Updated Capecitabine/5-FU Labeling Calls for DYPD Testing Before Use

The FDA updated the product labeling for capecitabine (Xeloda) and 5-fluorouracil (5-FU) to reflect significant risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency.

The DPYD gene encodes the DPD enzyme, which is responsible for catabolizing more than 80% of fluorouracil. Certain genetic variants in DPYD can lead to a complete or partial absence of DPD activity. Patients with complete DPD deficiency are at a significantly increased risk for acute, early-onset toxicities and serious or fatal adverse events (AEs), including mucositis, diarrhea, neutropenia, and neurotoxicity. Those with partial deficiency also face an increased risk of serious AEs.

The updated labeling includes major revisions to several sections, most notably a boxed warning, which now emphasizes the risk of serious AEs or death in patients with complete DPD deficiency and recommends avoiding the use of these drugs in such individuals. It also advises testing for DPYD variants prior to initiating treatment.

A new subsection has been added to provide instructions for DPYD evaluation. Although an FDA-authorized test for DPYD is not currently available, providers should utilize available tests while noting they may vary in design and the specific variants they identify. For patients with partial DPD deficiency, providers should individualize the starting dose and modify as needed based on the patient’s tolerance of the drug. No dose of capecitabine has been proven safe for patients with complete DPD deficiency.

Other Toxicities and Warning for Capecitabine

Clinical monitoring by oncology nurses and APPs remains critical for identifying other serious toxicities. Cardiotoxicity, including myocardial infarction, angina, and cardiac failure, may occur, particularly in patients with pre-existing coronary artery disease. Severe diarrhea is common; clinical trials showed a median time to the first occurrence of grade 2 to 4 diarrhea of 34 days. Additionally, palmar-plantar erythrodysesthesia syndrome (PPES) may occur, with a median onset of 2.6 months for grade 1 to 3 events. Other risks include serious skin toxicities, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, which can become fatal.

Further, the boxed warning reiterates the risk of altered coagulation and bleeding when capecitabine is used concomitantly with vitamin K antagonists like warfarin. Clinically significant increases in prothrombin time and internalized normal ratio have been reported, regardless of liver metastases.

Patient counseling should focus on administration and toxicity recognition. Capecitabine tablets must be swallowed whole with water within 30 minutes after a meal. Patients and caregivers should be instructed not to chew, cut, or crush the tablets, as exposure to crushed medication can lead to eye irritation and swelling, skin rash, gastrointestinal distress, paresthesia, and headache. Patients should be advised to stop taking the medication immediately and contact their healthcare provider if they experience grade 2 or higher toxicities, such as a significant increase in daily stools, painful mouth ulcers, or vomiting. Frequent monitoring of renal function and blood counts is also required throughout the treatment course.

Oncology nurses and advanced practice providers (APPs) are advised to be aware of these risks, inform patients about potential life-threatening toxicities, and ensure DPYD genetic testing is performed before treatment initiation unless immediate therapy is required.

About Capecitabine

Capecitabine is a nucleoside metabolic inhibitor with approved indications in several solid tumors. In colorectal cancer, it is indicated for the adjuvant treatment of stage III colon cancer, the perioperative treatment of locally advanced rectal cancer when combined with radiation, and the management of unresectable or metastatic disease. For advanced or metastatic breast cancer, the drug may be used as a single agent if anthracyclines or taxanes are not indicated, or in combination with docetaxel following disease progression on anthracycline-containing chemotherapy.

Indications for upper gastrointestinal malignancies include unresectable or metastatic gastric, esophageal, or gastroesophageal junction (GEJ) cancers. Specifically, it is approved for HER2-overexpressing metastatic gastric or GEJ adenocarcinoma in patients who have not received prior therapy for metastatic disease. Additionally, capecitabine is indicated for the adjuvant treatment of pancreatic adenocarcinoma when administered as a component of a combination chemotherapy regimen. Safety and effectiveness have not been established in pediatric populations.

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 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/safety-labeling-update-capecitabine-and-fluorouracil-5-fu-risks-associated-dihydropyrimidine
2. Xeloda. Prescribing information. H2-Pharma; 2025. Accessed February 6, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/020896s052lbl.pdf