Vistogard (uridine triacetate) for the emergency treatment of overdose of fluorouracil or capecitabine.

December 11, 2015

The U.S. Food and Drug Administration 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.

DESCRIPTION

VISTOGARD oral granules contain the active ingredient uridine triacetate which is a pyrimidine analog.

The chemical name for uridine triacetate is (2′,3′,5′-tri-O-acetyl-ß-D-ribofuranosyl)-2,4(1H,3H)- pyrimidinedione. The molecular weight is 370.3 grams/mole and it has an empirical formula of C15H18N2O9. The structural formula is:

visto structure

 

CLINICAL PHARMACOLOGY

Mechanism of Action

  • Uridine triacetate is an acetylated pro-drug of uridine.
  • Following oral administration, uridine triacetate is deacetylated by nonspecific esterases present throughout the body, yielding uridine in the circulation.
  • Uridine competitively inhibits cell damage and cell death caused by fluorouracil.
  • Fluorouracil is a cytotoxic antimetabolite that interferes with nucleic acid metabolism in normal and cancer cells.
  • Cells anabolize fluorouracil to the cytotoxic intermediates 5-fluoro-2’-deoxyuridine-5’- monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
  • FdUMP inhibits thymidylate synthase, blocking thymidine synthesis. Thymidine is required for DNA replication and repair.
  • Uridine is not found in DNA. The second source of fluorouracil cytotoxicity is the incorporation of its metabolite, FUTP, into RNA.
  • This incorporation of FUTP into RNA is proportional to systemic fluorouracil exposure. Excess circulating uridine derived from VISTOGARD is converted into uridine triphosphate (UTP), which competes with FUTP for incorporation into RNA.

 

INDICATIONS AND USAGE

VISTOGARD is indicated for the emergency treatment of adult and pediatric patients:

  • following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, or
  • who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration.

Limitations of Use

  • VISTOGARD is not recommended for the non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs.
  • The safety and efficacy of VISTOGARD initiated more than 96 hours following the end of fluorouracil or capecitabine administration have not been established.

 

DOSAGE AND ADMINISTRATION

Recommended Dosage

  • Adults: 10 grams (1 packet) orally every 6 hours for 20 doses, without regard to meals.
  • Pediatric: 6.2 grams/m2 of body surface area (not to exceed 10 grams per dose) orally every 6 hours for 20 doses, without regard to meals.
  • The VISTOGARD dose to be administered at 6.2 grams/m2 is presented in Table 1. Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon accurate to ¼ teaspoon.
  • Discard any unused portion of granules.
  • Do not use granules left in the open packet for subsequent dosing.

visto

Safety & Efficacy

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.

Side Effects

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 grantedpriority 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.

Reference:

FDA News

Prescription Label