Uridine Triacetate (Monograph)

Brand names: Vistogard, Xuriden
Drug class: Antidotes
Chemical name: Uridine 2′,3′,5′-triacetate
Molecular formula: C₁₅H₁₈N₂O₉
CAS number: 4105-38-8

Introduction

Acetylated prodrug of uridine and a pyrimidine analog; a direct biochemical fluorouracil antagonist and a uridine replacement agent.

Uses for Uridine Triacetate

Fluorouracil or Capecitabine Overdosage or Toxicity

Emergency treatment following fluorouracil or capecitabine overdosage regardless of presence of symptoms.

Treatment of early-onset, severe or life-threatening toxicity affecting the cardiac system or CNS and/or early-onset, unusually severe adverse reactions (e.g., GI toxicity, neutropenia) ≤96 hours following the end of fluorouracil or capecitabine administration.

Designated an orphan drug by FDA for use as an antidote in the treatment of fluorouracil or capecitabine poisoning.

Not recommended for nonemergency treatment of adverse reactions associated with fluorouracil or capecitabine because it may decrease efficacy of these drugs.

Safety and efficacy of initiating drug >96 hours after end of fluorouracil or capecitabine administration not established.

Hereditary Orotic Aciduria

Treatment of hereditary orotic aciduria (designated an orphan drug by FDA for this use).

Related/similar drugs

uridine, Vistogard

Uridine Triacetate Dosage and Administration

General

Restricted Distribution Program

• Must obtain Vistogard through a specialty pharmacy. Contact specialty pharmacy at 844-293-0007 (for inpatient use) or 844-374-0604 (for outpatient use and information on the case management program) or consult the Vistogard website ([Web]) for specific ordering information.

• Must obtain Xuriden through a specialty pharmacy. Contact manufacturer at 800-914-0071 for availability and ordering information.

Administration

Oral Administration

Commercially available in the US as Vistogard and Xuriden.

Vistogard Granules

Begin treatment as soon as possible following overdosage or early-onset toxicity; administer ≤96 hours following the end of fluorouracil or capecitabine administration.

Weigh pediatric doses using a scale accurate to ≤0.1 g or measure using a graduated teaspoon accurate to one-fourth teaspoonful. For patients requiring 10-g doses of uridine triacetate, contents of a full packet may be administered without weighing or measuring.

Mix each dose with 3–4 ounces of a soft food (e.g., applesauce, pudding, yogurt) and administer orally ≤30 minutes of mixing, without regard to meals. Do not chew granules. Follow each dose with ≥120 mL (4 ounces) of water.

If patient vomits ≤2 hours after receiving dose (either due to capecitabine or fluorouracil toxicity or slightly bitter taste of the granules), administer another full dose as soon as possible after vomiting episode; administer the next dose at the regularly scheduled time. Administration of an antiemetic (e.g., a 5-HT₃ receptor antagonist) also may be helpful.

If a dose is missed, administer missed dose as soon as possible and the next dose at the regularly scheduled time.

NG or Gastrostomy Tube Vistogard Administration

Prepare about 100 mL (approximately 4 fluid ounces) of food starch-based thickening product in water and stir briskly until dissolved.

Crush contents of one full 10-g packet of Vistogard granules to a fine powder and add to the reconstituted food starch-based thickening product.

For pediatric patients receiving doses of <10 g, prepare the mixture in a ratio not exceeding uridine triacetate 1 g to 10 mL of reconstituted food starch-based thickening product and mix thoroughly.

Flush NG or gastrostomy tube with water after administration.

Xuriden Granules

Weigh doses using a scale accurate to ≤0.1 g or measure using a graduated teaspoon accurate to the fraction of the dose to be administered.

For patients requiring doses of uridine triacetate in multiples of 2 g (i.e., three-fourths teaspoonful), contents of the required number of full 2-g packets may be administered without weighing or measuring.

Mix each dose with 3–4 ounces of applesauce, pudding, or yogurt. Do not chew granules. Follow each dose with ≥120 mL (≥4 ounces) of water.

