December 11, 2015
Release
The U.S. Food and Drug Administration today approved Vistogard (uridine triacetate) for the emergency treatment of adults and children who receive an overdose of the cancer treatment fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within four days of receiving these cancer treatments.
“Treating cancer requires not only selecting which drug may be most effective and well tolerated, but ensuring the correct dose is given at proper intervals. While rare, unintentional overdose can occur,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents.”
Fluorouracil (taken by infusion) and capecitabine (taken orally) are similar types of chemotherapy that have been used for decades to treat several types of cancer, including breast and gastrointestinal cancers. An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal.
Vistogard, taken orally, blocks cell damage and cell death caused by fluorouracil chemotherapy. Patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within four days) of severe or life-threatening toxicity. The patient’s health care provider will determine when he or she should return to the prescribed chemotherapy after treatment with Vistogard.
The efficacy and safety of Vistogard were studied in 135 adult and pediatric cancer patients who were treated in two separate trials and had either received an overdose of flourouracil or capecitabine, or had early-onset, unusually severe or life-threatening toxicities within 96 hours after receiving flourouracil (not due to an overdose). The studies’ primary measure 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.
Vistogard is not recommended for treating non-emergency adverse reactions associated with flourouracil or capecitabine because Vistogard may lessen the efficacy of these drugs. The safety and efficacy of Vistogard initiated more than 96 hours following the end of treatment with flourouracil or capecitabine have not been established.
The most common side effects of treatment with Vistogard were diarrhea, vomiting and nausea.
The FDA granted Vistogard orphan drug designation, which provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Vistogard was also granted priority review and fast track designations, which are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions.
Vistogard is marketed by Wellstat Therapeutics Corporation based in Gaithersburg, Maryland.
Uridine, 5-hydroxy-, 2′,3′,5′-triacetate(CAS No. 170743-19-8)
Mechanism Of Action
Uridine triacetate is an acetylated form of uridine. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation (Figure 1).
Figure 1: Uridine Triacetate Conversion to Uridine
URIDEN provides uridine in the systemic circulation of patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis.
Production Example 1
5.6 g of uracil and 0.1 g of ammonium sulfate were dissolved in 22.4 ml of 1,1,1,3,3,3-hexamethyldisilazane and reacted at 120° C. for 2.5 hours. After the completion of the reaction, the reaction mixture was distilled to give 11.8 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine. 1H-NMR (400 MHz, in C2D6CO): δ=0.29 (s, 9H), 0.31 (s, 9H), 6.35 (d, J=5.6 Hz, 1H), 8.19 (d, J=5.5Hz, 1H)
Referential Example 11.21 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 1.15 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.8 ml of acetonitrile and cooled to 5° C. Next, 0.94 g of SnCl4 was added dropwise thereinto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted for 3 hours. The reaction mixture was analyzed by HPLC. Thus, β-uridine triacetate was obtained with a reaction yield of 83%.
Example 1
0.93 g of 2,4-bis(trimethylsilyloxy)-1,3-diazine obtained in PRODUCTION EXAMPLE 1 and 0.92 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose were dissolved in 4.7 ml of acetonitrile and cooled to 4° C. Then 0.49 g of FeCl3 was added thereto at the same temperature. After stirring for 10 minutes at the same temperature, the mixture was heated to 50° C. and reacted. The reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was added dropwise at 4° C. into a cold aqueous solution of sodium hydrogencarbonate which had been preliminarily prepared. After filtering off the catalyst residue, the filtrate was separated and the aqueous layer was extracted with 20 ml portions of ethyl acetate thrice. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After distilling off the solvent, 1.2 g (purity 80%) of the target compound was obtained as a viscous white solid.
Namely, the target compound could be obtained at a yield comparable to REFERNTIAL EXAMPLE 1 wherein SnCl4 was employed as the catalyst. 1H-NMR (400 MHz, in CDCl3): δ=2.11 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 4.35 (m, 3H), 5.33 (m, 2H), 5.79 (d, J=8.2 Hz, 1H), 6.04 (d, J=4.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H)
Filed under: FDA 2015, Uncategorized Tagged: FDA 2015, uridine triacetate, Vistogard
