Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of 5-HT3 Receptor Antagonists: 2026 Update.

5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are used to treat nausea and vomiting and in the prevention of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting. Most of the 5-HT3 receptor antagonists (i.e., ondansetron, tropisetron, dolasetron, palonosetron, and ramosetron) are metabolized by CYP2D6, but the extent of CYP2D6 involvement varies. CYP2D6 genetic variation can influence the metabolism of these medications, particularly ondansetron and tropisetron, thereby affecting drug efficacy. This guideline is an update to the 2016 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron and includes updated information on CYP2D6 genetic testing and evidence tables. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for 5-HT3 receptor antagonists based on CYP2D6 genotype, particularly where genetic variation is associated with reduced drug efficacy (updates at https://www.clinpgx.org/guideline/PA166251457).