After publication of this article on March 25, the updated 5-fluorouracil label became available. This story was updated on March 26 with a link to and information from that label.
NEW YORK – The US Food and Drug Administration last week updated the label of fluorouracil with further information on the risk of serious adverse events for patients with dihydropyrimidine dehydrogenase (DPD) deficiency taking this commonly prescribed chemotherapy.
Approximately 1 in 1,000 patients carry two copies of a variant in the DPYD gene that make them unable to produce any of the DPD enzyme needed to metabolize fluoropyrimidine-based chemotherapies such as capecitabine, which is marketed by Genentech as Xeloda, and 5-fluorouracil (5-FU). Up to 8 percent of patients carry one copy of a DPYD variant associated with reduced DPD activity. Fluoropyrimidines can quickly build up in these patients, resulting in severe and sometimes fatal toxicities, particularly in those with a complete deficiency.
In the latest label update for fluorouracil-based products, such as 5-FU, the agency has added information related to DPD deficiency-related adverse events to several sections, including "Highlights of Prescribing"; "Warnings and Precautions"; and "Patient Counseling Information." There's also a "Pharmacogenomics" section added to the "Clinical Pharmacology" portion of the label, in which the agency describes the prevalence of DPYD no function and reduced function variants in the population, including four variants known to impair DPD function in white patients and one variant associated with decreased DPD function in Black patients.
"DPD deficiency is estimated to be more prevalent in Black or African American populations compared to White populations," according to the updated label. "Insufficient information is available to estimate the prevalence of DPD deficiency in other populations."
The FDA said in its announcement that the changes to fluorouracil's label "align with those approved for another fluoropyrimidine drug, Xeloda tablets."
Patient advocates and pharmacogenetics experts have been urging the FDA and the National Comprehensive Cancer Network for years to recommend oncologists test all patients before prescribing fluoropyrimidine-based treatments for DPYD PGx variants and adjust dosing or give alternative therapies to those at risk of severe adverse events. In 2016, in response to a citizen petition, the FDA included language in the labels of capecitabine and 5-FU, warning doctors to avoid giving them to patients with a complete DPD deficiency.
However, patient advocates, disappointed that the agency did not explicitly recommend doctors test patients for DPYD variants, have continued to petition the FDA on the matter. In response to a 2020 citizen petition, the FDA in December 2022 again updated the label for capecitabine to more strongly state that patients with certain PGx variants are at heightened risk for life-threatening adverse events. This time, the FDA also told doctors to "consider testing" patients for DPYD genetic variants before administering the treatment but still stopped short of directly recommending testing for all patients considering fluoropyrimidine-based chemo, noting that there aren't any FDA-authorized DPYD PGx tests and "currently available tests used to identify DPYD variants may vary in accuracy and design."
This same language is now also in the updated 5-FU label. The labels for both 5-FU and Xeloda both also state that "there are insufficient data to recommend a specific dose in patients with partial DPD deficiency."
The NCCN's experts in charge of drafting guidelines that include Xeloda and 5FU want more evidence showing that lowering chemotherapy doses based on DPYD testing won't reduce treatment efficacy and negatively impact patients' survival outcomes. As such, they also don't recommend routine PGx testing for cancer patients considering fluoropyrimidine-based treatments.
The Clinical Pharmacogenetics Implementation Consortium, an internationally recognized guidelines body, recommends reducing starting doses of 5-FU or Xeloda by 50 percent in patients with a partial DPD deficiency, based on the currently available evidence. In those with a complete deficiency, the group advises avoiding these drugs entirely, or if fluoropyrimidines are necessary, starting at a 75 percent lower dose and closely monitoring for toxicities.
Based on CPIC guidelines and after reviewing data from retrospective and prospective studies suggesting that reducing the starting dose of fluoropyrimidine-based chemo in DPYD variant carriers is unlikely to impact survival outcomes, several institutions around the country have started implementing pretreatment DPYD testing for cancer patients. Without explicit support for DPYD testing from the FDA and NCCN, however, patient advocates and supporters of PGx testing say that US cancer centers are unlikely to widely implement such testing.