SUMMARY: It is estimated that about 3-8% of the Caucasian population have a partial DPD (DihydroPyrimidine Dehydrogenase) deficiency and 0.3% have a complete DPD deficiency. Asian and African populations may be at greater risk of DPD deficiency. More than 8,000 toxic reactions and 1,300 deaths each year are attributed to Fluorouracil and Capecitabine.
The FDA has issued an update regarding the labeling of Capecitabine and 5-FU to raise awareness about the risks linked to DPD deficiency. Healthcare providers are urged to familiarize themselves with these risks and ensure that patients are informed before treatment about the potential for severe and potentially life-threatening side effects associated with DPD deficiency. Providers are also encouraged to discuss DPD testing options with patients.
Fluoropyrimidines, which include both 5-FU and its prodrug Capecitabine, are chemotherapy drugs used to treat cancer. The enzyme DPD, encoded by the DPYD gene, is responsible for breaking down more than 80% of Fluorouracil in the body. In patients with specific genetic variants of the DPYD gene, known to cause a significant reduction or absence of DPD activity (referred to as complete DPD deficiency), there is an elevated risk of severe toxic reactions such as mucositis, diarrhea, neutropenia, and neurotoxicity, which can be fatal. Even patients with partial DPD activity (partial DPD deficiency) may face increased risks of these dangerous side effects.
As part of Project Renewal, the FDAs Oncology Center of Excellence has updated the product labels for both Capecitabine and Fluorouracil to include important information about DPD deficiency. This revision highlights the need for healthcare providers to discuss the possibility of DPD deficiency with patients prior to initiating treatment.
- Capecitabine or 5-FU should not be 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.
The FDA approved Uridine Triacetate (VISTOGARD®) in 2015, for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FU or Capecitabine . Uridine Triacetate is a Pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death.
https://www.fda.gov/drugs/resources-information-approved-drugs/safety-announcement-fda-highlights-importance-dpd-deficiency-discussions-patients-prior-capecitabine
