Hereditary orotic aciduria is treated with the orphan medication uridine triacetate (vistogard, Xuriden). Additionally, it is used to treat severe or life-threatening early-onset cardiac or CNS toxicity as well as unusually severe adverse reactions of early onset (such as neutropenia and GI tract within 96 hours following the end of fluorouracil or capecitabine administration), regardless of the presence of symptoms (in paediatrics 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 Adult

Uridine Triacetate Dose in the treatment of Fluoropyrimidine overdose/overexposure:  

Within 96 hours after fluorouracil or capecitabine administration:

• Dose: Oral intake of 10 grams every 6 hours for a total of 20 doses.
• Initiation: Start the treatment as soon as possible after overdose or early-onset toxicity.
• Duration: Administer the full course of 20 doses, even if the patient seems to be doing well.

Off-label use beyond 96 hours:

• Condition: Uridine triacetate may still be effective for severe gastrointestinal (GI), hematologic, cardiac, and neurologic toxicities.
• Based on limited data: Reports suggest improvement in severe toxicity even when started more than 96 hours after fluorouracil/capecitabine administration.
• Cases: Some patients with severe toxicity were found to have genetic mutations associated with the metabolism of these agents.
• Dose and schedule: Follow the same dosage and schedule as within 96 hours, if used off-label.

Uridine Triacetate Dose in the treatment of Hereditary orotic aciduria:

For treating hereditary orotic aciduria with uridine triacetate, the dose depends on the patient's weight:

• Initial Dose: 60 milligrams per kilogram (mg/kg) once daily orally.
• Increase for Insufficient Efficacy: Up to 120 mg/kg (maximum 8 grams) if needed. This might be necessary if urine orotic acid levels remain high or if the disease symptoms worsen.

The daily dose based on weight:

• For Patients Weighing 5 kg or Less:
  • Initial Dose: 0.4 grams (1/8 teaspoon)
  • Increased Dose: 0.8 grams (1/4 teaspoon)
• For Patients Weighing 6 to 10 kg:
  • Initial Dose: 0.4 to 0.6 grams (1/4 teaspoon)
  • Increased Dose: 0.8 to 1.2 grams (1/2 teaspoon)
• For Patients Weighing 11 to 15 kg:
  • Initial Dose: 0.7 to 0.9 grams (1/2 teaspoon)
  • Increased Dose: 1.4 to 1.8 grams (3/4 teaspoon or 1 entire packet)
• And so on, up to patients weighing more than 75 kg:
  • Where the initial dose ranges from 3.7 to 6 grams (1 1/2 to 2 teaspoons or 2 entire packets) and the increased dose is 8 grams (2 3/4 teaspoons or 4 entire packets).
• Each packet contains 2 grams of uridine triacetate (Xuriden), approximately equivalent to 3/4 teaspoon.
• The doses are rounded by the manufacturer to ensure approximate levels according to weight categories.

Uridine Triacetate Dose in Children

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.

Uridine Triacetate dose in the treatment of Fluoropyrimidine (fluorouracil/ capecitabine) overdose/overexposure:

In treating Fluoropyrimidine (fluorouracil/capecitabine) overdose or overexposure with uridine triacetate, the dose is based on body surface area (BSA) for children and adolescents:

• Initial Dose: 6.2 grams per square meter (g/m²) orally, every 6 hours for 20 doses.
• Maximum Dose: 10 grams per dose (1 packet).
• Initiation: Begin treatment as soon as possible after overdose or early-onset toxicity, within 96 hours after the end of fluorouracil or capecitabine administration.
• Full Course: Administer the full course of 20 doses, regardless of the patient's condition.

The dose based on BSA:

• For BSA 0.34 to 0.44 m²:
  • Dose: 2.1 to 2.7 grams (1 teaspoon)
• For BSA 0.45 to 1.43 m²:
  • Dose: Ranges from 2.8 to 8.8 grams (1 1/4 to 3 1/4 teaspoons)
• For BSA ≥1.44 m²:
  • Maximum Dose: 10 grams (1 full packet)
• One Vistogard packet contains 10 grams of uridine triacetate.
• Doses are rounded by BSA to ensure approximate levels.
• Measurement: Use a scale accurate to at least 0.1 gram or a graduated teaspoon accurate to 1/4 teaspoon.

Special Note: One entire 10 gram packet can be used without weighing or measuring. Do not exceed 10 grams per dose.

Uridine Triacetate dose in the treatment of Hereditary orotic aciduria:

When treating Hereditary orotic aciduria with uridine triacetate, the dose for infants, children, and adolescents is determined by their body weight:

• Initial Dose: 60 milligrams per kilogram (mg/kg) once daily orally.
• Maximum Daily Dose: 8 grams.
• Adjustment: Increase to 120 mg/kg if initial dose is insufficient.
• Measurement: Can be given in grams or teaspoons; use a scale (accurate to at least 0.1 gram) or a graduated teaspoon (accurate to the fraction being measured).
• Duration: Administer daily.

The dosing based on weight:

• For Patients Weighing 5 kg or Less:
  • Initial Dose: 0.4 grams (1/8 teaspoon)
  • Increased Dose: 0.8 grams (1/4 teaspoon)
• For Patients Weighing 6 to 75 kg:
  • Initial Dose: Ranges from 0.4 to 4.5 grams (1/4 to 11/2 teaspoons) for 60 mg/kg and from 0.8 to 8 grams (1/4 to 4 entire packets) for 120 mg/kg.
• For Patients Weighing More Than 75 kg:
  • Fixed Dose: 6 grams (2 teaspoons or 3 entire packets) for 60 mg/kg and 8 grams (2 3/4 teaspoons or 4 entire packets) for 120 mg/kg.
• One packet contains 2 grams of uridine triacetate (Xuriden), approximately equivalent to 3/4 teaspoon.
• Doses are rounded by weight category to achieve the approximate dose level.

