Fluorouracil label tightened

The Food and Drug Administration has tightened the safety label for fluorouracil injection, a chemotherapy drug that has been in routine use since 1962. The change started in March 2024, when the agency approved stronger warnings about a genetic problem called dihydropyrimidine dehydrogenase deficiency, or DPD deficiency, which can leave patients unable to break down the drug safely. By late 2025 and early 2026, updated labels for fluorouracil products had gone further, adding a boxed warning that says serious adverse reactions or death may occur in patients with complete DPD deficiency and advising clinicians to test for DPYD gene variants before treatment unless therapy cannot wait (fda.gov, dailymed.nlm.nih.gov, accessdata.fda.gov). That is a striking move for a drug this old. Fluorouracil, often called 5-FU, is one of the backbone medicines of solid-tumor oncology. It is used in colorectal, gastric, pancreatic, and breast cancers, often as part of standard combination regimens that oncologists know almost by muscle memory. The FDA did not revisit the label because the drug stopped working. It did it because the agency concluded that long-known toxicity signals had become specific enough, and actionable enough, to demand clearer instructions tied to genetics (accessdata.fda.gov, targetedonc.com). The biology is blunt. DPD is the main enzyme that clears fluorouracil from the body. If that enzyme is missing or badly impaired, the drug can accumulate fast and hit normal tissues as hard as it hits the tumor. The label now points directly to early-onset, sometimes fatal toxicities including mucositis, diarrhea, neutropenia, and neurotoxicity. It also says no fluorouracil dose has been proven safe for patients with complete DPD deficiency, which is why the new language tells clinicians to avoid use in patients with certain homozygous or compound heterozygous DPYD variants linked to complete loss of enzyme activity (dailymed.nlm.nih.gov, accessdata.fda.gov). This is where the story gets bigger than one label. For years, pharmacogenetics groups have argued that fluoropyrimidine dosing should be tied to DPYD genotype, and European regulators moved earlier than the United States. In 2020, the European Medicines Agency recommended testing patients for DPD deficiency before starting fluorouracil given by injection or infusion. CPIC, the Clinical Pharmacogenetics Implementation Consortium, has also maintained genotype-based dosing guidance and updated its DPYD materials again in January 2024 as the evidence base evolved (ema.europa.eu, clinpgx.org). The FDA’s move still stops short of a simple national rule that every patient must be screened in every circumstance. The label says to test before starting treatment unless immediate treatment is necessary. It also notes that an FDA-authorized test for detecting DPYD variants is not currently available, and that the tests already on the market differ in which variants they look for. That matters because partial DPD deficiency is more common than complete deficiency, and the evidence is strongest for a limited set of variants rather than every possible genetic change in the pathway (dailymed.nlm.nih.gov, fda.gov, downloads.regulations.gov). Even so, the direction of travel is clear. The FDA opened a public docket in 2025 focused on DPD deficiency and fluoropyrimidine chemotherapy, asking for information on testing and clinical use. Then it sharpened the labels again. This is what modern drug safety looks like for old medicines: not a dramatic recall, not a new molecule, just a familiar vial with new language that tells doctors to check a patient’s genes before hanging the bag if there is time (federalregister.gov, accessdata.fda.gov).