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Uridine Triacetate

Class: Antidotes
Chemical Name: Uridine 2′,3′,5′-triacetate
Molecular Formula: C15H18N2O9
CAS Number: 4105-38-8
Brands: Vistogard, Xuriden

Introduction

Acetylated prodrug of uridine and a pyrimidine analog; a direct biochemical fluorouracil antagonist and a uridine replacement agent.1 3 9 10

Uses for Uridine Triacetate

Fluorouracil or Capecitabine Overdosage or Toxicity

Emergency treatment following fluorouracil or capecitabine overdosage regardless of presence of symptoms.1 6 7 9 10

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.1 6 10

Designated an orphan drug by FDA for use as an antidote in the treatment of fluorouracil or capecitabine poisoning.2

Not recommended for nonemergency treatment of adverse reactions associated with fluorouracil or capecitabine because it may decrease efficacy of these drugs.1

Safety and efficacy of initiating drug >96 hours after end of fluorouracil or capecitabine administration not established.1

Hereditary Orotic Aciduria

Treatment of hereditary orotic aciduria (designated an orphan drug by FDA for this use).2 3

Uridine Triacetate Dosage and Administration

General

Restricted Distribution Program

  • Must obtain Vistogard through a specialty pharmacy.11 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 () for specific ordering information.11

  • Must obtain Xuriden through a specialty pharmacy.15 Contact manufacturer at 800-914-0071 for availability and ordering information.15

Administration

Oral Administration

Commercially available in the US as Vistogard and Xuriden.1 3

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.1

Weigh pediatric doses using a scale accurate to ≤0.1 g or measure using a graduated teaspoon accurate to one-fourth teaspoonful.1 For patients requiring 10-g doses of uridine triacetate, contents of a full packet may be administered without weighing or measuring.1

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.1 Do not chew granules.1 Follow each dose with ≥120 mL (4 ounces) of water.1

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.1 7 Administration of an antiemetic (e.g., a 5-HT3 receptor antagonist) also may be helpful.7

If a dose is missed, administer missed dose as soon as possible and the next dose at the regularly scheduled time.1

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.1

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.1

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.1

Flush NG or gastrostomy tube with water after administration.1

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.3

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.3

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

May mix granules with 5 mL of milk or infant formula for patients receiving up to three-fourths teaspoonful (2 g).3 Consult manufacturer's instructions for preparing doses of the drug using a medicine cup and oral syringe.3 Administer doses mixed in milk or infant formula using an oral syringe placed between patient's cheek and gum at back of mouth.3 May follow with a bottle of milk or infant formula, if desired.3

Dosage

Dosage of uridine triacetate expressed in terms of the salt.1 3

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.1 (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.1

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

Table 1. Uridine Triacetate (Vistogard) Pediatric Dosing Based on Body Surface Area.

Vistogard 6.2 g/m2 per dose

Body Surface Area (m2)

Dose (g)

Dose (graduated teaspoonsful)

0.34–0.44

2.1–2.7

1

0.45–0.55

2.8–3.4

0.56–0.66

3.5–4.1

0.67–0.77

4.2–4.8

0.78–0.88

4.9–5.4

2

0.89–0.99

5.5–6.1

1–1.1

6.2–6.8

1.11–1.21

6.9–7.5

1.22–1.32

7.6–8.1

3

1.33–1.43

8.2–8.8

≥1.44

10

1 full 10-g packet

Hereditary Orotic Aciduria
Oral

Initially, 60 mg/kg once daily.3 (See Table 2.)

Note: One packet of Xuriden granules contains 2 g (approximately three-fourths teaspoon) of uridine triacetate.3 Total daily dosages by weight category in this table were rounded to achieve the approximate dosage level.3

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.

Table 2. Initial Uridine Triacetate (Xuriden) 60 mg/kg Daily Dosage Based on Body Weight.

Xuriden 60 mg/kg Daily Dosage

Patient weight (in kg)

Dose (in grams using a scale)

Dose (in teaspoonsful)

≤5

0.4

1/8

6–10

0.4–0.6

¼

11–15

0.7–0.9

½

16–20

1–1.2

½

21–25

1.3–1.5

½

26–30

1.6–1.8

¾

31–35

1.9–2.1

¾

36–40

2.2–2.4

1

41–45

2.5–2.7

1

46–50

2.8–3

1

51–55

3.1–3.3

56–60

3.4–3.6

61–65

3.7–3.9

66–70

4–4.2

71–75

4.3–4.5

>75

6

2

May increase dosage to 120 mg/kg (not to exceed 8 g) once daily for insufficient response.3 (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.3

Note: One packet of Xuriden granules contains 2 g (approximately three-fourths teaspoon) of uridine triacetate.3 Total daily dosages by weight category in this table were rounded to achieve the approximate dosage level.3

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.

