XURIDEN

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Xuriden
-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. If the patient requires doses in multiples of 2 grams, an entire packet can be used without weighing or measuring.
-Storage: Discard any unused portion of granules. Do not use granules left in the open packet, or any part of the soft food, milk, or infant formula mixture for subsequent dosing.
Administration with Soft Food
-Mix each dose with 3 to 4 ounces of soft food such as applesauce, pudding, or yogurt in a small clean container.
-Ingest the mixture immediately. Do not chew the granules.
-Consume at least 4 ounces of water after ingesting the dose.
Administration in Milk or Infant Formula
-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.

Vistogard
-Administer as soon as possible after an overdose or early-onset toxicity within 96 hours after the end of fluorouracil or capecitabine administration.
-Measure the dose using either a scale accurate to at least 0.1 gram, or a graduated teaspoon accurate to one-fourth teaspoon. If the patient is to receive a 10-gram dose, the entire packet can be used without weighing or measuring.
-If the patient vomits within 2 hours of taking a dose, initiate another complete dose as soon as possible. Administer the next dose at the regularly scheduled time.
-If the patient misses a dose at the scheduled time, administer that dose as soon as possible. Administer the next dose at the regularly scheduled time.
-Storage: Discard any unused portion of granules. Do not use granules left in the open packet, or any part of the soft food or thickening product mixture for subsequent dosing.
Administration with Soft Food
-Mix each dose with 3 to 4 ounces of soft food such as applesauce, pudding, or yogurt in a small clean container.
-Ingest within 30 minutes. Do not chew the granules.
-Consume at least 4 ounces of water after ingesting the dose.
Administration via NG tube or G-tube
-Vistogard may be administered via nasogastric tube (NG tube) or gastrostomy tube (G-tube) when necessary (e.g., severe mucositis or coma).
-Prepare an appropriate amount of a food starch-based thickening product (see below) in water; stir briskly until the thickener has dissolved.
-Crush the contents of one 10-gram packet of uridine triacetate granules to a fine powder.
-For a 10-gram dose: Add the entire contents of the packet to approximately 100 mL (4 fluid ounces) of reconstituted food starch-based thickening product and mix thoroughly.
-For doses less than 10 grams: The mixture should be prepared at a ratio of no more than 1 gram per 10 mL. Add the appropriate amount of crushed granules to the appropriate amount of reconstituted food starch-based thickening product and mix thoroughly.
-Flush the tube with water after administration.

Uridine triacetate is available as 2 oral products, Xuriden and Vistogard. At the time of FDA approval, the product labeling for Xuriden reported no adverse reactions in patients with hereditary orotic aciduria. Hereditary orotic aciduria is a very rare condition, and the safety of uridine triacetate was assessed in 4 patients ranging in age from 3 to 19 years.

In a pooled analysis of 2 open-label clinical trials (n = 135), gastrointestinal adverse reactions including vomiting (10%), nausea (5%), and diarrhea (3%) were reported in patients (age range, 1 to 83 years) who received uridine triacetate (Vistogard) after an overdose of fluorouracil or capecitabine or in those who presented with severe or life-threatening toxicities within 96 hours of fluorouracil or capecitabine administration. In this analysis, 1 patient experienced grade 3 nausea and vomiting.

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

Description: Uridine triacetate (Xuriden, Vistogard) is an orally administered pyrimidine analog. Xuriden is indicated as uridine replacement therapy in patients with hereditary orotic aciduria, a rare congenital autosomal recessive disorder of pyrimidine metabolism. Hereditary orotic aciduria is caused by a defect in uridine monophosphate synthase (UMPS), which results in the body being unable to normally synthesize uridine, a necessary component of ribonucleic acid (RNA). Clinically, the metabolic defect is manifested by blood abnormalities, urinary tract obstruction due to the formation of orotic acid crystals, failure to thrive, and developmental delays. During uridine triacetate therapy, blood abnormalities (anemia and decreased white blood cell count), urine orotic acid concentrations, and worsening of signs and symptoms of the disease are monitored to help determine when a dosage increase is necessary. Vistogard is indicated for the emergency treatment of patients who receive an overdose of fluorouracil or capecitabine, or who develop certain severe or life-threatening toxicities within 4 days of receiving these cancer treatments. Uridine triacetate blocks cell damage and cell death caused by these agents; patients should take Vistogard as soon as possible after the overdose (whether or not they have symptoms) or early-onset toxicity. Safety and efficacy of Vistogard were studied in 135 patients (age range, 1 to 83 years; pediatric n = 6) who were treated in 2 separate trials. Of those treated for overdose (n = 117), survival at 30 days was 97%. Of those treated for early-onset toxicity (n = 18), survival at 30 days was 89%. In both studies, 33% of patients resumed chemotherapy in less than 30 days. Vistogard is not recommended for non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may reduce the efficacy of these drugs. Safety and efficacy if initiated more than 96 hours after the end of fluorouracil or capecitabine administration have not been established. During clinical trials, the most common adverse reactions of Vistogard treatment included vomiting, nausea, and diarrhea. No adverse reactions were reported with Xuriden treatment. Uridine triacetate is FDA-approved for use in pediatric patients with no defined age range; it has been studied in patients as young as 2 months and 1 year for hereditary orotic aciduria and fluorouracil or capecitabine overdose and toxicity, respectively.

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):
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 of 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.
Oral dosage:
Children and Adolescents: 6.2 grams/m2/dose (Max: 10 grams/dose) PO every 6 hours for 20 doses; administer as soon as possible after an overdose. The safety and efficacy of uridine triacetate initiated more than 96 hours after the end of fluorouracil or capecitabine administration have not been established. Uridine triacetate is not recommended for non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may reduce the efficacy of these drugs.

For the 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 after 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.
Oral dosage (Vistogard only):
Children and Adolescents: 6.2 grams/m2/dose (Max: 10 grams/dose) PO every 6 hours for 20 doses; administer as soon as possible after early-onset toxicity presents. The safety and efficacy of uridine triacetate initiated more than 96 hours after the end of fluorouracil or capecitabine administration have not been established. Uridine triacetate is not recommended for non-emergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may reduce the efficacy of these drugs.

Maximum Dosage Limits:
-Infants
120 mg/kg/day PO for hereditary orotic aciduria; safety and efficacy for other indications have not been established.
-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.
-Adolescents
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.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

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 acid 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- 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.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, maximum uridine plasma concentrations are usually achieved within 2 to 3 hours. Food does not affect the overall rate and extent of uridine exposure.

Xuriden: The pharmacokinetics (PK) 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 hour and 465.6 +/- 95.3 micromolar x hour, 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.

Vistogard: Two studies (n = 135, 6 of which were pediatric) 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) after 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.