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

Hosohata K ，Inada A ，Oyama S ，Niinomi I ，Wakabayashi T ，Iwanaga K ... -  《-》

Association of Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs in pediatric patients: Subgroup analysis based on a Japanese spontaneous database.

Antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous disorders; however, real-world data remain limited, especially on pediatric patients. The objective of this study was to investigate the association of AEDs with SJS and TEN in pediatric patients based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Adverse event reports submitted to the JADER database between 2004 and 2017 were analysed. We performed a retrospective pharmacovigilance disproportionality analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). A total of 159 605 adverse events were reported in pediatric patients. Significant SJS signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine, zonisamide, clonazepam and lamotrigine. TEN signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine and zonisamide, but the signal was strongest for gabapentin (ROR, 24.76; 95% CI, 11.4-53.9). Severe cutaneous disorders were associated with multiple AEDs, but individual AEDs were associated with variable signals. These results may be useful for minimizing the risk of SJS or TEN during treatment of children with AEDs.

Inada A ，Oyama S ，Niinomi I ，Wakabayashi T ，Iwanaga K ，Hosohata K ... -  《-》

Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: An analysis of the US Food and Drug Administration Adverse Event Reporting System.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially fatal adverse skin reactions that are most commonly triggered by certain medications. One class of medications that has been highly associated with SJS/TEN reactions is antiepileptic drugs (AEDs). We sought to quantify the risk of SJS/TEN associated with AEDs as a class, as well as individual AEDs, in the United States. An analysis was performed of the US Food and Drug Administration Adverse Event Reporting System (FAERS) from July 2014 through December 2017. Rates of SJS/TEN were calculated for each AED compared with all other non-AEDs. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), and 95% confidence intervals (CIs) were calculated using OpenEpi. With 198 reports, AEDs had more reports of SJS/TEN than any other medication class. AEDs as a class had an ROR of 8.7 (95% CI 7.5-10.2) and a PRR of 8.7 (95% CI 7.5-10.2) compared with all other non-AEDs. The AEDs with the highest risk estimates were zonisamide (ROR 70.2, 95% CI 33.1-148.7; PRR 68.7, 95% CI 32.9-143.5), rufinamide (ROR 60.0, 95% CI 8.3-433.5; PRR 58.9, 95% CI 8.4-411.5), clorazepate (ROR 56.0, 95% CI 7.8-404.1; PRR 55.1, 95% CI 7.8-385.0), lamotrigine (ROR 53.0, 95% CI 43.2-64.9; PRR 52.2, 95% CI 42.7-63.7), phenytoin (ROR 26.3, 95% CI 15.5-44.7; PRR 26.1, 95% CI 15.4-44.2), and carbamazepine (ROR 24.5, 95% CI 16.0-37.5; PRR 24.3, 95% CI 16.0-37.1). Although AEDs as a class were associated with 9 times the risk of SJS/TEN compared with non-AEDs, there were 6 AEDs with risk estimates greater than 20. Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS/TEN signs/symptoms, may help mitigate the number and severity of these adverse events.

Borrelli EP ，Lee EY ，Descoteaux AM ，Kogut SJ ，Caffrey AR ... -  《-》

Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in vietnamese spontaneous adverse drug reaction database: A subgroup approach to disproportionality analysis.

Despite the numerous studies investigating drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), the understanding and quantitative data in developing countries remain limited. The study aimed to describe and quantify the drug-related risk of SJS/TEN in a resource-limited context using the Vietnamese spontaneous reporting database (VSRD) of adverse drug reactions. Spontaneous reports relating to medium- and late-onset severe cutaneous adverse reactions (MLOSCAR) and SJS/TEN recorded in the VSRD from 2010 to 2015 were retrospectively analysed. The demographic characteristics and drug information were described and compared between SJS/TEN and other MLOSCAR reports. The drug-induced SJS/TEN signals were estimated using subgrouped disproportionality analysis with calculation of the reporting odds ratio (ROR) and the respective 95% confidence interval (CI). The VSRD received 2,849 MLOSCAR reports, 136 of which focus on SJS/TEN over a 6-year period. About 60% of SJS/TEN patients were male, and the majority of them were adults (mean age 42.5 ± 22.9). Up to 91.8% of drugs induced SJS/TEN within 1-28 days, and 45% SJS/TEN cases were evaluated as life-threatening. Positive signals were generated with carbamazepine (n = 25, ROR [95% CI] = 11.99 [7.07-19.92]), allopurinol (n = 15, ROR [95% CI] = 4.2 [2.20-7.59]), traditional/herbal medicines (n = 7, ROR [95% CI] = 2.76 [1.12-5.86]), colchicine (n = 4, ROR [95% CI] = 6.22 [1.69-18.72]), valproic acid (n = 3, ROR [95% CI] = 8.71 [1.89-30.19]) and meloxicam (n = 3, ROR [95% CI] = 7.09 [1.55-24.29]), which are well known for SJS/TEN. Cefixime (n = 5, ROR [95% CI] = 3.34 [1.13-8.00]) and paracetamol (n = 22, ROR [95% CI] = 5.23 [3.10-8.49]) also generated positive signals despite their popularity in Vietnam. This first Vietnamese population-based study has highlighted original characteristics and signals of drug-induced SJS/TEN, which are relatively consistent with other worldwide data and typical for a developing country.

Nguyen KD ，Tran TN ，Nguyen MT ，Nguyen HA ，Nguyen HA Jr ，Vu DH ，Nguyen VD ，Bagheri H ... -  《-》

Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008-2017.

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. 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. 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). 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.

Kim HK ，Kim DY ，Bae EK ，Kim DW ... -  《-》