Table 3. Increased Uridine Triacetate (Xuriden) 120 mg/kg Daily Dosage for Insufficient Response Based on Body Weight.3

Xuriden 120 mg/kg Daily Dosage

Patient weight (in kg)

Dose (in grams using a scale)

Dose (in teaspoonsful)

≤5

0.8

¼

6–10

0.8–1.2

½

11–15

1.4–1.8

¾

16–20

2–2.4

1

21–25

2.6–3

1

26–30

3.2–3.6

31–35

3.8–4.2

36–40

4.4–4.8

41–45

5–5.4

2

46–50

5.6–6

2

51–55

6.2–6.6

56–60

6.8–7.2

61–65

7.4–7.8

66–70

8

71–75

8

>75

8

Adults

Fluorouracil or Capecitabine Overdosage or Toxicity
Oral

10 g every 6 hours for 20 doses.1

Hereditary Orotic Aciduria
Oral

Initially, 60 mg/kg once daily.3 (See Table 2.)

May increase dosage to 120 mg/kg (not to exceed 8 g) once daily for insufficient response.3 (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.3

Prescribing Limits

Pediatric Patients

Fluorouracil or Capecitabine Overdosage or Toxicity
Oral

10 g/dose.1

Hereditary Orotic Aciduria
Oral

8 g daily.3

Adults

Fluorouracil or Capecitabine Overdosage or Toxicity
Oral

10 g/dose.1

Hereditary Orotic Aciduria
Oral

8 g daily.3

Special Populations

Dosage adjustment not necessary based on age, body size, race, or gender in adults.6

Cautions for Uridine Triacetate

Contraindications

  • Manufacturer states none known.1 3

Warnings/Precautions

Warnings and Precautions

Manufacturer states there are no warnings or precautions associated with uridine triacetate therapy.1 3

Specific Populations

Pregnancy

Limited case reports of uridine triacetate use during pregnancy are insufficient to inform of drug-associated risk.1 3

Animal studies have not revealed evidence of teratogenicity or fetal harm.1 3

Lactation

Not known whether uridine triacetate distributed into human milk; effects of drug on breast-fed infants or milk production also not known.1 3

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.1 3

Pediatric Use

Safety and efficacy have been established in pediatric patients.1 3

Clinical response and safety in adults and pediatric patients are similar; however, data are limited.1 3

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond to uridine triacetate (Vistogard) differently than younger adults.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Fluorouracil or capecitabine overdosage or toxicity: Vomiting,1 nausea,1 diarrhea.1

Hereditary orotic aciduria: No adverse effects reported.3

Interactions for Uridine Triacetate

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

Weak substrate for P-glycoprotein (P-gp).1 3 6

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important interactions with inhibitors or inducers of CYP isoenzymes unlikely.1 3 14

Drugs Affecting or Affected by the P-glycoprotein Transport System

Substrates of P-gp: Potential pharmacokinetic interaction with orally administered P-gp substrates.1 3

Specific Drugs

Drug

Interaction

Comments

Bismuth subsalicylate

Clinically important pharmacokinetic interaction unlikely15

Capecitabine

Uridine triacetate is used as an antidote for capecitabine overdosage or toxicity; possible decreased capecitabine efficacy1 6

Cholestyramine

Clinically important pharmacokinetic interaction unlikely15

Digoxin

Potential pharmacokinetic interaction; uridine triacetate inhibited transport of digoxin (a P-gp substrate) in vitro1 3

Fluorouracil

Uridine triacetate is used as an antidote for fluorouracil overdosage or toxicity; possible decreased fluorouracil efficacy1 6 but effect on antitumor activity of fluorouracil not known6

Sucralfate

Clinically important pharmacokinetic interaction unlikely15

Uridine Triacetate Pharmacokinetics

Absorption

Bioavailability

Uridine triacetate provides fourfold to sixfold more uridine into systemic circulation than equimolar oral doses of uridine.1 3 7

Peak plasma uridine concentrations generally achieved within 2–3 hours following single-dose, oral administration of uridine triacetate.1 3 6

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.1 3 6

Distribution

Extent

Circulating uridine taken up by mammalian cells via specific nucleoside transporters.1 3

Not known whether distributed into human milk.1 3

Crosses the blood-brain barrier.1 3

Elimination

Metabolism

Uridine triacetate is a prodrug; deacetylated by nonspecific esterases throughout the body to uridine.1 3 7

