):27–33.CrossRef
18.
go back to reference Bate A, Evans SJ. Quantitative signal detection using spontaneous adr reporting. Pharmacoepidemiol Drug Saf. 2009;18:427–36.CrossRefPubMed Bate A, Evans SJ. Quantitative signal detection using spontaneous adr reporting. Pharmacoepidemiol Drug Saf. 2009;18:427–36.CrossRefPubMed
19.
go back to reference Maignen F, Hauben M, Hung E, Van Holle L, Dogne JM. Assessing the extent and impact of the masking effect of disproportionality analyses on two spontaneous reporting systems databases. Pharmacoepidemiol Drug Saf. 2014;23:195–207.CrossRefPubMed Maignen F, Hauben M, Hung E, Van Holle L, Dogne JM. Assessing the extent and impact of the masking effect of disproportionality analyses on two spontaneous reporting systems databases. Pharmacoepidemiol Drug Saf. 2014;23:195–207.CrossRefPubMed
20.
go back to reference Italiano D, Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. Clin Pharmacokinet. 2013;52:627–45.CrossRefPubMed Italiano D, Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. Clin Pharmacokinet. 2013;52:627–45.CrossRefPubMed
21.
go back to reference Theitler J, Brik A, Shaniv D, Berkovitch M, Gandelman-Marton R. Antiepileptic drug treatment in community-dwelling older patients with epilepsy: a retrospective observational study of old- versus new-generation antiepileptic drugs. Drugs Aging. 2017;34:479–87.CrossRefPubMed Theitler J, Brik A, Shaniv D, Berkovitch M, Gandelman-Marton R. Antiepileptic drug treatment in community-dwelling older patients with epilepsy: a retrospective observational study of old- versus new-generation antiepileptic drugs. Drugs Aging. 2017;34:479–87.CrossRefPubMed
22.
go back to reference Mohd-Tahir NA, Li SC. Meta-analyses of newer antiepileptic drugs as adjunct for treatment of focal epilepsy in children. Epilepsy Res. 2018;139:113–22.CrossRefPubMed Mohd-Tahir NA, Li SC. Meta-analyses of newer antiepileptic drugs as adjunct for treatment of focal epilepsy in children. Epilepsy Res. 2018;139:113–22.CrossRefPubMed
23.
go back to reference Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: Influence by gender, age, and learning disability. Epilepsia. 2007;48:1360–5.CrossRefPubMed Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: Influence by gender, age, and learning disability. Epilepsia. 2007;48:1360–5.CrossRefPubMed
24.
go back to reference Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1000–15.CrossRefPubMedPubMedCentral Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1000–15.CrossRefPubMedPubMedCentral
25.
go back to reference Zeng QY, Fan TT, Zhu P, He RQ, Bao YX, Zheng RY, et al. Comparative long-term effectiveness of a monotherapy with five antiepileptic drugs for focal epilepsy in adult patients: a prospective cohort study. PLoS One. 2015;10:e0131566.CrossRefPubMedPubMedCentral Zeng QY, Fan TT, Zhu P, He RQ, Bao YX, Zheng RY, et al. Comparative long-term effectiveness of a monotherapy with five antiepileptic drugs for focal epilepsy in adult patients: a prospective cohort study. PLoS One. 2015;10:e0131566.CrossRefPubMedPubMedCentral
26.
go back to reference Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens–Johnson Syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600–7.CrossRefPubMed Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens–Johnson Syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600–7.CrossRefPubMed
27.
go back to reference Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson Syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The euroscar-study. J Investig Dermatol. 2008;128:35–44.CrossRefPubMed Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson Syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The euroscar-study. J Investig Dermatol. 2008;128:35–44.CrossRefPubMed
28.
go back to reference Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens–Johnson Syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64:1134–8.CrossRefPubMed Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens–Johnson Syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64:1134–8.CrossRefPubMed
29.
go back to reference Lee HJ, Son JM, Mun J, Kim DW. Safety and efficacy of zonisamide in patients with epilepsy: a post-marketing surveillance study. J Epilepsy Res. 2015;5:89–95.CrossRefPubMedPubMedCentral Lee HJ, Son JM, Mun J, Kim DW. Safety and efficacy of zonisamide in patients with epilepsy: a post-marketing surveillance study. J Epilepsy Res. 2015;5:89–95.CrossRefPubMedPubMedCentral
30.
go back to reference Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 1999;21:489–501.CrossRefPubMed Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf. 1999;21:489–501.CrossRefPubMed
31.
go back to reference 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;94:213–7.CrossRefPubMed 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;94:213–7.CrossRefPubMed
32.
go back to reference Lu W, Uetrecht JP. Possible bioactivation pathways of lamotrigine. Drug Metab Dispos. 2007;35:1050–6.CrossRefPubMed Lu W, Uetrecht JP. Possible bioactivation pathways of lamotrigine. Drug Metab Dispos. 2007;35:1050–6.CrossRefPubMed
33.
go back to reference Naisbitt DJ, Farrell J, Wong G, Depta JP, Dodd CC, Hopkins JE, et al. Characterization of drug-specific t cells in lamotrigine hypersensitivity. J Allergy Clin Immunol. 2003;111:1393–403.CrossRefPubMed Naisbitt DJ, Farrell J, Wong G, Depta JP, Dodd CC, Hopkins JE, et al. Characterization of drug-specific t cells in lamotrigine hypersensitivity. J Allergy Clin Immunol. 2003;111:1393–403.CrossRefPubMed
34.
go back to reference Franciotta D, Kwan P, Perucca E. Genetic basis for idiosyncratic reactions to antiepileptic drugs. Curr Opin Neurol. 2009;22:144–9.CrossRefPubMed Franciotta D, Kwan P, Perucca E. Genetic basis for idiosyncratic reactions to antiepileptic drugs. Curr Opin Neurol. 2009;22:144–9.CrossRefPubMed
Metadata
Title
Adverse Cutaneous Drug Reactions Associated with Old- and New- Generation Antiepileptic Drugs Using the Japanese Pharmacovigilance Database
Authors
Keiko Hosohata
Ayaka Inada
Saki Oyama
Iku Niinomi
Tomohito Wakabayashi
Kazunori Iwanaga
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
Clinical Drug Investigation / Issue 4/2019
Print ISSN: 1173-2563
Electronic ISSN: 1179-1918
DOI
https://doi.org/10.1007/s40261-019-00754-z

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