Uridine Triacetate dose in pregnancy and lactation: C

• No harmful effects were seen in animal studies regarding uridine triacetate use during pregnancy.
• However, information on its use for treating hereditary orotic aciduria and severe fluoropyrimidine overdose in pregnant women is scarce.
• Close monitoring is advised, and dosage adjustments may be necessary.
• When considering medication like uridine triacetate as an antidote during pregnancy, the mother's health and prognosis should be the priority.
• If there's a clear need for its use, it should be administered without concern for potential birth defects, as withholding treatment solely due to fears of teratogenicity is not recommended.

Uridine triacetate use during breastfeeding:

• Whether uridine triacetate is excreted in breast milk is currently unknown.
• Therefore, when considering breastfeeding while undergoing therapy with uridine triacetate, it's important to weigh the potential risk of exposing the infant to the medication against the benefits of treatment for the mother.

Uridine Triacetate Dose in Renal Disease:

• The manufacturer's labeling does not include specific dosage adjustments for patient with kidney disease.

Uridine Triacetate Dose in Liver Disease:

• The manufacturer's labeling does not include specific dosage adjustments for patient with liver disease.

Side Effects of Uridine triacetate Include:

• Gastrointestinal:
  • Vomiting
  • Nausea
  • Diarrhea

Contraindication to Uridine triacetate Include:

• According to the manufacturer's labeling, there are no contraindications listed for the use of uridine triacetate.

Warnings and Precautions

• According to the manufacturer's labeling, there are no specific warnings listed for the use of uridine triacetate.

Monitor:

Monitoring for Fluoropyrimidine Overdose/Overexposure:

• CBC with Differential: Regular monitoring of complete blood count (CBC) with a focus on differential counts can help assess for any abnormalities in blood cell levels, which may occur due to fluoropyrimidine toxicity.
• Gastrointestinal Toxicity: Close attention should be paid to gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and mucositis, which are common manifestations of fluoropyrimidine overdose or overexposure.

How to administer Uridine triacetate?

Administration of Granules:

• Measurement: Measure the prescribed dose using a scale accurate to at least 0.1 gram or a graduated teaspoon, ensuring accuracy to the fraction of the dose to be administered.
• Preparation: Discard any unused portion of the granule packet after measuring out the dose. Do not chew the granules.
• Timing: Granules may be administered without regard to meals, as food does not affect uridine exposure.

Management of Fluoropyrimidine Overdose/Overexposure:

• Initiation: Begin oral administration as soon as possible after overdose or early-onset toxicity within 96 hours following the end of fluorouracil or capecitabine overdose/overexposure.
• Off-label Use: Based on limited data, uridine triacetate may still be effective in managing severe toxicities when initiated beyond 96 hours after fluorouracil or capecitabine administration.
• Administration:
  • Administer within 30 minutes of preparation, mixed with soft food like applesauce, pudding, or yogurt, followed by at least 120 mL water.
  • If vomiting occurs within 2 hours of taking the dose, administer another complete dose as soon as possible.
  • If a dose is missed, administer it as soon as possible and then resume the regular schedule.
  • If necessary to administer through a tube, mix with a thickening agent and flush the tube with water after administration.
• Full Treatment Course: Administer all 20 doses, even if the patient seems well.

Treatment of Hereditary Orotic Aciduria:

• Administration: Mix the granules in food (e.g., 3 to 4 ounces of applesauce, pudding, or yogurt) and administer immediately, followed by drinking at least 120 mL water.
• Instructions: Do not chew the granules, and do not save them for later use.

Mechanism of action of Uridine triacetate:

• Uridine triacetate acts as a treatment for hereditary orotic aciduria by providing uridine to the body after it's administered.
• It helps balance uridine levels in patients with this condition.
• Additionally, in cases of fluorouracil overdose or overexposure, uridine triacetate acts as a direct chemical antagonist against fluorouracil toxicity.
• It works by reducing the incorporation of fluorouridine triphosphate (FUTP), a metabolite of fluorouracil, into the RNA of certain cells in the body, such as hematopoietic progenitor cells and gastrointestinal mucosal cells.
• This reduction helps decrease the toxicity of fluorouracil in normal tissues.

Onset and Duration:

• Hereditary Orotic Aciduria: Oral administration of exogenous uridine typically improves hematologic abnormalities within 2 to 3 weeks of starting therapy. Reduction in urinary orotic acid levels is usually observed within 1 to 2 weeks of initiating treatment. However, once therapy is discontinued or the dose is reduced, hematologic abnormalities and orotic aciduria may return within days to 2 to 3 weeks.

Distribution and Metabolism:

• Uridine triacetate distributes into cells and can cross the blood-brain barrier. Once in the body, it undergoes metabolism by nonspecific esterases, leading to the deacetylation of uridine and the release of free acetate.

Half-life and Time to Peak:

• The elimination half-life of uridine triacetate is relatively short, typically ranging from 2 to 2.5 hours. It reaches peak levels in the bloodstream within 2 to 3 hours after administration.

Excretion:

• Uridine triacetate is primarily excreted through urine. Additionally, it undergoes catabolic metabolism in tissues as part of the elimination process.

International Brands of Uridine triacetate:

• Vistogard
• Xuriden

Uridine Triacetate Brands in Pakistan:

No Brands Available in Pakistan.