Comprehensive Monograph: Uridine Triacetate (DB09144)

Section 1: Executive Summary

[Uridine triacetate is a pyrimidine analog with a unique dual-indication profile, functioning as both an orphan drug for a rare genetic metabolic disorder and a critical emergency antidote in oncology. Identified by DrugBank ID DB09144 and CAS Number 4105-38-8, it is a small molecule chemically engineered as a highly bioavailable oral prodrug of the naturally occurring nucleoside, uridine.][1][ This structural modification significantly enhances its therapeutic utility by enabling the achievement of systemic uridine concentrations that are 4- to 6-fold higher than what is possible with equimolar doses of uridine itself.][1]

[The drug's clinical applications are governed by two distinct pharmacological mechanisms. For the treatment of hereditary orotic aciduria, a rare condition caused by a deficiency in uridine monophosphate synthase, uridine triacetate acts as a replacement therapy. Marketed as Xuriden®, it bypasses the genetic defect by providing an exogenous source of uridine, thereby restoring the pyrimidine nucleotide pool and reducing the toxic accumulation of orotic acid through feedback inhibition.][1][ In its second role, marketed as Vistogard®, it serves as a life-saving antidote for overdose or severe, early-onset toxicity resulting from the chemotherapeutic agents fluorouracil or capecitabine. In this context, it functions as a competitive antagonist, where the supplemental uridine outcompetes the toxic fluorouracil metabolite, fluorouridine triphosphate (FUTP), for incorporation into the RNA of healthy cells, thus preventing cellular damage and death.][1]

[Clinical evidence supporting its use as an antidote is robust, demonstrating a 96% survival rate in patients with fluoropyrimidine overdose, a dramatic improvement over the 16% survival rate observed in historical cohorts receiving only supportive care.][5][ The safety profile of uridine triacetate is notably favorable, characterized by generally mild and transient gastrointestinal side effects and a complete absence of listed contraindications, warnings, or precautions in its prescribing information.][7]

[Despite its proven efficacy and safety, global access to uridine triacetate is fragmented. While it has full marketing approval from the U.S. Food and Drug Administration (FDA) for both indications, its regulatory status elsewhere is varied. It recently received an orphan designation from the European Medicines Agency (EMA) for hereditary orotic aciduria but is not yet approved for marketing.][9][ In Australia, it is available only through a Special Access Scheme for emergency use.][10][ This report provides a comprehensive analysis of uridine triacetate, covering its physicochemical properties, detailed pharmacology, clinical applications, safety profile, and global regulatory landscape.]

Section 2: Drug Identification and Physicochemical Characteristics

[A complete understanding of uridine triacetate begins with its fundamental chemical and physical identity. This section provides a detailed catalogue of its nomenclature, structural properties, and key physicochemical characteristics that are foundational to its pharmaceutical function.]

2.1 Nomenclature and Identifiers

[Uridine triacetate is known by a variety of names and identifiers across scientific literature, regulatory filings, and clinical practice.]

• Generic Name:[ Uridine triacetate ][1]
• DrugBank ID:[ DB09144 ][1]
• CAS Number:[ 4105-38-8 ][11]
• Commercial Brand Names:
• Vistogard®:[ For the emergency treatment of fluorouracil or capecitabine overdose and toxicity.][1]
• Xuriden®:[ For the treatment of hereditary orotic aciduria.][1]
• Synonyms and Code Designations:[ The compound has been referred to by numerous synonyms throughout its development, including: 2',3',5'-tri-O-acetyluridine, 2',3',5'-Triacetyluridine, Tri-O-acetyluridine, Triacetyl uridine, Triacetyluridine, Uridine 2',3',5'-triacetate, Vistonuridine, PN401, PN 401, PN-401, RG 2133, RG-2133, RG2133, and TAU.][1]

2.2 Chemical Structure and Formula

[Uridine triacetate is an acetate ester of the nucleoside uridine. Its structure is central to its function as a prodrug.]

