FDA Underscores Risks Associated With DPD Deficiency and Capecitabine/5-FU Use in Cancer Care

The FDA issued a communication to increase awareness of updates to the prescribing information for capecitabine (Xeloda) and fluorouracil (5-FU) related to risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency.¹

The agency stated that clinicians should be aware of the risks of DPD deficiency and counsel patients prior to treatment regarding the potential for serious, including life-threatening, toxicities due to DPD deficiency. Furthermore, the FDA underscored the necessity of testing for genetic variants of DPYD before initiating therapy with capecitabine or 5-FU, unless immediate treatment is necessary.

The awareness announcement from the FDA followed the agency’s approval of safety label changes for 5-FU in March 2024 to include information regarding the risks of serious adverse effects (AEs) associated with the agent in patients with DPD deficiency.2 The 5-FU label update aligned with the revised prescribing information for capecitabine, which was updated in December 2022 to reflect information regarding DPD deficiency.

The DPYD gene encodes DPD, the enzyme responsible for the breakdown of more than 80% of 5-FU.¹ Patients with certain homozygous or compound heterozygous DPYD variants that result in complete or near-complete absence of DPD activity—known as complete DPD deficiency—are at increased risk for acute early-onset toxicity and serious, including fatal, AEs such as mucositis, diarrhea, neutropenia, and neurotoxicity, when exposed to capecitabine or fluorouracil. Patients with partial DPD activity (partial DPD deficiency) may also have an elevated risk of serious, including fatal AEs.

“The FDA will continue to monitor this safety issue and evaluate the evolving landscape and impact of DPD deficiency on the safety of capecitabine and [5-FU]; additional regulatory actions may be considered. The FDA urges patients and healthcare providers to report side effects to the FDA MedWatch program,” the agency wrote in a news release.

As the FDA updates labeling for capecitabine and fluorouracil to reinforce the risks of DPD deficiency and encourage DPYD testing prior to treatment initiation when feasible, this issue continues to generate active debate in clinical practice.

In this video series, panelists discussed how DPD testing remains controversial within the colorectal cancer (CRC) treatment paradigm, with institutions weighing whether to adopt universal pharmacogenomic screening amid ongoing challenges with test standardization, incomplete genotype–phenotype correlation, and the relatively low incidence of severe deficiency in routine care.

What were the updates to the labels for capecitabine and 5-FU?

The Boxed Warning now highlights the risk of serious AEs or death in patients with complete DPD deficiency. DPYD testing is also advised prior to initiating capecitabine or 5-FU, unless immediate treatment is necessary. The label recommends avoiding use in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Under dosage and administration, a new subsection (2.1) called Evaluation and Testing for DPD Deficiency Before Initiating capecitabine or 5-FU, was added. The section instructs clinicians to avoid use of these agents in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. For patients with partial DPD deficiency, dosing should be individualized. The warnings and precautions section also reiterates the importance of testing for DPYD variants prior to the start of therapy, unless immediate treatment is required.

What AEs are most commonly associated with capecitabine across its approved indications?

Across labeled capecitabine indications, the most common adverse effects reported in at least 30% of patients vary by setting but consistently include gastrointestinal and dermatologic toxicities.³ In the adjuvant treatment of CRC with capecitabine monotherapy, the most frequent AEs were palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), diarrhea, and nausea.

In metastatic CRC treated with capecitabine monotherapy, common toxicities included anemia, diarrhea, hand-foot syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. In metastatic breast cancer, capecitabine plus docetaxel was most commonly associated with diarrhea, stomatitis, hand-foot syndrome, nausea, alopecia, vomiting, edema, and abdominal pain, while capecitabine monotherapy most frequently resulted in lymphopenia, anemia, diarrhea, hand-foot syndrome, nausea, fatigue, vomiting, and dermatitis.

References

1. Safety labeling update for capecitabine and fluorouracil (5-FU) on risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. FDA. February 5, 2026. Accessed February 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/safety-labeling-update-capecitabine-and-fluorouracil-5-fu-risks-associated-dihydropyrimidine
2. FDA approves safety labeling changes regarding DPD deficiency for fluorouracil injection products. FDA. March 21, 2024. Accessed February 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-safety-labeling-changes-regarding-dpd-deficiency-fluorouracil-injection-products
3. Xeloda. Prescribing information. FDA. Updated December 2022. Accessed Feburary 5, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf