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  • CLASSES

    Cytoprotectant Agents
    Metabolic Disorder Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Orally administered pyrimidine analog
    Approved for the treatment of hereditary orotic aciduria; also approved for emergency use following a fluorouracil or capecitabine overdose or in patients who exhibit early-onset, severe or life-threatening toxicity within 96 hours following the end of fluorouracil or capecitabine administration
    In patients with hereditary orotic aciduria, monitoring of blood abnormalities, urine orotic acid concentrations, and worsening signs and symptoms of the disease help guide dosing

    COMMON BRAND NAMES

    Vistogard, Xuriden

    HOW SUPPLIED

    Uridine triacetate/VISTOGARD/Xuriden Oral Gran: 2g, 10g

    DOSAGE & INDICATIONS

    For the treatment of hereditary orotic aciduria.
    NOTE: The FDA has designated uridine triacetate as an orphan drug for the treatment of hereditary orotic aciduria.
    Oral dosage (Xuriden only)
    Adults

    60 mg/kg/dose PO once daily initially. Increase the dosage to 120 mg/kg/dose PO once daily (Max: 8 grams) if initial dose is not effective. Insufficient efficacy can be identified by the following: orotic acid concentrations in the urine remain above normal or increase above the usual or expected range for the patient, laboratory values (e.g., RBC or WBC indices) affected by hereditary orotic aciduria show evidence of worsening, or worsening of other signs or symptoms of the disease.

    Infants, Children, and Adolescents

    60 mg/kg/dose PO once daily initially. Increase the dosage to 120 mg/kg/dose PO once daily (Max: 8 grams) if initial dose is not effective. Insufficient efficacy can be identified by the following: orotic acid concentrations in the urine remain above normal or increase above the usual or expected range for the patient, laboratory values (e.g., RBC or WBC indices) affected by hereditary orotic aciduria show evidence of worsening, or worsening of other signs or symptoms of the disease.

    For emergency treatment following a fluorouracil overdose or capecitabine overdose (regardless of the presence of symptoms).
    NOTE: The FDA has designated uridine triacetate as an orphan drug as an antidote for 5-fluorouracil poisoning. It is not recommended for non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may reduce the efficacy of these drugs. The safety and efficacy of uridine triacetate started more than 96 hours following the end of fluorouracil or capecitabine administration have not been established.
    Oral dosage (Vistogard only)
    Adults

    10 grams (1 packet) orally every 6 hours for 20 doses; administer as soon as possible after an overdose. In a pooled analysis of 2 open-label trials (n = 135; age range, 1 to 83 years), the overall survival rate at 30 days (or at the resumption of chemotherapy if prior to 30 days) was 97% in patients who received uridine triacetate following a fluorouracil or capecitabine overdose (n = 117). Overdose was defined as a fluorouracil dose or infusion rate that was greater than the intended fluorouracil dose or maximum tolerated dose. Of patients who received a fluorouracil overdose (n = 112), 94% of patients had an infusion rate-related overdose (1.3 to 720-times the planned infusion rate), 4% of patients had a dose-related overdose, and 3% of patients had an infusion rate- and dose-related overdose. In this analysis, 4 patients received uridine triacetate more than 96 hours following the end of fluorouracil or capecitabine administration; 2 of these patients died.

    Children and Adolescents

    6.2 grams/m2 (not to exceed 10 grams per dose) orally every 6 hours for 20 doses; administer as soon as possible after an overdose. In a pooled analysis of 2 open-label trials (n = 135; age range, 1 to 83 years), the overall survival rate at 30 days (or at the resumption of chemotherapy if prior to 30 days) was 97% in patients who received uridine triacetate following a fluorouracil or capecitabine overdose (n = 117). There were only 6 pediatric patients (age range, 1 to 16 years) included in the analysis. Overdose was defined as a fluorouracil dose or infusion rate that was greater than the intended fluorouracil dose or maximum tolerated dose. Of patients who received a fluorouracil overdose (n = 112), 94% of patients had an infusion rate-related overdose (1.3 to 720-times the planned infusion rate), 4% of patients had a dose-related overdose, and 3% of patients had an infusion rate- and dose-related overdose. In this analysis, 4 patients received uridine triacetate more than 96 hours following the end of fluorouracil or capecitabine administration; 2 of these patients died.

