Annotation of CPIC Guideline for venlafaxine and CYP2D6

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Summary

The CPIC Dosing Guideline for venlafaxine recommends to consider a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2D6 for CYP2D6 poor metabolizers.

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Annotation

This annotation is based on the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

February 2023

  • The authors of the CPIC® guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants evaluated the available evidence for therapeutic dose recommendations for venlafaxine and CYP2D6 metabolizer phenotypes.

  • These guidelines are applicable to:

    • adult patients
    • pediatric consideration: "Citalopram, escitalopram, and sertraline had the most pharmacogenetic data supporting potential genotype-guided prescribing changes in children. Based on this evidence, the recommendations for these drugs are relevant to pediatric patients and are consistent with smaller pharmacokinetic studies available for this population." ..... "The generalizability of other recommendations to pediatric patients needs to be established. As such, clinicians treating children and adolescents should determine their applicability to younger patients while considering the unique and more limited evidence base for these medications in youth, as well as pediatric-specific differences in tolerability (e.g., activation)and disorder-specific response trajectory. Because CYP2D6, CYP2C19, and CYP2B6 activity reach adult levels by early childhood, it may be appropriate to extrapolate genotype-guided recommendations for antidepressants related to CYP2D6, CYP2C19 and CYP2B6 to adolescents or possibly younger children with close monitoring."
  • Excerpts from the guideline:

    • "Regarding venlafaxine, increased metabolism to the active metabolite (O-desmethylvenlafaxine) is seen in UMs; however, there is minimal evidence to suggest that this is clinically significant. Therefore, no dosing recommendations are provided for venlafaxine for CYP2D6 UMs."
    • "When administered similar doses, CYP2D6 PMs had significantly greater drug exposure or parent to metabolite ratios for paroxetine, fluvoxamine, venlafaxine, and vortioxetine when compared to NMs (Table S1). Increased drug exposure increases the risk for dose/concentration-dependent side effects. Data for venlafaxine suggest increased concentration-dependent side effects in CYP2D6 PMs (Table S2). The paucity of prospective studies, uncommon clinical use of therapeutic drug monitoring for antidepressants, and the potential that decreasing the dose may compromise medication efficacy was the basis for the optional recommendation to consider alternatives to venlafaxine in CYP2D6 PMs."
    • "The FDA Table of Pharmacogenetic Associations lists venlafaxine and vortioxetine as drugs warranting dose adjustments in CYP2D6 PMs."
  • Download and read:

Table 1: Dosing recommendations for venlafaxine based on CYP2D6 phenotype

Adapted from Tables 1 and 2c of the guideline.

a Rating scheme described in Supplemental Materials.

PharmGKB ID

PA166288201