Uridine triacetate for Orotic aciduria

Uridine triacetate (vistogard, Xuriden) is an orphan drug that is used in the treatment of hereditary orotic aciduria. It is also used in the emergency treatment of overdose of fluorouracil or capecitabine (regardless of the presence of symptoms) or severe or life-threatening early onset cardiac or CNS toxicity and unusually severe adverse reactions of early-onset (eg, neutropenia and GI tract within 96 hours following the end of fluorouracil or capecitabine administration (in pediatrics and adults).

Limitations of use:

It is not recommended for non-emergency treatment of adverse reactions associated with capecitabine or fluorouracil or (because the efficacy of these medications may be diminished).
Safety and efficacy of uridine triacetate started more than 96 hours following the end of the administration of fluorouracil or capecitabine have not been established.

Uridine Triacetate Dose in Adults

Dose in the treatment of Fluoropyrimidine overdose/overexposure:

Initiate within 96 hours after the end of fluorouracil or capecitabine administration:
- 10 g per oral every 6 hours for 20 doses beginning as soon as possible after an overdose or early-onset toxicity.
- Administer the full course of 20 doses, even if the patient appears or feels well.
Off-label: >96 hours after the end of fluorouracil or capecitabine administration (based on limited data):
- Uridine triacetate may be effective in managing severe GI, hematologic, cardiac, and neurologic toxicities when initiated beyond 96 hours following the end of fluorouracil/capecitabine administration.
- Case reports of use >96 hours post fluorouracil/capecitabine administration described an improvement in severe toxicity associated with these agents.
- One patient was later determined to be homozygous for dihydropyrimidine dehydrogenase gene mutation and another patient was later found to have a thymidylate synthase gene variation (Baldeo 2018; Zurayk 2019).

Dose in the treatment of Hereditary orotic aciduria:

Oral: Initial:
- 60 mg/kg once daily.
- Increase the dose to 120 mg/kg (maximum: 8 g) for insufficient efficacy (eg, urine orotic acid levels remaining above normal or increasing above the usual/expected range for the patient, lab values affected by orotic acid [red or white blood cell indices] worsening, or worsening disease signs/symptoms).

Daily dose of Uridine Triacetate for Hereditary Orotic Aciduria Based on Weight (kg)

Patient weight	60 mg/kg1 dose Dose in grams (dose in teaspoons2)	120 mg/kg1 dose Dose in grams (dose in teaspoons2)
≤5 kg	0.4 g (1/8 tsp)	0.8 g (1/4 tsp)
6 to 10 kg	0.4 to 0.6 g (1/4 tsp)	0.8 to 1.2 g (1/2 tsp)
11 to 15 kg	0.7 to 0.9 g (1/2 tsp)	1.4 to 1.8 g (3/4 tsp or 1 entire packet)
16 to 20 kg	1 to 1.2 g (1/2 tsp)	2 to 2.4 g (1 tsp)
21 to 25 kg	1.3 to 1.5 g (1/2 tsp)	2.6 to 3 g (1 tsp)
26 to 30 kg	1.6 to 1.8 g (3/4 tsp or 1 entire packet)	3.2 to 3.6 g (11/4 tsp)
31 to 35 kg	1.9 to 2.1 g (3/4 tsp or 1 entire packet)	3.8 to 4.2 g (11/2 tsp or 2 entire packets)
36 to 40 kg	2.2 to 2.4 g (1 tsp)	4.4 to 4.8 g (13/4 tsp)
41 to 45 kg	2.5 to 2.7 g (1 tsp)	5 to 5.4 g (2 tsp or 3 entire packets)
46 to 50 kg	2.8 to 3 g (1 tsp)	5.6 to 6 g (2 tsp or 3 entire packets)
51 to 55 kg	3.1 to 3.3 g (11/4 tsp)	6.2 to 6.6 g (21/4 tsp)
56 to 60 kg	3.4 to 3.6 g (11/4 tsp)	6.8 to 7.2 g (21/2 tsp)
61 to 65 kg	3.7 to 3.9 g (11/2 tsp or 2 entire packets)	7.4 to 7.8 g (21/2 tsp)
66 to 70 kg	4 to 4.2 g (11/2 tsp or 2 entire packets)	8 g (23/4 tsp or 4 entire packets)
71 to 75 kg	4.3 to 4.5 g (11/2 tsp or 2 entire packets)	8 g (23/4 tsp or 4 entire packets)
>75 kg	6 g (2 tsp or 3 entire packets)	8 g (23/4 tsp or 4 entire packets)
Note: One packet contains uridine triacetate 2 g.
1Doses rounded (by the manufacturer) by weight category to achieve approximate dose level
2A 2 gram uridine triacetate (Xuriden) packet contains approximately 3/4 tsp

Uridine Triacetate Dose in Childrens

Note: Package (packet) size of products is different (Vistogard: 10 g/packet, Xuridine: 2 g/packet of uridine triacetate). Use caution with product selection and calculations.

