U.S. Health officials are alerting healthcare providers to updated safety information regarding two commonly used chemotherapy drugs, capecitabine (Xeloda) and fluorouracil (5-FU), due to the risk of severe and potentially life-threatening toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. The updates, announced on , emphasize the importance of awareness, patient education, and, when feasible, testing for DPD deficiency before initiating treatment.
Understanding DPD Deficiency
DPD is an enzyme crucial for metabolizing fluoropyrimidines, a class of chemotherapy drugs that includes 5-FU and capecitabine, which is a prodrug converted into 5-FU within the body. Individuals with DPD deficiency have reduced or absent activity of this enzyme, leading to a buildup of the drug and increasing the risk of severe side effects. These side effects can manifest rapidly and include mucositis (inflammation of the mucous membranes), severe diarrhea, neutropenia (low white blood cell count), and neurotoxicity.
The deficiency can range in severity. Patients with complete DPD deficiency
, resulting from specific genetic variants, are at the highest risk of acute, early-onset toxicity and potentially fatal reactions. However, individuals with partial DPD deficiency
may also experience increased risk, though the extent of that risk is still being studied. Currently, no safe dose has been established for patients with complete DPD deficiency.
What’s Changing in Drug Labeling
The Food and Drug Administration (FDA), through its Oncology Center of Excellence’s Project Renewal initiative, has revised the product labeling for both capecitabine and fluorouracil to reflect the updated understanding of DPD deficiency risks. Key changes include a strengthened boxed warning
– the most prominent warning on a drug label – highlighting the potential for serious adverse reactions or death in patients with complete DPD deficiency. The labeling now explicitly recommends DPYD testing prior to starting treatment, unless immediate treatment is necessary.
Beyond the boxed warning, the updated labeling includes a new subsection dedicated to dosage and administration, providing further guidance on managing patients with suspected or confirmed DPD deficiency. The FDA advises against using capecitabine or fluorouracil in patients known to have specific genetic variants associated with complete DPD deficiency.
Who is Affected and What Should Patients Do?
Patients currently undergoing or scheduled to undergo treatment with capecitabine or 5-FU should discuss their risk for DPD deficiency with their healthcare provider. It’s particularly important for patients with a family history of severe reactions to these drugs to raise this concern. The FDA emphasizes that healthcare providers should inform patients about the potential for serious toxicities associated with DPD deficiency before starting treatment.
Genetic testing for variants in the DPYD gene is available and can help identify individuals at risk. However, the FDA notes that there is currently insufficient data to recommend a specific dose adjustment for patients with partial DPD deficiency. The decision to proceed with treatment, and at what dose, must be made on a case-by-case basis, carefully weighing the risks and benefits.
The Importance of Proactive Screening
The FDA’s announcement underscores a growing recognition of the importance of proactive screening for genetic predispositions to drug toxicities. DPD deficiency is not a rare condition, and early identification can prevent potentially devastating consequences. While immediate treatment may sometimes preclude pre-treatment testing, healthcare providers are encouraged to consider DPD deficiency as a potential cause of unexpected or severe adverse reactions during treatment.
The updated labeling and FDA communication are intended to equip healthcare professionals with the information they need to make informed decisions about the use of capecitabine and fluorouracil, ultimately improving patient safety and outcomes. The FDA continues to monitor the safety of these drugs and will provide further updates as new information becomes available.
Looking Ahead
Further research is needed to better understand the spectrum of DPD deficiency, including the optimal testing strategies and management approaches for patients with partial DPD activity. Ongoing efforts to improve genetic testing accessibility and affordability will also be crucial in ensuring that all patients who could benefit from screening have access to it.