May mix granules with 5 mL of milk or infant formula for patients receiving up to three-fourths teaspoonful (2 g). Consult manufacturer's instructions for preparing doses of the drug using a medicine cup and oral syringe. Administer doses mixed in milk or infant formula using an oral syringe placed between patient's cheek and gum at back of mouth. May follow with a bottle of milk or infant formula, if desired.

Dosage

Dosage of uridine triacetate expressed in terms of the salt.

Pediatric Patients

Fluorouracil or Capecitabine Overdosage or Toxicity

Oral

6.2 g/m² (not to exceed 10 g/dose) every 6 hours for 20 doses. (See Table 1.)

Note: One packet of Vistogard granules contains 10 g of uridine triacetate. Dose by body surface area in this table was rounded to achieve the approximate dose. Each dose is administered every 6 hours for 20 doses.

One entire 10-g packet may be used without weighing or measuring.

Hereditary Orotic Aciduria

Oral

Initially, 60 mg/kg once daily. (See Table 2.)

Note: One packet of Xuriden granules contains 2 g (approximately three-fourths teaspoon) of uridine triacetate. Total daily dosages by weight category in this table were rounded to achieve the approximate dosage level.

One entire 2-g packet may be used without weighing or measuring.

Two entire 2-g packets may be used without weighing or measuring.

Three entire 2-g packets may be used without weighing or measuring.

May increase dosage to 120 mg/kg (not to exceed 8 g) once daily for insufficient response. (See Table 3.) Signs of insufficient response may include urinary concentrations of orotic acid that remain above normal or increase above the usual or expected range for the patient, worsening of laboratory parameters affected by hereditary orotic aciduria (e.g., RBC or WBC indices), or worsening of other manifestations.

Note: One packet of Xuriden granules contains 2 g (approximately three-fourths teaspoon) of uridine triacetate. Total daily dosages by weight category in this table were rounded to achieve the approximate dosage level.

Two entire 2-g packets may be used without weighing or measuring.

Three entire 2-g packets may be used without weighing or measuring.

Four entire 2-g packets may be used without weighing or measuring.

Adults

Fluorouracil or Capecitabine Overdosage or Toxicity

Oral

10 g every 6 hours for 20 doses.

Hereditary Orotic Aciduria

Oral

Initially, 60 mg/kg once daily. (See Table 2.)

May increase dosage to 120 mg/kg (not to exceed 8 g) once daily for insufficient response. (See Table 3.) Signs of insufficient response may include urinary concentrations of orotic acid that remain above normal or increase above the usual or expected range for the patient, worsening of laboratory parameters affected by hereditary orotic aciduria (e.g., RBC or WBC indices), or worsening of other manifestations.

Prescribing Limits

Pediatric Patients

Fluorouracil or Capecitabine Overdosage or Toxicity

Oral

10 g/dose.

Hereditary Orotic Aciduria

Oral

8 g daily.

Adults

Fluorouracil or Capecitabine Overdosage or Toxicity

Oral

10 g/dose.

Hereditary Orotic Aciduria

Oral

8 g daily.

Special Populations

Dosage adjustment not necessary based on age, body size, race, or gender in adults.

Cautions for Uridine Triacetate

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Warnings and Precautions

Manufacturer states there are no warnings or precautions associated with uridine triacetate therapy.

Specific Populations

Pregnancy

Limited case reports of uridine triacetate use during pregnancy are insufficient to inform of drug-associated risk.

Animal studies have not revealed evidence of teratogenicity or fetal harm.

Lactation

Not known whether uridine triacetate distributed into human milk; effects of drug on breast-fed infants or milk production also not known.

Consider benefits of breast-feeding and the woman's clinical need for the drug; also consider potential adverse effects on breast-fed infant from drug or underlying maternal condition.

Pediatric Use

Safety and efficacy have been established in pediatric patients.

Clinical response and safety in adults and pediatric patients are similar; however, data are limited.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond to uridine triacetate (Vistogard) differently than younger adults. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Fluorouracil or capecitabine overdosage or toxicity: Vomiting, nausea, diarrhea.

Hereditary orotic aciduria: No adverse effects reported.