Dose in the treatment of Fluoropyrimidine (fluorouracil/ capecitabine ) overdose/overexposure:

Children and Adolescents:
- Vistogard: Oral:
  - 6.2 g/m (maximum dose: 10 g/dose [1 packet]) every 6 hours for 20 doses beginning as soon as possible after an overdose or early-onset toxicity within 96 hours after the end of fluorouracil or capecitabine administration.
  - It may be dosed as g or teaspoon.
  - Measure the dose using either a scale (accurate to at least 0.1 g) or a graduated teaspoon (accurate to / teaspoon).
  - See table for BSA range dose recommendations (including rounding) for g and teaspoon doses.
  - Note: Administer the full course of 20 doses, even if the patient appears or feels well.

Uridine Triacetate Dose (g or teaspoons) Based on Body Surface Area (BSA in m2)

Patient BSA	Dose of Uridine Triacetate (Vistogard) 6.2 g/m2/dosea
Patient BSA	Dose in grams	Dose in graduated teaspoons
0.34 to 0.44 m2	2.1 to 2.7 g	1 tsp
0.45 to 0.55 m2	2.8 to 3.4 g	1 1/4 tsp
0.56 to 0.66 m2	3.5 to 4.1 g	1 1/2 tsp
0.67 to 0.77 m2	4.2 to 4.8 g	1 3/4 tsp
0.78 to 0.88 m2	4.9 to 5.4 g	2 tsp
0.89 to 0.99 m2	5.5 to 6.1 g	2 1/4 tsp
1 to 1.1 m2	6.2 to 6.8 g	2 1/2 tsp
1.11 to 1.21 m2	6.9 to 7.5 g	2 3/4 tsp
1.22 to 1.32 m2	7.6 to 8.1 g	3 tsp
1.33 to 1.43 m2	8.2 to 8.8 g	3 1/4 tsp
≥1.44 m2	10 g b	1 full packetb
Note: One Vistogard packet contains uridine triacetate 10 g.
aDoses rounded by BSA to achieve approximate dose; administer each dose every 6 hours for 20 doses. bMay use 1 entire 10 g packet without weighing or measuring. Do not exceed 10 g/dose

Dose in the treatment of Hereditary orotic aciduria:

Infants, Children, and Adolescents:
- Oral: Xuridine:
  - Initial: 60 mg/kg once daily.
  - The dose may be increased to 120 mg/kg up to a maximum daily dose of 8 g/day) for insufficient efficacy (eg, urine orotic acid levels remaining above normal or increased above the usual/expected range for the patient, lab values affected by orotic aciduria [red or white blood cell indices] worsening, or worsening disease signs/symptoms).
  - It may be dosed as g or teaspoon.
  - Measure the dose using either a scale (accurate to at least 0.1 g) or a graduated teaspoon (accurate to the fraction being measured).

See table for weight-band dosing (including dose rounding).

Uridine Triacetate (Xuridine) Dose (g or teaspoons) Based on Body Weight (kg)
Patient weight	60 mg/kga dose Dose in grams (dose in teaspoonsb)	120 mg/kga dose Dose in grams (dose in teaspoonsb)

≤5 kg	0.4 g (1/8 tsp)	0.8 g(1/4 tsp)
6 to 10 kg	0.4 to 0.6 g (1/4 tsp)	0.8 to 1.2 g (1/2 tsp)
11 to 15 kg	0.7 to 0.9 g (1/2 tsp)	1.4 to 1.8 g (3/4 tsp or 1 entire packet)
16 to 20 kg	1 to 1.2 g (1/2 tsp)	2 to 2.4 g (1 tsp)
21 to 25 kg	1.3 to 1.5 g (1/2 tsp)	2.6 to 3 g (1 tsp)
26 to 30 kg	1.6 to 1.8 g (3/4 tsp or 1 entire packet)	3.2 to 3.6 g (11/4 tsp)
31 to 35 kg	1.9 to 2.1 g (3/4 tsp or 1 entire packet)	3.8 to 4.2 g (11/2 tsp or 2 entire packets)
36 to 40 kg	2.2 to 2.4 g (1 tsp)	4.4 to 4.8 g (13/4 tsp)
41 to 45 kg	2.5 to 2.7 g (1 tsp)	5 to 5.4 g (2 tsp or 3 entire packets)
46 to 50 kg	2.8 to 3 g (1 tsp)	5.6 to 6 g (2 tsp or 3 entire packets)
51 to 55 kg	3.1 to 3.3 g (11/4 tsp)	6.2 to 6.6 g (21/4 tsp)
56 to 60 kg	3.4 to 3.6 g (11/4 tsp)	6.8 to 7.2 g (21/2 tsp)
61 to 65 kg	3.7 to 3.9 g (11/2 tsp or 2 entire packets)	7.4 to 7.8 g (21/2 tsp)
66 to 70 kg	4 to 4.2 g (11/2 tsp or 2 entire packets)	8 g (23/4 tsp or 4 entire packets)
71 to 75 kg	4.3 to 4.5 g (11/2 tsp or 2 entire packets)	8 g (23/4 tsp or 4 entire packets)
>75 kg	6 g (2 tsp or 3 entire packets)	8 g (23/4 tsp or 4 entire packets)
aDoses rounded (by the manufacturer) by weight category to achieve approximate dose level
bA 2 gram of uridine triacetate (Xuriden) packet contains 3/4 tsp approximately