Elimination Route

May be excreted by kidneys; also metabolized by normal pyrimidine catabolic pathways present in most tissues.1 3

Half-life

Approximately 2–2.5 hours.1 3 6

Special Populations

Although trend toward increased clearance with increasing body surface area noted in adults,6 no clinically important effect on uridine pharmacokinetics based on body size in adults.1

No clinically important effect on uridine pharmacokinetics based on age (range: 20–83 years), race, or gender in adults.1 6

Stability

Storage

Oral

Granules

25°C (may be exposed to 15–30°C).1 3

Once Vistogard granules are mixed with soft food, use within 30 minutes.1

Once Xuriden granules are mixed with soft food, milk, or infant formula, use immediately.3

Actions

  • Pyrimidine analog; acetylated prodrug of uridine.1 3 9

  • In fluorouracil or capecitabine overdosage or toxicity, uridine triacetate acts as a direct biochemical antagonist of fluorouracil.1 9 10 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.1 9

  • In hereditary orotic aciduria, uridine triacetate provides an exogenous source of uridine for replacement therapy in patients who are unable to synthesize adequate quantities.3 Uridine can be used for the synthesis of uridine nucleotides by essentially all cells.3 Feedback inhibition from restoration of intracellular uridine nucleotide concentrations to normal range limits overproduction of orotic acid and reduces urinary excretion of orotic acid.3

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).1 3

  • 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).1 3

  • Granules should not be chewed; granules may be mixed with food (e.g., applesauce, pudding, yogurt).1 3 Xuriden also may be mixed in milk or infant formula.3 Discard any unused portion of granules in a packet after measuring out the appropriate dose.1 3

  • Importance of patients completing the full course of Vistogard treatment (i.e., 20 doses) even if they feel well.1 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.1 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.1

  • 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.1 3

  • Importance of advising women receiving uridine triacetate to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1 3

  • Importance of informing patients of other important precautionary information.1 3 (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.11 15 (See Restricted Distribution Program under Dosage and Administration.)

Uridine Triacetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Granules

2 g (of uridine triacetate) per packet

Xuriden

Wellstat

10 g (of uridine triacetate) per packet

Vistogard

Wellstat, (marketed by BTG)

AHFS DI Essentials. © Copyright 2017, Selected Revisions April 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Wellstat Therapeutics Corporation. Vistogard (uridine triacetate) oral granules prescribing information. Gaithersburg, MD; 2015 Dec.

2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Jul 18.

3. Wellstat Therapeutics Corporation. Xuriden (uridine triacetate) oral granules prescribing information. Gaithersburg, MD; 2015 Sep.

4. Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005 Sep-Oct; 86:25-33. [PubMed 16176880]

5. . In brief: Uridine triacetate (Xuriden) for hereditary orotic aciduria. Med Lett Drugs Ther. 2016; 58:e49. [PubMed 27027693]

6. Ison G, Beaver JA, McGuinn WD et al. FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs. Clin Cancer Res. 2016; 22:4545-9. [PubMed 27401247]

7. McEvilly M, Popelas C, Tremmel B. Use of uridine triacetate for the management of fluorouracil overdose. Am J Health Syst Pharm. 2011; 68:1806-9. [PubMed 21930638]

8. O'Malley PA. Vistogard (Uridine Triacetate): The First and Only Drug Approved for the Treatment of 5-Fluorouracil or Capecitabine Overdose: Implications for the Clinical Nurse Specialist. Clin Nurse Spec. 2016 May-Jun; 30:145-7. [PubMed 27055035]

9. von Borstel R, O'Neil J, Bamat M. Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. J Clin Oncol. 2009; 27: Abstract 9616 (presented at the 2009 ASCO annual meeting).

10. Bamat MK, Tremmel R, von Borstel R et al. Clinical experience with uridine triacetate for 5-FU overexposure: an update. J Clin Oncol. 2013; 31: Abstract e20592 (presented at the 2013 ASCO annual meeting).

11. Wellstat Therapeutics Corporation. Vistogard (uridine triacetate) oral granules: ordering information. 2016 May. Accessed 2016 Sep 29.

12. Food and Drug Administration. FDA news release: FDA approves new orphan drug to treat rare autosomal recessive disorder. Silver Spring, MD. From FDA website. Accessed 2016 Sep 29.

13. Saif MW, Diasio RB. Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency. Cancer Chemother Pharmacol. 2016; 78:151-6. [PubMed 27278667]

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208169Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

15. Wellstat Therapeutics, Cincinnati, OH: Personal communication.

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