FDA Approves Safety Label Changes for Fluorouracil Injection

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The FDA strengthened safety warnings for fluorouracil due to dihydropyrimidine dehydrogenase deficiency that can cause severe adverse effects.

  • The FDA updated the label to warn about serious and potentially fatal adverse effects (AEs) in patients with a genetic condition called (dihydropyrimidine dehydrogenase) DPD deficiency.
  • The updates target 3 sections of the label: «Warnings and Precautions,» «Patient Counseling Information,» and «Clinical Pharmacology.»
  • The new label advises against using fluorouracil for patients with specific genetic variations linked to complete or near-complete absence of DPD activity.

Safety label changes for fluorouracil injection products have been approved by the FDA. Additional information regarding the risk of serious AEs in patients with DPD deficiency will now be included.1

Though the initial approval for fluorouracil injection was granted in 1962 for the treatment of colon and rectum adenocarcinoma, breast adenocarcinoma, gastric adenocarcinoma, and pancreatic adenocarcinoma, the regulatory agency made changes to the safety label after safety information regarding the risk of serious AEs related to fluorouracil use in patients with DPD deficiency was noted. These new changes align with those made to the prescribing information for capecitabine (Xeloda), which was amended in December 2022.

Revisions on the fluorouracil label have been made to the “Warnings and Precautions,” “Patient Counseling Information,” and “Clinical Pharmacology” sections.2

The updated label under the “Warnings and Precautions” sections states that fluorouracil can cause serious and fatal AEs among patients with certain homozygous or compound heterozygous DPYD variants associated with complete or near complete absence of DPD activity. Specifically, the agent is not recommended for patients at elevated risk for acute, early-onset toxicities, which could be serious or fatal, including mucositis, diarrhea, neutropenia, and neurotoxicity. There is also a risk for those with partial DPD deficiency.

If patients treated with fluorouracil injection products have evidence of acute, early-onset, or unusually severe reactions, the agent should be withheld or discontinued as no fluorouracil dose has been proven safe for patients with complete DPD deficiency, and insufficient data are available to recommend a specific dose in patients with partial DPD deficiency

While no specific DPD tests are currently FDA-approved, genetic testing may be considered to help determine if fluorouracil is safe. The updated label also emphasizes the importance of patients being informed about these potential AEs and instructed to report them immediately to their doctor.

About DPD

The gene DYPD encodes an enzyme called DPD, which is responsible for breaking down more than 80% of fluorouracil. While partial DPD deficiency occurs in approximately 3% to 5% of White patient populations, complete DPD deficiency is even more rare at around 0.2% of White patients. It is important to note that these rates of DPD deficiency are higher in Black patient populations. However, there is not enough data to estimate the proportion of DPD deficiency in non-White populations.

Researchers have identified 4 specific genetic variations (c.1905+1G>A [DPYD *2A], c.1679T>G [DPYD *13], c.2846A>T, and c.1129-5923C>G [Haplotype B3]) that can reduce DPD activity.

Fuente: https://www.targetedonc.com/view/fda-approves-safety-label-changes-for-fluorouracil-injection