• Chemical Formula:[ .][1]
• Molecular Weight:
• Average:[ 370.314 g/mol.][1]
• Monoisotopic:[ 370.101230168 g/mol.][1]
• Chemical Names (IUPAC):
• [(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diacetate.][12]
• [Uridine, 2',3',5'-triacetate.][18]
• Structural Identifiers:
• SMILES:[ CC(=O)OCC1C(C(C(O1)N2C=CC(=O)NC2=O)OC(=O)C)OC(=O)C.][19]
• InChI Key:[ AUFUWRKPQLGTGF-FMKGYKFTSA-N.][12]

[The chemical modification of the parent uridine molecule is a deliberate and highly effective pharmaceutical strategy. Uridine itself is a hydrophilic molecule with poor oral absorption and is subject to rapid first-pass metabolism, limiting its clinical utility when administered orally. The addition of three acetate ester groups at the 2', 3', and 5' positions of the ribose sugar renders the molecule significantly more lipophilic (fat-soluble).][15][ This increased lipophilicity enhances its ability to passively diffuse across the lipid-rich membranes of the gastrointestinal tract, leading to rapid and efficient absorption into the systemic circulation. Once absorbed, ubiquitous non-specific esterase enzymes present in the blood and tissues quickly cleave the acetate groups, releasing the active uridine moiety.][2][ This prodrug approach effectively circumvents the pharmacokinetic barriers faced by uridine, resulting in substantially higher and more reliable plasma concentrations, which is the cornerstone of its clinical efficacy.][1]

2.3 Physical and Chemical Properties

[The physical characteristics of uridine triacetate are consistent with its formulation as an oral medication.]

• Appearance:[ It is a white solid powder.][12]
• Solubility:[ It exhibits solubility in various solvents, which is relevant for research and formulation purposes.]
• DMSO:[  74 mg/mL ][19][ to 100 mg/mL.][15]
• Water:[ 7 mg/mL ][19][ to 10 mg/mL.][15]
• Ethanol:[ 4 mg/mL.][19]
• Storage and Stability:[ The compound is stable enough for shipment at ambient temperatures. For long-term storage, it should be kept as a powder at -20°C, where it has a shelf life of over 3 to 5 years. Prepared stock solutions have variable stability depending on the solvent and storage temperature, with long-term storage recommended at -20°C or -80°C.][12]

Table 1: Uridine Triacetate - Key Identifiers and Properties

Property	Details
Generic Name	Uridine triacetate
Brand Names	Vistogard®, Xuriden®
DrugBank ID	DB09144
CAS Number	4105-38-8
Molecular Formula
Molecular Weight	Average: 370.314 g/mol; Monoisotopic: 370.101230168 g/mol
IUPAC Name	(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyl diacetate
Key Synonyms	2',3',5'-tri-O-acetyluridine, Vistonuridine, PN401, RG2133
Appearance	White solid powder
Solubility	DMSO:  74-100 mg/mL; Water: 7-10 mg/mL; Ethanol: 4 mg/mL

Section 3: Comprehensive Pharmacological Profile

[The pharmacological profile of uridine triacetate is unique, as it possesses two distinct mechanisms of action that address two completely unrelated pathological conditions. The common denominator is its function as a highly efficient oral delivery system for the active moiety, uridine. Its utility is therefore defined by any condition where a systemic surplus of uridine is therapeutically beneficial.]

