FDA Strengthens Capecitabine Labeling with Required DPYD Genotyping
The Food and Drug Governance (FDA) has recently updated the labeling for the chemotherapy drug capecitabine, substantially strengthening guidance regarding pharmacogenomic safety. The revised label now requires clinicians to test for dihydropyrimidine dehydrogenase (DPYD) variants before initiating capecitabine treatment, with exceptions only made when immediate therapy is necessary. This marks a substantial change from previous labeling, which merely suggested clinicians “consider testing” for thes variants.
Previously, the capecitabine label did not present pharmacogenomic details as a boxed warning, and testing was not explicitly recommended. The updated label addresses the risk of severe, potentially life-threatening toxicity in patients with complete DPD deficiency – a condition identified through DPYD genetic testing. Individuals carrying homozygous or compound heterozygous DPYD variants associated with complete deficiency should not receive capecitabine.
The FDA acknowledges that treatment may occasionally need to begin before DPYD test results are available. However, the label encourages testing even in these urgent situations, with the intention of adjusting treatment based on the genetic information once it becomes available. This approach aims to minimize risk and optimize dosing strategies.
The update also highlights variability among available DPYD testing panels, emphasizing the importance of selecting assays that detect clinically relevant variants. The Association for Molecular pathology (AMP) PGx Working Group published updated recommendations for DPYD genotyping in 2024, outlining a tiered list of clinically relevant variants (PMID: 39032821). These recommendations are accessible through the ClinPGx platform, which has updated its capecitabine annotation and now classifies the pharmacogenomic level for the drug as “Testing Required.”
Several clinical decision support tools have been updated to reflect the FDA’s changes. ClinPGx, PharmDOG, and GSI platforms now incorporate the new requirements, promoting consistency across clinical informatics resources. pharmcat is planning to integrate the updated language in a future release. These updates aim to harmonize implementation across laboratory reporting, clinical workflows, and decision-making technologies.
Caris Life sciences has responded to the FDA update by incorporating DPYD analysis into its Caris Assure liquid biopsy platform, ensuring patients undergoing testing receive genotype-informed risk assessment for fluoropyrimidine toxicity.
This FDA guidance represents a meaningful step towards precision oncology. Routine DPYD genotyping prior to capecitabine initiation is anticipated to reduce severe toxicities, enhance patient safety, and establish a more standardized approach to pharmacogenomic testing in cancer treatment. The update underscores the increasing importance of genetic information in guiding therapy decisions and preventing avoidable harm to patients.
