NEW YORK – The US Food and Drug Administration on Friday issued a safety announcement emphasizing the importance of discussing dihydropyrimidine dehydrogenase (DPD) deficiency with patients before prescribing a set of commonly used chemotherapy drugs.
The FDA said it wanted to draw awareness to risks outlined in product labeling of fluoropyrimidine-based chemotherapies Xeloda (capecitabine) and 5-fluorouracil (5-FU).
Certain variants in the DPYD gene lead to decreased production of the enzyme DPD, a protein needed to break down fluoropyrimidines. Patients with these genetic variants are likely to be poor or intermediate metabolizers of fluoropyrimidines and risk drug overexposure and the potential to experience severe, and at times fatal, toxicities when taking these medications.
"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," the FDA wrote in the safety announcement.
The FDA-approved labels for Xeloda and 5-FU specify that the drugs are not recommended for use in patients known to have certain DPYD variants that result in complete DPD deficiency, while adding there is insufficient data to recommend a dose for patients who have partial DPD deficiency. In the safety alert, the agency notes there are four DPYD variants that have been associated with impaired DPD activity that have primarily been seen in White populations, and one variant that's been associated with impaired activity in patients with African ancestry.
However, the FDA stops short of recommending doctors test patients' DPYD status before prescribing these chemotherapies. In the safety alert, the FDA reinforced language in the drug labeling that physicians should discuss DPYD testing with patients and consider testing options before initiating Xeloda or 5-FU to decrease the risk of serious adverse reactions.
Patient advocates and pharmacogenomics experts for years have been urging the FDA to recommend genetic testing for all patients before prescribing Xeloda and 5-FU and adjust dosing or give alternative therapies to those at risk of severe adverse events. However, some oncologists have raised concerns that there isn't enough evidence to support dose adjustments, especially in those with a partial DPD deficiency, despite recommendations from the Clinical Pharmacogenetics Implementation Consortium, an internationally recognized guidelines body. Oncologists and the FDA have also expressed concerns about the ability of DPYD tests on the market to reliably identify those at risk for toxicities.
Some hospitals, such as the Dana-Farber Cancer Institute, Mass General Brigham, and Atrium Health, have instituted their own policies to screen cancer patients for these genetic variants.
In the labels of these chemotherapies, the FDA further states that physicians should be aware of signs associated with adverse reactions due to DPD deficiency and, in cases where severe reactions occur, should discontinue the drugs.
The FDA in its alert said it would continue to monitor this safety issue.