3.1 Mechanism of Action in Hereditary Orotic Aciduria

[In the context of hereditary orotic aciduria, uridine triacetate functions as a replacement therapy.][3][ This rare, congenital autosomal recessive disorder is caused by a defect in the bifunctional enzyme uridine monophosphate synthase (UMPS).][1][ The UMPS enzyme catalyzes the final two steps of the ][de novo][ pyrimidine biosynthetic pathway, specifically the conversion of orotic acid to uridine monophosphate (UMP), a precursor for all other pyrimidine nucleotides.][1]

[The genetic defect leads to two primary consequences: a deficiency of pyrimidine nucleotides essential for DNA and RNA synthesis, and a toxic accumulation of the precursor, orotic acid.][22][ These biochemical derangements manifest clinically as megaloblastic anemia, developmental delays, and failure to thrive.][5][ Uridine triacetate administration provides an exogenous source of uridine. This uridine can be utilized by cells through the pyrimidine salvage pathway to synthesize UMP and other necessary pyrimidine nucleotides, effectively bypassing the defective ][de novo][ pathway.][1][ This mechanism is constructive, directly replenishing a deficient metabolite. Furthermore, the restoration of normal intracellular uridine nucleotide levels re-establishes the natural feedback inhibition loop of the pyrimidine synthesis pathway, which in turn suppresses the overproduction of orotic acid and reduces its urinary excretion.][1]

3.2 Mechanism of Action in Fluoropyrimidine Toxicity

[For the treatment of fluorouracil (5-FU) or capecitabine overdose, uridine triacetate acts as a competitive antidote.][1][ The anticancer drugs 5-FU and its oral prodrug capecitabine exert their cytotoxic effects through their active metabolites, which disrupt DNA and RNA synthesis in both cancerous and healthy cells.][3][ The two primary toxic metabolites are:]

1. 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP):[ This metabolite inhibits the enzyme thymidylate synthase, blocking the synthesis of thymidine, a critical component of DNA. This action disrupts DNA replication and repair.][1]
2. 5-fluorouridine triphosphate (FUTP):[ This metabolite structurally mimics the natural nucleoside uridine triphosphate (UTP) and is erroneously incorporated into RNA strands by RNA polymerase. This leads to the production of fraudulent, dysfunctional RNA, which disrupts protein synthesis and other vital cellular processes, causing widespread cell damage and death.][1]

[Uridine triacetate, after its conversion to uridine and subsequent phosphorylation to UTP, directly counteracts the toxicity of FUTP.][1][ By creating a massive systemic surplus of natural UTP, it effectively outcompetes the toxic FUTP for incorporation into the RNA of healthy, non-cancerous cells.][4][ This protective, antagonistic mechanism prevents RNA damage and mitigates the severe toxicities associated with fluoropyrimidine chemotherapy, such as mucositis, diarrhea, neutropenia, and cardiotoxicity.][1][ This pharmacological dichotomy showcases how a single drug, by delivering a fundamental biological molecule, can be repurposed from a constructive replacement therapy in a genetic disease to a protective antidote in iatrogenic poisoning.]

3.3 Pharmacokinetics

[The pharmacokinetic profile of uridine triacetate is defined by its success as a prodrug.]

• Absorption and Bioavailability:[ It is an orally active prodrug that is rapidly absorbed from the gastrointestinal tract. Its primary advantage is its ability to deliver 4- to 6-fold more uridine into the systemic circulation compared to equivalent molar doses of uridine itself, due to enhanced lipophilicity and bypassing of first-pass metabolism.][1]
• Time to Peak Concentration ():[ Following oral administration, peak plasma concentrations of uridine are typically achieved within 2 to 3 hours.][2]
• Effect of Food:[ Administration is not dependent on meals. Clinical studies have shown no significant difference in the rate or extent of uridine exposure when administered under fed versus fasted conditions, providing important flexibility for critically ill patients.][1]
• Distribution:[ Circulating uridine is extensively distributed throughout the body and is taken up into cells via specific nucleoside transporters. Critically for its use as an antidote, uridine crosses the blood-brain barrier, allowing it to counteract the central nervous system toxicities of fluoropyrimidines.][2]
• Metabolism:[ Uridine triacetate is rapidly and completely deacetylated by non-specific esterases, which are widely present in the blood and tissues, to yield the active molecule uridine and free acetate.][2]
• Elimination and Half-Life:[ The elimination half-life of uridine is approximately 2 to 2.5 hours. Uridine is primarily cleared through catabolic pathways present in most tissues, with a smaller fraction excreted unchanged by the kidneys.][2]

3.4 Pharmacodynamics

[The pharmacodynamic effects of uridine triacetate differ based on the indication.]