    For emergency treatment of fluorouracil toxicity or capecitabine toxicity in patients with 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.
    NOTE: The FDA has designated uridine triacetate as an orphan drug as an antidote for 5-fluorouracil poisoning. It is not recommended for non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may reduce the efficacy of these drugs. The safety and efficacy of triacetate started more than 96 hours following the end of fluorouracil or capecitabine administration have not been established.
    Oral dosage (Vistogard only)
    Adults

    10 grams (1 packet) orally every 6 hours for 20 doses. In a pooled analysis of 2 clinical trials (n = 135; age range, 1 to 83 years), the overall survival rate at 30 days (or at the resumption of chemotherapy if prior to 30 days) was 89% in 18 patients who received uridine triacetate for severe or life-threatening fluorouracil-related toxicities involving the central nervous system (e.g., encephalopathy, acute mental status change), cardiovascular system, gastrointestinal system (e.g., mucositis), and bone marrow. In this analysis, 4 patients received uridine triacetate more than 96 hours following the end of fluorouracil or capecitabine administration; 2 of these patients died.

    Children and Adolescents

    6.2 grams/m2 (not to exceed 10 grams per dose) orally every 6 hours for 20 doses. In a pooled analysis of 2 clinical trials (n = 135; age range, 1 to 83 years), the overall survival rate at 30 days (or at the resumption of chemotherapy if prior to 30 days) was 89% in 18 patients who received uridine triacetate for severe or life-threatening fluorouracil-related toxicities involving the central nervous system (e.g., encephalopathy, acute mental status change), cardiovascular system, gastrointestinal system (e.g., mucositis), and bone marrow. There were only 6 pediatric patients (age range, 1 to 16 years) included in the analysis. Additionally, 4 patients received uridine triacetate more than 96 hours following the end of fluorouracil or capecitabine administration; 2 of these patients died.

    MAXIMUM DOSAGE

    Adults

    8 grams/day PO for hereditary orotic aciduria; 40 grams/day PO for fluorouracil or capecitabine overdose and toxicity.

    Geriatric

    8 grams/day PO for hereditary orotic aciduria; 40 grams/day PO for fluorouracil or capecitabine overdose and toxicity.

    Adolescents

    120 mg/kg/day PO (Max: 8 grams/day) for hereditary orotic aciduria; 6.2 grams/m2/dose (Max: 10 grams/dose) and 24.8 grams/m2/day (Max: 40 grams/day) for fluorouracil or capecitabine overdose and toxicity.

    Children

    120 mg/kg/day PO (Max: 8 grams/day) for hereditary orotic aciduria; 6.2 grams/m2/dose PO (Max: 10 grams/dose) and 24.8 grams/m2/day PO (Max: 40 grams/day) for fluorouracil or capecitabine overdose and toxicity.

    Infants

    120 mg/kg/day PO for hereditary orotic aciduria; safety and efficacy for other indications have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Uridine triacetate is available as 2 formulations, a single-use 2 gram packet of oral granules (Xuriden) indicated for use in hereditary orotic aciduria and a single-use 10 gram packet of oral granules (Vistogard) indicated for use in fluorouracil or capecitabine overdose or severe toxicity.
     
    Xuriden
    Calculate the dose based on body weight (do not exceed 8 grams/dose).
    Measure the dose using either a scale accurate to at least 0.1 gram or a graduated teaspoon, accurate to the fraction of the dose to be administered; discard any unused portion of granules in the packet.
    Each 2-gram packet contains approximately three-fourths of a teaspoon of uridine triacetate; one packet (2 grams/dose) may be used without weighing or measuring.
    To administer the dose, refer to the instructions for use provided by manufacturer.
     
    Vistogard
    The oral granule may be given without regard to meals; however, the dose needs to be mixed with soft food (or in a food starch-based thickening product in water for nasogastric tube (NG-tube) or a gastrostomy tube (G-tube) administration).
    If a dose is delayed, take the dose as soon as possible; otherwise, take the next dose at the scheduled time.
    If vomiting occurs within 2 hours after a dose, take another dose as soon as possible; resume therapy at the next scheduled dose.
    Adults: one packet (10 grams/dose) may be used without weighing or measuring.
    Pediatric patients: calculate the dose based on body surface area (do not exceed 10 grams/dose). Measure the dose using either a scale accurate to at least 0.1 gram or a graduated teaspoon accurate to one-fourth teaspoon; discard any unused portion of granules in the packet.
     
    Administration with Soft Food
    Mix measured granules in 3 to 4 ounces of a soft food such as applesauce, pudding, or yogurt in a small clean container.
    Ingest the mixture immediately (Xuriden) or within 30 minutes (Vistogard) and do not save any part of the mixture for later use; do not chew granules.
    Drink at least 4 ounces of water after ingesting the dose.
     
