FDA Approves VISTOGARD®, an Antidote for 5-FU Overexposure

SUMMARY: The United States FDA approved VISTOGARD® (Uridine Triacetate) for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). VISTOGARD® is a Pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death.

The approval of VISTOGARD® was based on two separate trials in which 135 adult and pediatric cancer patients at increased risk for toxicity with 5-FU or XELODA® were included. Risk for toxicity could be due to 5-FU overdose and accidental XELODA® ingestion (N=111) or DihydroPyrimidine Dehydrogenase (DPD) deficiency and/or patients who experienced rapid onset of severe toxicities (N=24). These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU therapy. The primary endpoint of the studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of those who were treated with VISTOGARD® for overdose, 97 percent were still alive at 30 days. Of those treated with VISTOGARD® for early-onset severe or life-threatening toxicity, 89 percent were alive at 30 days. In both studies, 33 percent of patients resumed chemotherapy in less than 30 days. Adverse events were mild and uncommon and included nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity. Ma WW, Saif WM, El-Rayes BF, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 655)