Association of HLA-A*31:01 Screening with the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Popul

Supplementary Online Content

Mushiroda T, Takahashi Y, Onuma T, et al; GENCAT Study Group. Association of HLA- A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population. JAMA Neurol. Published online April 2, 2018. doi:10.1001/jamaneurol.2018.0278

eTable 1. Detailed Classification Criteria of Cutaneous Adverse Drug Reactions (cADRs) Used for the Review by Expert Dermatologists eTable 2. List of Drugs Prescribed Before and After HLA-A*31:01 Screening of 198 HLA-A*31:01-Positive Participants eTable 3. Details of the Review by Expert Dermatologists of Cases Initially Diagnosed as Cutaneous Adverse Drug Reactions (cADRs) According to HLA-A*31:01 Screening Results eTable 4. Comparison of the Incidences of other Adverse Events Between HLA-A*31:0- Positive and HLA-A*31:0-Negative Patients

This supplementary material has been provided by the authors to give readers additional information about their work.

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eTable 1. Detailed Classification Criteria of Cutaneous Adverse Drug Reactions (cADRS) Used for the Review by Expert Dermatologists Category of Definition of “carbamazepine- Definition of “cADRs” cADR induced cADRs” There is sufficient information to Definite cADR and can specify Definite diagnose a cADR and specify a carbamazepine as a culprit drug. culprit drug. Some information is missed, but Probable cADR and can specify the collected information is carbamazepine as a culprit drug. Probable sufficient to diagnose a cADR and specify a culprit drug. Collected information cannot Not included in the exclude the possibility of a cADR, carbamazepine-induced cADR. Possible but indicate a possibility of other skin diseases. Collected information indicates Not included in the high possibility of cADR caused carbamazepine-induced cADR. by other drugs, high possibility of Unlikely other skin diseases, or collected information are insufficient to diagnose either cADR or other skin diseases.

Clinical information of cADR including 1) days from the drug start to the onset, 2) treatment, 3) clinical course, and 4) outcome. Required Photographs of a cADR information to Initial diagnosis of attended dermatologists diagnose a cADR Information of concurrent drugs (to estimate the possibility of other suspected culprit drugs)

Drugs that satisfy all of the three criteria written below: 1) Drugs which was started or terminated during the carbamazepine Definition of the treatment. possibility of culprit 2) The date of cADR onset was within one week from the start of the drug other than drug. carbamazepine 3) Exclude drugs which was started during the carbamazepine treatment and continued even after the cADR disappeared.

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eTable 2. List of Drugs Prescribed Before and After HLA-A*31:01 Screening of 198 HLA-A*31:01-Positive Participants Drugs prescribed Drugs added after HLA- Number Number of patients who before the study A*31:01 screening of stopped additional patients drugs (reasons) None Carbamazepine 1 1 (other causes) None Clonazepam 3 1 (other causes) None Gabapentin 1 None Lamotrigine 1 None Levetiracetam 6 2 (other causes) None Levetiracetam + 2 Clonazepam None Levetiracetam + 1 1 (cADRs) Gabapentin None Levetiracetam + 2 Nitrazepam None Levetiracetam + 1 Phenobarbital None Levetiracetam + 2 Phenytoin None Levetiracetam + 1 Phenytoin + Lamotrigine None Phenobarbital 2 None Phenytoin 8 None Sodium valproate 42 1 (cADRs), 1 (other adverse reactions), 2 (other causes) None Sodium valproate + 1 Gabapentin None Sodium valproate + 11 Levetiracetam None Sodium valproate + 1 Levetiracetam + Clobazam None Sodium valproate + 2 Phenobarbital None Sodium valproate + 1 1 (other causes) Zonisamide + Levetiracetam None Tiapride 1 None Tramadol-acetaminophen 1 1 (other causes) None Tramadol-acetaminophen 2 + Pregabalin None Zonisamide 17 1 (cADRs) None Zonisamide + Diazepam 1 None Zonisamide + 1 Levetiracetam Clonazepam None 1