• Hereditary Orotic Aciduria:[ The onset of clinical effect is gradual. A reduction in urinary orotic acid levels is typically observed within 1 to 2 weeks of initiating therapy, while improvements in hematologic abnormalities, such as anemia and neutropenia, may take 2 to 3 weeks to become apparent.][16][ The therapeutic effect is sustained only with continuous daily administration; upon discontinuation, biochemical and hematologic markers revert to their abnormal baseline within days to weeks.][16]
• Fluoropyrimidine Toxicity:[ The pharmacodynamic effect is rapid, as the circulating uridine immediately becomes available to compete with FUTP. Clinical trials have demonstrated a rapid reversal of severe toxicity, with one-third of patients recovering sufficiently to resume cancer chemotherapy within 30 days of treatment.][25]

Section 4: Clinical Indications and Efficacy

[The clinical utility of uridine triacetate is sharply defined by its two distinct, FDA-approved indications, each supported by specific clinical evidence and marketed under a different brand name.]

4.1 Indication 1: Hereditary Orotic Aciduria (Xuriden®)

[Uridine triacetate, under the brand name Xuriden®, is indicated for the treatment of hereditary orotic aciduria in both adult and pediatric patients.][1][ It is the first and only drug approved by the FDA for this ultra-rare orphan disease, which has an estimated birth prevalence of less than one in one million.][5]

[The FDA approval was based on a single-arm, open-label trial involving four patients aged 3 to 19 years.][5][ In this small cohort, treatment with uridine triacetate at 60 mg/kg once daily for six weeks, followed by a six-month extension at 60-120 mg/kg daily, demonstrated clear clinical benefit. All four patients maintained stability in their baseline hematologic parameters, including neutrophil count, white blood cell count, and mean corpuscular volume. Furthermore, three patients who were measured for growth showed either improvement or stability in weight and stable height growth over the six-month period. Notably, no adverse effects were reported during the trial.][5][ This approval highlights the regulatory flexibility and reliance on small but well-defined studies when addressing diseases with extremely small patient populations.]

4.2 Indication 2: Emergency Treatment of Fluoropyrimidine Overdose and Toxicity (Vistogard®)

[Under the brand name Vistogard®, uridine triacetate is indicated for the emergency treatment of adult and pediatric patients who experience fluoropyrimidine-related toxicity.][1][ The indication covers two specific scenarios:]

1. Overdose:[ Following a confirmed or suspected overdose of fluorouracil or capecitabine, regardless of whether symptoms are present.][1]
2. Severe Early-Onset Toxicity:[ In patients who exhibit early-onset (defined as within 96 hours of the last chemotherapy dose), severe, or life-threatening toxicity. This includes toxicities affecting the cardiac or central nervous system, and/or unusually severe adverse reactions such as gastrointestinal toxicity or neutropenia.][3]

[A critical limitation of its use is that Vistogard® is not recommended for the non-emergent treatment of routine or expected adverse reactions associated with fluorouracil or capecitabine, as it may diminish the antineoplastic efficacy of these drugs.][3][ The safety and efficacy of Vistogard® when initiated more than 96 hours after the end of fluoropyrimidine administration have not been formally established by the FDA.][14]

4.3 Summary of Pivotal Clinical Trial Evidence

[The FDA approval of Vistogard® was based on compelling efficacy data from two single-arm, open-label, expanded-access trials that enrolled a total of 135 patients, including both adults and children.][5][ The patient population consisted of 117 individuals treated for fluoropyrimidine overdose and 18 treated for early-onset severe toxicity.][6]