    Administration with Milk or Infant Formula (Xuriden only)
    Up to 2 grams of uridine triacetate may be mixed with milk or infant formula.
    Pour 5 mL of milk or infant formula into a 30 mL medicine cup. Draw up the 5 mL of milk/infant formula into a syringe and hold the syringe with the tip pointing upward.
    Pull down on the plunger until it reaches 10 mL (introducing air into the syringe). Place the cap over the tip of the syringe, invert the syringe so that the syringe tip is pointing down, and remove the plunger.
    Pour the measured amount of uridine triacetate granules into the syringe barrel and reinsert the syringe plunger. Do not push up on the plunger. Gently swirl the syringe to mix the granules with the liquid and then turn the syringe so that the syringe tip is pointing up.
    After removing the syringe cap, push up on the plunger until it reaches the 5 mL mark to remove air from the syringe.
    Place the tip of the syringe in the back of the patient’s mouth between the cheek and gum. Gently push the plunger all the way down.
    Refill the syringe with another 5 mL of milk/infant formula and gently swirl the syringe to rinse any remaining uridine triacetate granules from the syringe barrel.
    Again, place the tip of the syringe in the back of the patient’s mouth between the cheek and gum. Gently push the plunger all the way down.
    Follow with a bottle of milk or infant formula, if desired.
     
    Administration via NG-tube or G-tube (Vistogard only)
    Prepare approximately 4 fluid ounces (or 100 mL) of a food starch-based thickening product in water; stir briskly until the thickener has dissolved.
    After crushing the contents of one 10-gram packet of uridine triacetate granules to a fine powder, add the crushed granules to the reconstituted food starch-based thickening product.
    For doses less than 10 grams, prepare the mixture at a ratio of no greater than 1 gram per 10 mL of reconstituted food starch-based thickening product; mix thoroughly.
    Administer the mixture using the NG tube or G-Tube; flush the tube with water after use.

    STORAGE

    Vistogard:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Xuriden:
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    At the time of FDA approval, the product labeling reported no contraindications, warnings, or precautions for the use of uridine triacetate (Xuriden or Vistogard).

    Pregnancy

    Uridine triacetate is available as 2 oral formulations, Xuriden and Vistogard. There is no human data on Xuriden use during pregnancy and there is limited data on Vistogard use during pregnancy; therefore, no information on the risk of birth defects, miscarriage, or fetal toxicity from uridine triacetate use during pregnancy is provided by the manufacturer. There was no evidence of teratogenicity or adverse effects on embryo-fetal development when uridine triacetate was administered to pregnant rats during fetal organogenesis. In this animal study, the dose of uridine triacetate was 2000 mg/kg per day which was about 2.7-times the maximum recommended human dose (MRHD) of Xuriden and about one-half the MRHD of Vistogard.

    Breast-feeding

    According to the manufacturer, it is not known whether uridine triacetate is excreted in human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    vomiting / Early / 0-0.7
    nausea / Early / 0-0.7

    Mild

    diarrhea / Early / 3.0-3.0

    DRUG INTERACTIONS

    Digoxin: (Moderate) Coadministration of uridine triacetate and digoxin may increase digoxin serum concentrations; monitor digoxin serum concentrations and therapeutic/adverse effects if these drugs are administered together. Both digoxin and uridine triacetate are substrates for P-glycoprotein (P-gp). Due to the potential for high local gut concentrations of the drug after dosing, the interaction of uridine triacetate with digoxin and other orally administered P-gp substrate drugs cannot be ruled out.

    PREGNANCY AND LACTATION

    Pregnancy

    Uridine triacetate is available as 2 oral formulations, Xuriden and Vistogard. There is no human data on Xuriden use during pregnancy and there is limited data on Vistogard use during pregnancy; therefore, no information on the risk of birth defects, miscarriage, or fetal toxicity from uridine triacetate use during pregnancy is provided by the manufacturer. There was no evidence of teratogenicity or adverse effects on embryo-fetal development when uridine triacetate was administered to pregnant rats during fetal organogenesis. In this animal study, the dose of uridine triacetate was 2000 mg/kg per day which was about 2.7-times the maximum recommended human dose (MRHD) of Xuriden and about one-half the MRHD of Vistogard.