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Levetiracetam + None 2 Phenytoin Phenytoin + None 1 Gabapentin + Phenobarbital Sodium valproate None 2 1 (other causes) Sodium valproate + None 1 1 (other causes) Chlorpromazine Sodium valproate + None 1 Levetiracetam Sodium valproate + None 1 Zonisamide Aripiprazole Levetiracetam + 1 Phenytoin Bromazepam Phenytoin + 1 Bromazepam (dose escalation) + Sertraline Brotizolam Sodium valproate + 1 Trazodone Clonazepam Levetiracetam 1 Clonazepam + Aripiprazole 1 Biperiden + Hydroxyzine + Paliperidone Clonazepam + Olanzapine 1 Biperiden + Saikokaryukotsuborei to + Paroxetine + Chlorpromazine- promethazine- phenobarbital + Lorazepam + Flunitrazepam Clonazepam + Sodium valproate 1 Biperiden + Zopiclone + Quetiapine + Lithium Clonazepam + Amoxapine + Lithium 1 1 (other adverse Quetiapine reactions) Diazepam Sodium valproate 1 Diazepam Sodium valproate + 1 1 (other causes) Phenytoin + Phenobarbital Gabapentin Levetiracetam 1 Levetiracetam Lamotrigine 2 Levetiracetam Sodium valproate 1 Levetiracetam Topiramate 1 Levetiracetam Zonisamide 3 Levetiracetam + Topiramate 1

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Gabapentin Lorazepam + Sodium valproate 1 Clotiazepam Nitrazepam Zonisamide 1 1 (other adverse reactions) Paliperidone Aripiprazole + Sertraline 1 Paliperidone Blonanserin 1 Paliperidone + Sodium valproate 1 Etizolam + Promethazine + Ethyl loflazepate + Trazodone Paliperidone + Olanzapine 1 Triazolam Paroxetine + Olanzapine 1 Lorazepam Phenytoin Levetiracetam + 1 Phenytoin (dose escalation) Phenytoin Levetiracetam + Sultiame 1 Phenytoin Sodium valproate 1 Phenytoin Topiramate 1 Pregabalin Amitriptyline + 1 Cyanocobalamin Pregabalin Sodium valproate 1 Pregabalin + Sodium valproate 1 Goreisan Sodium valproate Aripiprazole + Lorazepam 1 + Promethazine + Risperidone + Brotizolam Sodium valproate Lamotrigine 1 Sodium valproate Levetiracetam 9 Sodium valproate Olanzapine + 1 Flunitrazepam Sodium valproate Phenytoin 2 1 (other adverse reactions) Sodium valproate Zonisamide 5 Sodium valproate + Olanzapine + Etizolam 1 Biperiden + Paliperidone Sodium valproate + Aripiprazole 1 Biperiden + Zopiclone + Paliperidone + Lithium Sodium valproate + Quetiapine + Biperiden 1 Biperiden + Zopiclone (dose escalation) + Paliperidone + Olanzapine + Lorazepam +

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Flunitrazepam

Sodium valproate + Zonisamide 1 1 (cADRs) Clonazepam + Diazepam Sodium valproate + Aripiprazole 1 Clonazepam + Flunitrazepam + Triazolam + Lithium Sodium valproate + Sodium valproate (dose 1 Diazepam + escalation) + Quetiapine Haloperidol + (dose escalation) + Quetiapine + Triazolam + Levomepromazine + Flunitrazepam (dose Chlorpromazine- escalation) promethazine- phenobarbital + Lamotrigine + Risperidone + Trazodone + Brotizolam + Ramelteon + Flunitrazepam Sodium valproate + Topiramate 1 Lamotrigine + Diazepam Sodium valproate + Lamotrigine 1 Levetiracetam Sodium valproate + Phenytoin 1 Levetiracetam Sodium valproate + Levetiracetam (dose 1 Levetiracetam + escalation) Phenytoin + Gabapentin Sodium valproate + Zonisamide (dose 1 Levetiracetam + escalation) Zonisamide + Phenytoin Sodium valproate + Olanzapine 1 Paliperidone + Lorazepam Sodium valproate + Levetiracetam 1 Phenytoin + Diazepam Sodium valproate + Levetiracetam 1 Phenytoin + Phenobarbital Sodium valproate + Olanzapine 1 Quetiapine + Alprazolam + © 2018 American Medical Association. All rights reserved.