[The major efficacy endpoint was survival at 30 days or until the resumption of chemotherapy if it occurred prior to 30 days.][25][ The results were striking: the overall survival rate among patients treated with uridine triacetate was 96% (130 out of 135 patients survived).][5][ This outcome stands in stark contrast to data from a retrospective historical cohort of 25 patients who received only supportive care following a fluorouracil overdose; in that group, the survival rate was a mere 16%.][5]

[An important secondary finding from the trials was that 33% of patients with a cancer diagnosis recovered from the toxic event sufficiently to resume chemotherapy in less than 30 days.][25][ This indicates not only that the drug is life-saving but also that it enables a rapid enough recovery to allow for the continuation of essential cancer treatment.]

4.4 Off-Label and Investigational Use

[The strict 96-hour window for initiating Vistogard® is a defining feature of its FDA-approved label, established based on the population studied in the pivotal trials.][14][ From a mechanistic standpoint, the protective effect of uridine should be present as long as toxic FUTP persists in cells and continues to cause damage, a timeframe which is not fully characterized and may extend beyond 96 hours. This creates a tension between the regulatory boundary and clinical reality, as some patients develop severe, life-threatening toxicities well after this window has closed.]

[Emerging evidence from case reports and small series suggests that uridine triacetate may retain efficacy when administered beyond the 96-hour mark for delayed-onset toxicities.][16][ One notable case report detailed the successful treatment of a patient who developed severe, life-threatening encephalopathy 18 days after initiating 5-FU therapy. Despite the significant delay, administration of uridine triacetate led to rapid and complete neurological recovery.][29][ While this level of evidence is insufficient for a label change, it presents a compelling option for clinicians in dire situations where no other specific antidote exists. This discrepancy highlights a critical unmet need and a priority for future research: to formally evaluate the safety and efficacy of uridine triacetate in patients with delayed-onset fluoropyrimidine toxicity.]

Section 5: Dosage, Formulation, and Patient Administration

[The practical application of uridine triacetate is highly dependent on the specific indication, a distinction that is reinforced by its marketing under two different brand names with distinct formulations and dosing regimens. This separation is not merely a commercial strategy but a crucial safety measure designed to prevent catastrophic medication errors.]

5.1 Commercial Formulations

[Uridine triacetate is available as oral granules in single-use packets, with the formulation tailored to each indication:]

• Xuriden®:[ Supplied as orange-flavored oral granules in 2-gram packets for chronic, daily administration in hereditary orotic aciduria.][3]
• Vistogard®:[ Supplied as orange-flavored, white-to-off-white oral granules in larger 10-gram packets for acute, high-dose emergency treatment of fluoropyrimidine toxicity.][3]

[The use of distinct brand names, packet sizes, and dosing schedules represents a deliberate "human factors" engineering approach. It physically and nominally separates the treatment for the acute emergency from that of the chronic disease, minimizing the risk of a pharmacist or clinician accidentally substituting one for the other. Such an error would have severe consequences: using the smaller Xuriden® dose for an overdose would be sub-therapeutic and likely fatal, while using the high-dose Vistogard® regimen for chronic management of orotic aciduria would constitute a massive overdose.]

5.2 Dosing Regimen for Vistogard®

[The dosing for Vistogard® is designed to rapidly achieve and sustain high plasma uridine levels to counteract acute toxicity.]

• Adults:[ The recommended dose is 10 grams (one 10-gram packet) administered orally every 6 hours for a total of 20 doses. The full course of treatment lasts for 5 days.][3]
• Pediatric Patients:[ The dose is based on body surface area (BSA) and is 6.2 g/m² administered orally every 6 hours for 20 doses. The maximum dose per administration should not exceed 10 grams.][8][ The full prescribing information provides detailed tables for calculating the precise dose based on BSA.][24]

5.3 Dosing Regimen for Xuriden®

[The dosing for Xuriden® is designed for chronic, once-daily maintenance therapy and is adjusted based on patient weight and clinical response.]

