The U.S. Food and Drug Administration (FDA) has provided a safety announcement to increase awareness of recent updates to the product labeling of capecitabine and fluorouracil related to the risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency.
Background
Fluoropyrimidines are a class of anticancer drugs that include fluorouracil and capecitabine, a prodrug of fluorouracil. The DPYD gene encodes the enzyme DPD, which breaks down more than 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—are at increased risk of acute early-onset toxicity and serious adverse reactions. Patients with partial DPD deficiency may also have an increased risk of serious, including fatal, adverse reactions.
Four DPYD variants have been associated with impaired DPD activity in White patients. And one variant has been associated with impaired activity in Black patients.
Project Renewal
Under Project Renewal, the FDA Oncology Center of Excellence updated the product labeling of capecitabine tablets to include additional information on DPD deficiency and the significance of discussing DPD deficiency with patients. A safety labeling change updated the fluorouracil labeling to include the same DPD deficiency information as in capecitabine tablets.
The product labeling of both drugs stated that capecitabine or fluorouracil was 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 in patients with complete DPD deficiency. There were insufficient data to recommend a specific dose in patients with partial DPD deficiency.
The FDA emphasized that health-care providers should be aware of the potential for life-threatening toxicities as a result of DPD deficiency and inform patients of the risks prior to treatment. Health-care providers were also advised to discuss whether patients should be tested for genetic variants that are associated with an increased risk of serious adverse reactions from the use of capecitabine or fluorouracil. They should consider testing prior to the initiation of capecitabine or fluorouracil to reduce the risk of serious adverse reactions.
Further, health-care providers should be aware of the signs and symptoms associated with DPD deficiency–related adverse reactions—including mucositis, diarrhea, neutropenia, and neurotoxicity—and encourage patients to immediately contact their providers if they occur. They were advised to withhold or permanently discontinue capecitabine or fluorouracil based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients presenting with acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency.
Conclusions
The FDA emphasized that the agency will continue to monitor the 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 urged patients and health-care providers to report side effects involving capecitabine or fluorouracil products to the FDA’s MedWatch program at fda.gov.
