The FDA has approved the pyrimidine analog uridine triacetate (Vistogard – Wellstat Therapeutics) for emergency treatment of a fluorouracil (5-FU) or capecitabine (Xeloda, and generics) overdose or severe toxicity that occurs within 96 hours following administration of one of these drugs. Fluorouracil is a cytotoxic antimetabolite used to treat breast, colorectal, and other cancers; capecitabine is an oral prodrug of fluorouracil.

Uridine triacetate, a prodrug, is deacetylated to uridine after oral administration. Excess circulating uridine is converted into uridine triphosphate, which inhibits the cytotoxic activity of 5-fluorouridine triphosphate, a fluorouracil metabolite, by competing with it for incorporation into RNA.

FDA approval was based on two unpublished open-label studies (summarized in the package insert) in a total of 135 adults and children with overdoses of fluorouracil or capecitabine (n=117) or severe or life-threatening toxicities within 96 hours after their administration (n=18). The overall survival rate at 30 days was 96%. In retrospective case reports that included 25 patients who received only supportive care after a fluorouracil overdose, the survival rate was 16%.

Vistogard is supplied as orange-flavored oral granules in single-dose packets containing 10 grams of uridine triacetate. The granules should be mixed with 3-4 ounces of soft food and taken every 6 hours for 20 doses. The recommended dose is 10 grams for adults and 6.2 grams/m² (10 grams maximum) for children. Mild to moderate nausea, vomiting, and diarrhea have been reported. The cost for one course of treatment is $75,000.1

1. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. June 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

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The FDA has approved the pyrimidine analog uridine triacetate (Xuriden [zur' uh den] – Wellstat Therapeutics) for treatment of hereditary orotic aciduria, a rare autosomal recessive disorder (estimated birth prevalence: <1:1,000,000) in infants and children caused by a deficiency in uridine 5'-monophosphate (UMP) synthase. This deficiency prevents synthesis of uridine nucleotides and causes developmental delays, failure to gain weight, hematologic abnormalities, and excessive urinary excretion of orotic acid, which can lead to urinary obstruction.1 Xuriden is the first drug to be approved in the US for this indication. Uridine triacetate is also available as Vistogard for treatment of fluorouracil (5-FU) or capecitabine (Xeloda, and generics) overdose or severe or life-threatening toxicity.

In an unpublished, single-arm, 6-week trial with a 6-month extension (summarized in the package insert), 4 patients 3-19 years old with hereditary orotic aciduria were treated with uridine triacetate 60 mg/kg once daily for 6 weeks, followed by 60-120 mg/kg once daily for 6 months. After 6 months of treatment, hematologic parameters (neutrophil count, WBC count, or mean corpuscular volume) either improved or remained stable and orotic acid levels remained stable in all 4 patients. Weight growth either improved or remained stable and height growth remained stable in 3 patients measured after 6 months of treatment. No adverse effects were reported.

Xuriden is available as oral granules in 2-gram single-use packets. The recommended starting dosage is 60 mg/kg once daily. The dose can be increased to 120 mg/kg (max 8 grams) once daily if urine orotic acid levels increase or remain above normal, or for worsening disease. The granules should be mixed in applesauce, pudding, yogurt, milk, or infant formula and swallowed immediately, without chewing. Once the packet is opened, any unused granules should be discarded. The cost for 30 2-gram packets of Xuriden is $22,500.2

1. S Balasubramaniam et al. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis 2014: 37:687.
2. Approximate WAC = wholesaler acquisition cost, or manufacturer's published price to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price. Source: AnalySource® Monthly. March 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

Download complete U.S. English article