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The role of cytochrome P450 ( CYP ) 2C9  and  CYP2C19  genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B ( HLA‐B ) *15:02  risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%)  CYP2C9*1/*1 , 77 (20%)  CYP2C9*1/*2 , and 29 (8%)  CYP2C9*1/*3 . We also determined  CYP2C19  genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with  CYP2C9*1/*3  or  CYP2C9*2/*2  genotypes were more likely to develop cutaneous adverse events compared with  CYP2C9*1/*1  participants (odds ratio 4.47; 95% confidence interval 1.64–11.69;  P  < 0.01). Among participants with low‐intermediate and poor  CYP2C9  metabolizer genotypes, eight (22%) who also had extensive and rapid  CYP2C19  metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate  CYP2C19  metabolizer genotypes ( P  = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin‐induced cutaneous adverse events in the absence of the  HLA‐B*15:02  risk allele.

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin‐Induced Cutaneous Adverse Drug Reactions