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

Abstract

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.

• Authors: Wen Wee Ma, Muhammad Wasif Saif, Bassel F El-Rayes, Marwan G Fakih, Thomas H Cartwright, James A Posey, Thomas R King, Reid W von Borstel, Michael K Bamat
• Journal: Cancer (Cancer) Vol. 123 Issue 2 Pg. 345-356 (01 01 2017) ISSN: 1097-0142 [Electronic] United States
• PMID: 27622829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Chemical References

• Acetates
• Antimetabolites, Antineoplastic
• uridine triacetate
• Capecitabine
• Fluorouracil
• Uridine

Topics

• Acetates (therapeutic use)
• Antimetabolites, Antineoplastic (adverse effects)
• Capecitabine (adverse effects, therapeutic use)
• Drug Overdose (drug therapy)
• Female
• Fluorouracil (adverse effects, therapeutic use)
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Uridine (analogs & derivatives, therapeutic use)