Drug Interactions

Uridine triacetate and uridine do not inhibit CYP isoenzymes 3A4, 1A2, 2C8, 2C9, 2C19, 2D6, or 2E1. Neither uridine triacetate nor uridine induces CYP isoenzymes 1A2, 2B6, or 3A4.

Weak substrate for P-glycoprotein (P-gp).

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions with inhibitors or inducers of CYP isoenzymes unlikely.

Drugs Affecting or Affected by the P-glycoprotein Transport System

Substrates of P-gp: Potential pharmacokinetic interaction with orally administered P-gp substrates.

Specific Drugs

Uridine Triacetate Pharmacokinetics

Absorption

Bioavailability

Uridine triacetate provides fourfold to sixfold more uridine into systemic circulation than equimolar oral doses of uridine.

Peak plasma uridine concentrations generally achieved within 2–3 hours following single-dose, oral administration of uridine triacetate.

Food

No difference in overall rate and extent of uridine exposure under fed and fasted conditions in healthy adults receiving a slightly different granule formulation.

Distribution

Extent

Circulating uridine taken up by mammalian cells via specific nucleoside transporters.

Not known whether distributed into human milk.

Crosses the blood-brain barrier.

Elimination

Metabolism

Uridine triacetate is a prodrug; deacetylated by nonspecific esterases throughout the body to uridine.

Elimination Route

May be excreted by kidneys; also metabolized by normal pyrimidine catabolic pathways present in most tissues.

Half-life

Approximately 2–2.5 hours.

Special Populations

Although trend toward increased clearance with increasing body surface area noted in adults, no clinically important effect on uridine pharmacokinetics based on body size in adults.

No clinically important effect on uridine pharmacokinetics based on age (range: 20–83 years), race, or gender in adults.

Stability

Storage

Oral

Granules

25°C (may be exposed to 15–30°C).

Once Vistogard granules are mixed with soft food, use within 30 minutes.

Once Xuriden granules are mixed with soft food, milk, or infant formula, use immediately.

Actions

• Pyrimidine analog; acetylated prodrug of uridine.

• In fluorouracil or capecitabine overdosage or toxicity, uridine triacetate acts as a direct biochemical antagonist of fluorouracil. Excess circulating uridine derived from uridine triacetate is converted into uridine triphosphate (UTP), which competes with 5-fluorouridine triphosphate (FUTP; a cytotoxic intermediate metabolite of fluorouracil) for incorporation into RNA, thereby inhibiting cell damage and cell death.

• In hereditary orotic aciduria, uridine triacetate provides an exogenous source of uridine for replacement therapy in patients who are unable to synthesize adequate quantities. Uridine can be used for the synthesis of uridine nucleotides by essentially all cells. Feedback inhibition from restoration of intracellular uridine nucleotide concentrations to normal range limits overproduction of orotic acid and reduces urinary excretion of orotic acid.

Advice to Patients

• Importance of providing patients or their caregivers with a copy of the manufacturer’s patient information (Vistogard) or instructions for use (Xuriden).

• For Vistogard or Xuriden doses less than the entire contents of a packet, importance of weighing or measuring the prescribed dose using appropriate equipment (e.g., a scale accurate to ≤0.1 g, a graduated teaspoon accurate to one-fourth teaspoonful or the fraction of the dose to be administered).

• Granules should not be chewed; granules may be mixed with food (e.g., applesauce, pudding, yogurt). Xuriden also may be mixed in milk or infant formula. Discard any unused portion of granules in a packet after measuring out the appropriate dose.

• Importance of patients completing the full course of Vistogard treatment (i.e., 20 doses) even if they feel well. If a patient vomits ≤2 hours after receiving a dose of Vistogard, another full dose should be administered as a replacement as soon as possible after the vomiting episode and the next dose should be administered at the regularly scheduled time. If a dose of Vistogard is missed, the missed dose should be administered as soon as possible and the next dose should be administered at the regularly scheduled time.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of advising women receiving uridine triacetate to inform clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of uridine triacetate (Vistogard and Xuriden) is restricted. (See Restricted Distribution Program under Dosage and Administration.)

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