Uridine Triacetate Granules for Fluorouracil or Capecitabine Overdose or Early Severe Toxicity

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Emergency Treatment for Fluorouracil or Capecitabine Overdose

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On December 11, 2015, uridine triacetate (Vistogard) was approved for emergency treatment of adult and pediatric patients following fluorouracil (5-FU) or capecitabine overdose regardless of the presence of symptoms or patients who exhibit early-onset severe or life-threatening cardiac or central nervous system (CNS) toxicity or early-onset unusually severe adverse reactions (eg, gastrointestinal toxicity or neutropenia) within 96 hours following the end of 5-FU or capecitabine administration.1,2

Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with 5-FU or capecitabine, since it may diminish the efficacy of these drugs. The safety and efficacy of uridine triacetate started > 96 hours after the end of 5-FU or capecitabine administration have not been established.

Supporting Efficacy Data

Approval was based on two single-arm open-label expanded access studies in 135 patients who had either 5-FU (n = 112) or capecitabine (n = 5) overdose or presented with severe or life-threatening toxicities within 96 hours after the end of receiving 5-FU (n = 18).2 Patients had a median age of  59 years (range = 1–83 years), 56% were male, 72% were white, 9% were black, 6% were Hispanic, 4% were Asian, and 95% had a cancer diagnosis; 6 were pediatric patients. The severe or life-threatening toxicities involved the CNS (eg, encephalopathy, acute mental status change), cardiovascular system, gastrointestinal system (eg, mucositis), and bone marrow.

Of the 112 patients with 5-FU overdose, 105 (94%) were overdosed by infusion rate only (range = 1.3–720 times planned infusion rate), 4 (4%) were overdosed by dose only, and 3 (3%) were overdosed by both dose and rate. Four patients initiated uridine triacetate at > 96 hours after the end of 5-FU or capecitabine administration. The major efficacy outcome was survival at 30 days or the resumption of chemotherapy if prior to 30 days.

Of the 135 patients in the two studies, 130 (96%) survived and 5 (4%) died. Of the five patients who died, two were treated at > 96 hours following the end of 5-FU administration. Retrospective historical data from 25 patients who were overdosed with 5-FU (by rate, range = 1.9–64 times planned rate) and received supportive care only indicate that 84% had died. Among the 117 patients with overdose, 114 (97%) were alive at 30 days. Of the 18 patients with severe toxicity, 16 (89%) were alive at 30 days. Overall, 45 patients (33%) resumed chemotherapy within 30 days.

How It Works

Uridine triacetate is an acetylated prodrug of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases throughout the body, yielding uridine in the circulation. Uridine competitively inhibits cell damage and cell death caused by the cytotoxic antimetabolite 5-FU. A cytotoxic intermediate of 5-FU (FdUMP) inhibits thymidylate synthase and blocks thymidine synthesis. Thymidine is required for DNA replication and repair; uridine is not found in DNA.

5-FU also exerts a cytotoxic effect through incorporation of the metabolite 5-fluoridine triphosphate (FUTP) into RNA, with incorporation being proportional to systemic 5-FU exposure. Excess circulating uridine derived from uridine triacetate is converted into uridine triphosphate, which competes with FUTP for incorporation into RNA.

How It Is Used

In adults, uridine triacetate should be given at 10 g (1 packet) orally every 6 hours for 20 doses without regard to meals. In pediatric patients, it should be given at 6.2 g/m2, not to exceed 10 g per dose, orally every 6 hours for 20 doses without regard to meals. Any unused portion of granules should be discarded. Treatment should begin as soon as possible after overdose or early-onset toxicity within 96 hours following the end of 5-FU or capecitabine administration.

Each dose should be mixed with 3 to 4 ounces of soft foods (eg, applesauce, pudding, or yogurt) and ingested within 30 minutes; granules should not be chewed. The patient should drink at least 4 ounces of water after the dose. If a patient vomits within 2 hours of a dose, another complete dose should be given as soon as possible after the vomiting episode, and the next dose should be given at the regularly scheduled time. Treatment can be given via nasogastric tube or gastrostomy tube when necessary.

Safety Profile

In the two single-arm trials (N = 135), the most common adverse events of any grade were vomiting (10%), nausea (5%), and diarrhea (3%). One patient experienced serious adverse events of grade 3 nausea and vomiting. Treatment was discontinued due to adverse events in two patients (1.4%). Five patients died within 30 days of the last dose of uridine triacetate, with none of the deaths being considered attributable to treatment.

Uridine triacetate carries no warnings/precautions and no contraindications. ■


1. U.S. Food and Drug Administration: Uridine triacetate. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm476930.htm. Accessed January 9, 2016.

2. Vistogard (uridine triacetate) oral granules prescribing information, Wellstat Therapeutics Corporation, December 2015. https://www.vistogard.com/Vistogard/media/Vistogard/Files/final-labeling-text-vistogard.pdf. Accessed January 9, 2016.

Report Adverse Events

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).