FDA Updates Safety Labels for Capecitabine, 5-FU

The FDA has updated the safety labeling for the chemotherapeutic agents capecitabine (Xeloda) and fluorouracil (5-FU) to include new warnings regarding the risk of severe, life-threatening, or fatal toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. The revised labeling, which affects both "Warnings and Precautions" and "Patient Counseling Information" sections, emphasizes the importance of identifying patients at increased risk for toxicity due to impaired drug metabolism.¹

Clinical Impact of DPD Deficiency

Fluoropyrimidines remain a cornerstone of treatment for various malignancies, including colorectal, gastric, and breast cancers. However, dihydropyrimidine dehydrogenase is the rate-limiting enzyme responsible for the catabolism of more than 80% of administered fluorouracil. Patients with a partial or complete deficiency of this enzyme, often caused by specific variations in the DPYD gene, are unable to effectively clear the drug, leading to the accumulation of cytotoxic metabolites.

Clinical manifestations of fluoropyrimidine toxicity in DPD-deficient patients typically present early, often during the first or second cycle of therapy. These toxicities include grade 3 or 4 neutropenia, thrombocytopenia, mucositis, diarrhea, and neurotoxicity. In cases of complete DPD deficiency, the administration of standard doses of capecitabine or fluorouracil can result in multiorgan failure and death.

New Labeling Recommendations

The updated FDA labeling advises health care providers to consider DPD deficiency in patients experiencing early-onset or unusually severe toxicity. Although the FDA does not currently mandate universal pretreatment genetic screening, the updated language states that "testing for DPD deficiency should be considered prior to administration of capecitabine or fluorouracil" when clinically indicated.

For patients identified with a partial DPD deficiency, the FDA recommends a reduced starting dose to mitigate the risk of severe toxicity. For those with a complete DPD deficiency, the label now explicitly states that capecitabine and fluorouracil are contraindicated. If severe toxicity occurs during treatment, clinicians are advised to discontinue the drug immediately and consider the administration of uridine triacetate, the only FDA-approved antidote for fluoropyrimidine overdose or early-onset severe toxicity.

Pharmacogenetic Considerations and Trials

The move toward genotype-guided dosing is supported by several large-scale studies. The Clinical Pharmacogenetics Implementation Consortium has established guidelines for fluoropyrimidine dosing based on DPYD genotypes, specifically focusing on the 4 most clinically relevant variants: *2A (c.1905+1G>A), *13 (c.1679T>G), c.2846A>T, and c.1129-5923C>G.²

A prospective clinical trial (NCT02324452) conducted in the Netherlands demonstrated that screening for the DPYD2A variant and subsequent dose reductions of 25% to 50% significantly improved patient safety.³ The researchers found that the risk of severe toxicity was reduced from 73% in historical controls to 28% in the genotype-guided group.

Implications for Clinical Practice

The labeling update places a greater emphasis on patient education and vigilant monitoring. Clinicians are encouraged to discuss the signs and symptoms of fluoropyrimidine toxicity with patients, including fever, persistent vomiting, or severe abdominal pain.¹

Health care providers should report any adverse events related to the use of these drugs to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

REFERENCES

1. Safety labeling update for capecitabine and fluorouracil (5-FU) on risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. News release. FDA. February 5, 2026. Accessed February 6, 2026. https://tinyurl.com/367ms26w

2. Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther. 2018;103(2):210-216. doi:10.1002/cpt.911

3. Henricks LM, Lunenburg CATC, de Man FM, et al. DPYD genotype-guided dose individualization of fluoropyrimidine therapy in routine clinical care: a prospective outcome analysis. Lancet Oncol. 2018;19(11):1459-1467. doi:10.1016/S1470-2045(18)30686-7