    According to the manufacturer, it is not known whether uridine triacetate is excreted in human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Uridine triacetate is a pyrimidine analog and an acetylated pro-drug of uridine. It is deacetylated by nonspecific esterases found in the body which results in the release of uridine into the circulation. This action provides uridine required by patients with hereditary orotic aciduria who cannot synthesize adequate quantities of uridine due to a genetic defect in uridine nucleotide synthesis. Additionally, uridine is converted to uridine triphosphate (UTP) which competitively inhibits the incorporation of 5-fluorouridine triphosphate (FUTP), a cytotoxic intermediary produced by fluorouracil, into RNA. This action mitigates the cell damage and cell death caused by fluorouracil (and capecitabine which is an oral prodrug of fluorouracil).
     
    Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congential autosomal recessive disorder of pyrimidine metabolism caused by a defect in uridine monophosphate synthase (UMPS). The UMPS gene encodes uridine 5'monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway. The UMP synthase defect has two primary biochemical consequences. First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease. Second, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Orotic acid crystals in the urine can cause episodes of obstructive uropathy. When uridine reaches the circulation, it can be used by essentially all cells to make uridine nucleotides. Once intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic is also reduced.
     
    Fluorouracil is a cytotoxic antimetabolite that interferes with DNA and RNA metabolism in normal and cancer cells. It is metabolized in the body to the cytotoxic intermediates, 5-fluoro-2’-deoxyuridine-5’monophosphate (FdUMP) and FUTP. FdUMP inhibits thymidylate synthase. This action stops thymidine synthesis and thymidine is required for DNA replication and repair. Uridine is not found in DNA; therefore, uridine triacetate does not prevent this mechanism of fluorouracil toxicity. FUTP incorporation into RNA is proportional to systemic fluorouracil exposure. UTP competes with FUTP for RNA incorporation and this action is how uridine reduces fluorouracil toxicity.

    PHARMACOKINETICS

    Uridine triacetate is administered orally. Uridine triacetate delivers 4-fold to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. Circulating uridine is taken up into cells via specific nucleoside transporters and crosses the blood brain barrier. Uridine can be excreted by the kidneys but is also metabolized by normal pyrimidine catabolic pathways present in most tissues. The half-life ranges from approximately 2 to 2.5 hours.
     
    Affected cytochrome P450 isoenzymes and transporters: P-glycoprotein (P-gp)
    In vitro data showed that uridine triacetate was a weak substrate for P-gp; uridine triacetate also inhibited the transport of digoxin (a known P-gp substrate). There may be potential for interaction with orally administered P-gp substrate drugs. In vitro data did not show meaningful inhibition or induction of cytochrome P450 enzymes studied.

    Oral Route

    After oral administration, maximum uridine plasma concentrations (Cmax) are usually achieved within 2 to 3 hours.
     
    Effects of food: There was no difference in the overall rate and extent of uridine exposure in healthy adult subjects who received a 6-gram dose of uridine triacetate granules under fed and fasted conditions.
     
    Vistogard: Two studies evaluated plasma uridine concentrations in a subgroup of 76 patients treated with up to 20 doses of oral uridine triacetate (adults, 10 grams/dose; pediatrics, 6.2 grams/m2/dose) following a fluorouracil overdose or early-onset serious fluorouracil toxicity. In study 1 (n = 49), the mean plasma uridine concentrations at baseline (predose) and 1 to 4 hours after the final dose were 8 +/- 33 micromolar and 160 +/- 81 micromolar, respectively. In study 2 (n = 27), the mean plasma uridine concentrations at baseline (predose) and 1 to 4 hours after the final dose were 5 +/- 17 micromolar and 153 +/- 68 micromolar, respectively.
     
    Xuriden: The pharmacokinetics of oral uridine triacetate were evaluated in 4 patients, 3 of the patients were previously treated with oral uridine. On Day 0, these 3 patients received their usual daily dose of oral uridine as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral uridine triacetate treatment (60 mg/kg once daily). The dose of uridine triacetate was increased on Day 116 to 120 mg/kg once daily in 2 patients and plasma uridine concentrations were assessed on Day 160. The PK parameters were determined at baseline (oral uridine 150 to 200 mg/kg/day), Day 1 (60 mg/kg/day uridine triacetate), Day 28 (60 mg/kg/day uridine triacetate), and Day 160 (120 mg/kg/day uridine triacetate). Baseline and Day 160 were reported, respectively, as follows: Cmax = 56 +/- 16.1 micromolar and 80.9 +/- 20 micromolar, AUC = 238 +/- 163.2 micromolar x hr and 465.6 +/- 95.3 micromolar x hr, and half-life = 1.6 +/- 0.7 hours and 8.2 +/- 6.8 hours. Plasma concentrations of the uridine catabolite uracil were generally below the limit of quantitation in all patients.