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  6. Safety announcement: FDA highlights importance of DPD deficiency discussions with patients prior to capecitabine or 5FU treatment
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Safety announcement: FDA highlights importance of DPD deficiency discussions with patients prior to capecitabine or 5FU treatment

The U.S. Food and Drug Administration (FDA) is providing this communication to increase awareness of recent updates to the product labeling of capecitabine and fluorouracil (5-FU) related to risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. All healthcare providers should be aware of the risks of DPD deficiency, inform patients prior to treatment about the potential for serious and life-threatening toxicities due to DPD deficiency, and discuss testing options for DPD deficiency with their patients. 

Fluoropyrimidines are a class of anti-cancer drugs that include fluorouracil (5-FU) and capecitabine, a prodrug of 5-FU. The DPYD gene encodes the enzyme DPD, which breaks down >80% of fluorouracil. Patients with certain homozygous or compound heterozygous variants in the DPYD gene, known to result in complete or near complete absence of DPD activity (complete DPD deficiency), are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.

Project Renewal

The FDA Oncology Center of Excellence, under Project Renewal, updated the product labeling of Xeloda (capecitabine tablets) to include additional information on DPD deficiency and the importance of discussing DPD deficiency with patients; a safety labeling change updated the 5-FU labeling to include the same DPD deficiency information as in Xeloda. The product labeling of both drugs state: 

  • Capecitabine or fluorouracil are not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No dose has been proven safe for patients with complete DPD deficiency. 
  • There is insufficient data to recommend a specific dose in patients with partial DPD deficiency. 
  • All healthcare providers should inform patients of the potential for serious and life-threatening adverse reactions due to DPD deficiency. Providers should discuss with their patient whether the patient should be tested for genetic variants that are associated with an increased risk of serious adverse reactions from the use of capecitabine or 5-FU. 
  • Providers should consider testing prior to initiating capecitabine or fluorouracil to reduce the risk of serious adverse reactions. 
  • Providers should be aware of the signs and symptoms associated with adverse reactions due to DPD deficiency and advise patients to immediately contact their provider if these occur, including severe mucositis, diarrhea, neutropenia, and neurotoxicity. 
  • Providers should withhold or permanently discontinue capecitabine or 5-FU based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. 
  • Four DPYD variants have been associated with impaired DPD activity in White populations, and one variant has been associated with impaired activity in individuals of African ancestry. 

See the full prescribing information for Xeloda and 5-FU for additional information on DPD deficiency, located in Sections 5, 12.5, and 17.

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 fluorouracil; additional regulatory actions will be considered. The FDA urges patients and healthcare providers to report side effects involving capecitabine or 5-FU products to the FDA MedWatch program.

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