Dihydropyrimidine Dehydrogenase Deficiency

The U.S. Food and Drug Administration (FDA) is providing this communication to increase awareness of recent updates to the product labeling of capecitabine and fluorouracil (5-FU) related to risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. 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. Fluoropyrimidines are a class of anti-cancer drugs that include fluorouracil (5-FU) and capecitabine, a prodrug of 5-FU. The DPYD gene encodes the enzyme DPD, which breaks down >80% of fluorouracil. Patients with certain homozygous or compound heterozygous variants in the DPYD gene, known to result in complete or near complete absence of DPD activity (complete DPD deficiency), are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.Project RenewalThe FDA Oncology Center of Excellence, under Project Renewal, updated the product labeling of Xeloda (capecitabine tablets) to include additional information on DPD deficiency and the importance of discussing DPD deficiency with patients; a safety labeling change updated the 5-FU labeling to include the same DPD deficiency information as in Xeloda. The product labeling of both drugs state: Capecitabine or fluorouracil are not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No dose has been proven safe for patients with complete DPD deficiency. There is insufficient data to recommend a specific dose in patients with partial DPD deficiency. All healthcare providers should inform patients of the potential for serious and life-threatening adverse reactions due to DPD deficiency. Providers should discuss with their patient whether the patient should be tested for genetic variants that are associated with an increased risk of serious adverse reactions from the use of capecitabine or 5-FU. Providers should consider testing prior to initiating capecitabine or fluorouracil to reduce the risk of serious adverse reactions. Providers should be aware of the signs and symptoms associated with adverse reactions due to DPD deficiency and advise patients to immediately contact their provider if these occur, including severe mucositis, diarrhea, neutropenia, and neurotoxicity. Providers should withhold or permanently discontinue capecitabine or 5-FU based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe reactions, which may indicate complete DPD deficiency. Four DPYD variants have been associated with impaired DPD activity in White populations, and one variant has been associated with impaired activity in individuals of African ancestry. See the full prescribing information for Xeloda and 5-FU for additional information on DPD deficiency, located in Sections 5, 12.5, and 17.The FDA will continue to monitor this safety issue and evaluate the evolving landscape and impact of DPD deficiency on the safety of capecitabine and fluorouracil; additional regulatory actions will be considered. The FDA urges patients and healthcare providers to report side effects involving capecitabine or 5-FU products to the FDA MedWatch program.

MINNEAPOLIS--(BUSINESS WIRE)-- OneOme announces its new approach to improving medication safety for cancer patients through focused germline pharmacogenomics (PGx) testing.1,2 RightMed Oncology is uniquely designed to help oncologists elevate their standard of care – to decrease the risk of chemotherapy-induced toxicity and improve medication safety and efficacy for supportive care medications for mental health, pain management, and chemotherapy-induced nausea and vomiting. This may be achieved by tailoring medications and dosages to match the unique genetic makeup of individual patients based on established guidelines. The RightMed oncology portfolio empowers innovative health systems, oncology practices and prescribers to be as focused or comprehensive as their program requires. OneOme offers single-gene RightMed tests including DPYD (c.557A>G, HapB3, *2A, *13, and c.2846A>T variants), UGT1A1 and TMPT/NUDT15, as well as the RightMed Oncology panel test, which covers dozens of medications used as chemotherapy and supportive care. Fluorouracil injection, one chemotherapy medication covered by the RightMed Oncology test and DPYD single-gene test, recently updated labeling in collaboration with FDA to include: “Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions... Inform patients of the potential for serious and life-threatening adverse reactions due to DPD deficiency and discuss with your patient whether they should be tested for genetic variants of DPYD that are associated with an increased risk of serious adverse reactions from the use of fluorouracil.”3 OneOme’s Chief Medical Officer, James Kelley, MD, PhD, said, “Precision medicine is enabling cancer treatment to become personalized. Using PGx can inform usage and dosage decisions for a wide range of chemotherapy and supportive care medications. It is another tool in reducing adverse drug events, predicting drug efficacy, and improving patient care.” RightMed Oncology incorporates insights from practicing oncology clinicians, a feasibility study with Mayo Clinic4, recent scientific and clinical literature, and established PGx guidelines such as the Clinical Pharmacogenetics Implementation Consortium (CPIC®) and FDA labeling. For more information about RightMed Oncology, please visit OneOmeInstitute.com/Oncology or reach out directly to discuss a PGx program for your health system. OneOme is a leader in precision medicine, providing pharmacogenomic solutions, population-level value-based care analyses, and clinical decision support solutions to health systems, health insurers, and self-insured employers. OneOme aims to improve patient safety, reduce overall cost of care, and improve patients' health outcomes. Co-founded by the Mayo Clinic, from its headquarters in Minneapolis, OneOme offers its services to clients around the world. For more information, visit . 1. Deenen MJ, Meulendijks D, Cats A, et al. Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol. 2016;34(3):227-34. 2. Hulshof EC, de With M, de Man FM, et al. UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients. Eur J Cancer. 2022;162:148-57. 3. FDA approves safety labeling changes regarding DPD deficiency for fluorouracil injection products, available at: . (March 21, 2024). 4. Kasi PM, Koep T, Schnettler E, Shahjehan F, Kamatham V, Baldeo C, Hughes CL. Feasibility of Integrating Panel-Based Pharmacogenomics Testing for Chemotherapy and Supportive Care in Patients With Colorectal Cancer. Technol Cancer Res Treat. 2019 Jan 1;18:1533033819873924. doi: 10.1177/1533033819873924. PMID: 31533552; PMCID: PMC6753511. View source version on businesswire.com: Contacts Travis Thompson Senior Director of Marketing, OneOme, LLC travisthompson@oneome.com Source: OneOme View this news release online at:

On March 21, 2024, the Food and Drug Administration approved safety labeling changes for fluorouracil injection products. This effort was a collaboration between FDA’s Office of Generic Drugs and the Oncology Center of Excellence (OCE). Fluorouracil injection was initially approved in 1962. The FDA became aware of additional safety information regarding the risk of serious adverse reactions related to fluorouracil use in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. Revisions have been made to the Highlights of Prescribing Information and sections 5 (Warnings and Precautions) and 17 (Patient Counseling Information) of the full prescribing information to provide information about these risks. In addition, a new subsection 12.5 (Pharmacogenomics) has been added to section 12 (Clinical Pharmacology). The labeling changes align with those approved for another fluoropyrimidine drug, Xeloda (capecitabine) tablets, on December 14, 2022. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088. For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov. Follow the Oncology Center of Excellence on X (formerly Twitter) @FDAOncologyExternal Link Disclaimer. Content current as of: 03/21/2024 Regulated Product(s) Drugs 03/21/2024 Drugs Resources for Information | Approved Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description