The U.S. Food and Drug Administration (FDA) has provided communication to increase awareness of recent updates to the product labeling of capecitabine (Xeloda) and fluorouracil—indicated for colorectal, breast, gastric/esophageal/gastroesophageal, and pancreatic cancers—related to risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. All health-care 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 test patients for genetic variants of DPYD prior to initiating treatment with capecitabine or fluorouracil unless immediate treatment is necessary.
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 (eg, mucositis, diarrhea, neutropenia, and neurotoxicity) when exposed to capecitabine or fluorouracil. Patients with partial DPD activity (partial DPD deficiency) may also have an increased risk of serious, including fatal, adverse reactions.
The FDA recently approved revisions to the capecitabine and fluorouracil product labeling to provide further information on DPD deficiency. Key changes include:
- Boxed Warning: The Boxed Warning now highlights the risk of serious adverse reactions or death in patients with complete DPD deficiency. It also advises DPYD testing prior to initiating capecitabine or fluorouracil, unless immediate treatment is necessary, and recommends avoiding use in patients with certain homozygous or compound heterozygous DYPD variants that result in complete DPD deficiency.
- Dosage and Administration: A new subsection, 2.1 Evaluation and Testing for DPD Deficiency Before Initiating Capecitabine or Fluorouracil, has been added and instructs to avoid use of these drugs in patients known to have certain homozygous or compound heterozygous DYPD variants that result in complete DPD deficiency. For patients with partial DPD deficiency, dosing should be individualized.
- Warnings and Precautions: Reiterates that prior to initiating capecitabine or fluorouracil, patients should be tested for genetic variants of the DPYD gene unless immediate treatment is necessary.
See the full prescribing information for Xeloda (capecitabine) and fluorouracil for additional information on DPD deficiency, located in the Boxed Warning and Sections 2, 5, 12, 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 may be considered. The FDA urges patients and health-care providers to report side effects to the FDA MedWatch program.
