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FDA Updates Xeloda Labeling to Make DPYD Variant Risks More Explicit

NEW YORK – The US Food and Drug Administration has updated labeling for Xeloda, a commonly prescribed chemotherapy for gastrointestinal, breast, and head and neck cancer, to further clarify that patients with certain pharmacogenetic variants are at increased risk for life-threatening adverse reactions.

In response to a citizen petition, the FDA in 2016 strengthened the toxicity warnings in labeling for fluoropyrimidine-based chemotherapies, Xeloda and 5-FU, and told doctors to avoid these drugs in patients completely lacking dihydropyrimidine dehydrogenase. But the agency also stated at the time that "there is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test."

The latest labeling update for Xeloda is spurred by another citizen petition filed in 2020 asking the FDA to add a new boxed warning more prominently highlighting the risk of severe toxicity when patients with DPD deficiency receive treatment with fluorouracil or Xeloda, and asking the agency to recommend that doctors screen patients for DPD deficiency before starting these treatments.

The FDA last week responded to the citizen petition and partly granted the request. To the existing language about the risk of DPD deficiency, the agency has added two new paragraphs telling doctors to "consider testing [patients] for genetic variants of DPYD prior to initiating Xeloda to reduce the risk of serious adverse reactions if the patient's clinical status permits and based on clinical judgement."

The agency informs doctors that even if patients don't have pathogenic DPYD variants, they still might have a serious adverse reaction. Furthermore, the agency-approved drug label states that there are no FDA-authorized DPYD PGx tests and that "currently available tests used to identify DPYD variants may vary in accuracy and design."

However, the FDA stopped short of adding a new boxed warning as requested in the citizen petition and did not recommend all patients be screened for DPD. The label still states that "there are insufficient data to recommend a specific dose in patients with partial DPD deficiency."

In the 2020 citizen petition, Ken Surprenant and others said that the agency's labeling language was placing the burden on patients to inform their doctors if they knew they had a DPD deficiency. "We do not agree with your contention that the current language places the burden of identifying DPD deficiency on patients themselves," the FDA wrote in response, but said it has decided to update labeling language to "more explicitly recommend that prescribers discuss the potential risks of treatment related to DPD deficiency with their patients."

The FDA's labeling update now and in 2016 were in response to a citizen petition from Surprenant, whose first wife Kathryn had rectal cancer and passed away a decade ago from the toxicities of FOLFOX (folinic acid, 5-FU, and oxaliplatin). Surprenant found out Kathryn was DPD deficient after her death, from testing their four children, who are all DPYD variant carriers. Several clinicians and pharmacologists also signed on to Surprenant's second citizen petition in 2020, and have also petitioned the National Comprehensive Cancer Network to update treatment guidelines to recommend DPD screening.

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