Dose in Pregnancy and Lactation: C

In animal reproduction studies adverse events were not observed.
Information related to the use of uridine triacetate for the treatment of hereditary orotic aciduria and fluoropyrimidine overdose/severe (life-threatening) toxicity during pregnancy is limited.
Monitor closely as dose adjustments may be required.
In general, medications used as antidotes should take into consideration the health and prognosis of the mother.
Antidotes should be administered to pregnant females if there is a clear indication for use and should not be withheld because of fears of teratogenicity.

Uridine triacetate use during breastfeeding:

It is not known if uridine triacetate is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.

Uridine Triacetate Dose in Renal Disease:

The manufacturer has not recommended any adjustment in the dose in patients with renal disease.

Uridine Triacetate Dose in Liver Disease:

The manufacturer has not recommended any adjustment in the dose in patients with liver disease.

Side Effects of Uridine triacetate Include:

Gastrointestinal:
- Vomiting
- Nausea
- Diarrhea

Contraindication to Uridine triacetate Include:

There are no contraindications listed in the manufacturer's labeling.

Warnings and Precautions

There are no warnings listed in the manufacturer's labeling.

Monitor:

Fluoropyrimidine overdose/overexposure:

CBC with differential counts
gastrointestinal toxicity

How to administer Uridine triacetate?

Granules:

The prescribed dose should be measured using either a graduated teaspoon, accurate to the fraction of the dose to be administered (accurate to / teaspoonful) or by using a scale accurate to at least 0.1 grams.
Discard the unused portion of the granule packet after measuring out the dose.
Do not chew granules.
It may be administered without regard to meals (food does not have an effect on uridine exposure).

Fluoropyrimidine overdose/overexposure:

Administer orally; begin as soon as possible after an overdose or early-onset toxicity within 96 hours following the end of fluorouracil or capecitabine overdose/overexposure.
Based on limited data, uridine triacetate may be effective in managing severe toxicities when initiated beyond 96 hours (off-label) after fluorouracil or capecitabine administration.
Administer within 30 minutes of preparation (in soft food such as applesauce, pudding, or yogurt), followed by at least 120 mL water.
If vomiting occurs within 2 hours of taking the dose, administrationof another complete dose as soon as possible after vomiting episode should be done.
If a dose is missed, administer the missed dose as soon as possible and then administer the next dose at the regularly scheduled time.
If necessary to administer through a nasogastric or gastrostomy tube (due to stomatitis or mucositis), mix with a thickening agent.
Following administration, flush the tube with water. Administer the full treatment course (all 20 doses), even if the patient appears or feels well.

Hereditary orotic aciduria:

May be mixed in food (ie, 3 to 4 ounces of applesauce, pudding, or yogurt) and administered immediately, followed by drinking at least 120 mL water.
Do not chew the granules.
Do not save for later use.

Mechanism of action of Uridine triacetate:

Uridine triacetate is an acetylated form of uridine which is deacetylated following administration to provide circulating uridine in patients with hereditary orotic aciduria.
In patients with fluorouracil overdose or overexposure, uridine triacetate is a direct chemical antagonist against fluorouracil toxicity.
Uridine reduces the incorporation of fluorouridine triphosphate (FUTP; a fluorouracil metabolite) into RNA of hematopoietic progenitor cells and gastrointestinal mucosal cells to reduce fluorouracil toxicity in normal tissues.

The onset of action: It takes 2 - 3 weeks for the hematologic abnormalities to improve after oral intake. The urinary orotic acid is reduced within 1 to 2 weeks of initiating therapy.

Duration of action: The hematologic abnormalities and orotic aciduria return within days to weeks after discontinuation or after reducing the dose.

Distribution: It is distributes into the cells and crosses the blood-brain barrier

Metabolism: It is deacetylated (by nonspecific esterases) to uridine and free acetate.

Half-life elimination: 2 to 2.5 hours

Time to reach peak serum concentration: 2 to 3 hours

Excretion is via Urine. It is also metabolized in tissues.