Prompt treatment with uridine triacetate improves survival and reduces toxicity due to fluorouracil and capecitabine overdose or dihydropyrimidine dehydrogenase deficiency.

Uridine triacetate has been shown to be an effective antidote against mortality and toxicity caused by either overdoses or exaggerated susceptibility to the widely used anticancer agents 5-fluorouracil (5-FU) and capecitabine. However, a direct assessment of efficacy based on when emergency treatment was initiated was not clinically feasible. In this study we used mouse models of 5-FU overdose and of dihydropyrimidine dehydrogenase (DPD) deficiency to compare the efficacy of uridine triacetate in reducing toxicity and mortality when treatment was initiated at time points from 4 to 144 h after administration of 5-FU. We found that uridine triacetate was effective both in the 5-FU overdose and DPD deficiency models. Starting treatment within 24 h was most effective at reducing toxicity and mortality in both models, while treatment starting more than 96 to 120 h after 5-FU was far less effective. Uridine triacetate also reduced mortality in the DPD deficiency model when mice were treated with the 5-FU prodrug capecitabine. The results of this study are supportive of clinical observations and practice, indicating that efficacy declined progressively with later and later treatment initiation. Prompt treatment with uridine triacetate, within 24 h, conferred the greatest protection against 5-FU overexposure.

Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity.

BACKGROUND: Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Life-threatening 5-FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early-onset severe or life-threatening 5-FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5-FU metabolites. METHODS: In 2 open-label clinical studies, patients who presented with a 5-FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5-FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care. RESULTS: A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate-treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5-FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%). CONCLUSIONS: In these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5-FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345-356. © 2016 American Cancer Society.