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Etizolam + Lithium Sodium valproate + Levetiracetam 1 Risperidone Sodium valproate + Aripiprazole + Ramelteon 1 Sertraline + Triazolam + Lomerizine + Lorazepam + Perospirone + Flunitrazepam Sodium valproate + Levetiracetam 1 Topiramate Sodium valproate + Levetiracetam 1 Zonisamide Sulpiride Lorazepam 1 Tramadol- Sodium valproate + 1 acetaminophen Flunitrazepam + Tramadol-acetaminophen (dose escalation) Triazolam + Aripiprazole 1 Lorazepam + Mirtazapine Zonisamide Clonazepam 1 Zonisamide + Sodium valproate 1 Clobazam Zonisamide + Sodium valproate 1 Diazepam + Lorazepam Total 198 One patient who tested positive for HLA-A*31:01 and prescribed carbamazepine is shown in red. As for the drugs of carbamazepine derivatives, oxcarbazepine was approved by Japanese government at November 2016 after we complete the enrolment of this study. Eslicarbazepine is still unavailable in Japan (as of 2017). The reasons for the discontinuation of alternative drugs are shown in the parenthesis. Discontinuation of alternative drugs due to cADRs was occurred in four patients. Among them, two patients who started zonisamide as an alternative drug discontinued zonisamide due to zonisamide-induced cADR. One patient who started levetiracetam and gabapentin as alternative drugs discontinued these drugs due to cADR caused by antibiotics (sulbactam/ampicillin). One patient who started sodium valproate as an alternative drug discontinued this alternative drug by the initial diagnosis of cADR, but this patient was categorized as unlikely after the expert review due to the insufficient information to diagnose either cADR or other skin diseases.

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eTable 3. Details of the Review by Expert Dermatologists of Cases Initially Diagnosed as Cutaneous Adverse Drug Reactions (cADRs) According to HLA- A*31:01 Screening Results cADR category HLA-A*31:01 positive HLA-A*31:01 negative Definite 0 11 Probable 0 12 Possible 1 9 Unlikely 3 11 Total 4 43 Among the HLA-A*31:01 positive cases, one case categorized as possible cADR was diagnosed as a zonisamide-induced cADR. Among three cases categorized as unlikely, two cases were diagnosed as cADRs caused by other drugs (sulbactam/ampicillin and zonisamide for each one case), and one case did not diagnose either cADR or other skin diseases due to insufficient information. Of the nine HLA-A*31:01 negative cases categorized as possible cADR, five cases had a possibility of other skin diseases and four cases had a possibility of cADRs caused by other drugs (aciclovir/meropenem, cefditoren pivoxil, clonazepam, and commercial drug of common cold for each one case). Of the 11 HLA-A*31:01 negative cases categorized as unlikely, six cases were diagnosed as other skin diseases, two cases were diagnosed as cADRs caused by other drugs (lamotrigine and zonisamide for each one case), and three cases did not have sufficient information to categorize.

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eTable 4. Comparison of the Incidences of other Adverse Events Between HLA-A*31:0-Positive and HLA-A*31:0-Negative Patients Adverse event HLA-A*31:01 negative HLA-A*31:01 positive P value (N = 932) (N = 198)

Fever 49 (5.3) 8 (4.0) 0.59 Sore throat 59 (6.3) 6 (3.0) 0.09 Fatigue 175 (18.8) 32 (16.2) 0.42 Dizziness 76 (8.2) 13 (6.6) 0.56 Insomnia 51 (5.5) 9 (4.5) 0.73 Anorexia 52 (5.6) 10 (5.1) 0.86 Constipation 66 (7.1) 7 (3.5) 0.08 Diarrhea 36 (3.9) 5 (2.5) 0.53 Xerostomia 26 (2.8) 2 (1.0) 0.21 Nausea 52 (5.6) 7 (3.5) 0.29 Vomiting 24 (2.6) 6 (3.0) 0.63 Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0 (NIH, 2006) and the development of the adverse event was defined by a comparatively worse grade from the baseline. P values were calculated for the comparison of incidences between HLA-A*31:01 positive and negative subjects. The percentages of each adverse event are shown in parentheses.

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