• Adults and Children:[ The recommended starting dose is 60 mg/kg administered orally once daily.][14]
• Dose Titration:[ The dosage may be increased to 120 mg/kg once daily if clinical efficacy is insufficient. The total daily dose should not exceed 8 grams. Indicators for insufficient efficacy include urinary orotic acid levels remaining above normal, worsening of hematologic parameters, or worsening of other clinical signs of the disease.][14]

5.4 Preparation and Administration Guidelines

[Proper administration is critical for ensuring the efficacy of uridine triacetate.]

• Dose Measurement:[ For pediatric or weight-based dosing, the prescribed amount of granules must be measured precisely using either a scale accurate to at least 0.1 g or a graduated teaspoon accurate to ¼ teaspoon. After the dose is measured, any remaining granules in an opened packet must be discarded and not saved for future use.][8]
• Oral Administration with Food:[ For both Vistogard® and Xuriden®, the measured granules should be mixed into 3 to 4 ounces (90 to 120 mL) of soft food, such as applesauce, pudding, or yogurt. The mixture must be swallowed immediately (within 30 minutes of preparation) without chewing the granules. After consumption, the patient should drink at least 4 ounces (120 mL) of water to ensure all medication is swallowed.][1]
• Administration with Milk or Formula (Xuriden®):[ For smaller doses of Xuriden® (up to 2 grams), the granules can be mixed with 5 mL of milk or infant formula in an oral syringe for administration.][14]
• Nasogastric (NG) or Gastrostomy (G-Tube) Administration:[ For patients unable to take medication orally (e.g., due to severe mucositis or coma), Vistogard® can be administered via a feeding tube. The contents of a 10-gram packet should be crushed to a fine powder, mixed with approximately 100 mL of a food starch-based thickening product, and administered through the tube, followed by a water flush to clear the line.][8]
• Management of Vomited or Missed Doses (Vistogard®):
• Vomited Dose:[ If a patient vomits within 2 hours of taking a Vistogard® dose, a complete replacement dose should be administered as soon as possible. The next dose should then be given at its regularly scheduled time.][8]
• Missed Dose:[ If a dose is missed, it should be taken as soon as it is remembered. The subsequent dose should then be administered at its next regularly scheduled time.][8]

Table 2: Comparative Dosing and Administration for Vistogard® and Xuriden®

Feature	Vistogard®	Xuriden®
Indication	Emergency treatment of fluorouracil or capecitabine overdose or severe early-onset toxicity 1	Treatment of hereditary orotic aciduria 1
Patient Population	Adults and pediatric patients 8	Adults and pediatric patients 30
Packet Size	10 grams 3	2 grams 3
Dosing Regimen	Adults: 10 g (1 packet) orallyPediatric: 6.2 g/m² orally (not to exceed 10 g/dose) 8	Adults & Pediatric: 60 mg/kg orally, may be increased to 120 mg/kg (not to exceed 8 g/day) 30
Frequency	Every 6 hours 8	Once daily 30
Total Duration	20 doses (5 days) 8	Chronic, long-term therapy 30
Administration Instructions	Mix with 3-4 oz of soft food (applesauce, pudding, yogurt). Consume within 30 mins. Do not chew granules. Follow with 4 oz of water. Can be given via NG/G-tube.1	Mix with 3-4 oz of soft food or small amounts of milk/infant formula. Consume immediately. Do not chew granules.30
Guidance for Vomited/Missed Doses	Vomited (<2 hrs): Take another full dose immediately.Missed: Take as soon as possible. Continue with regular schedule for next dose.8	Missed: Take as soon as possible. If near next dose, skip missed dose. Do not double dose.21

Section 6: Safety, Tolerability, and Risk Management

[The safety profile of uridine triacetate is remarkably favorable, particularly for a drug used in emergency and critical care settings. It is generally well-tolerated, with a predictable and manageable side effect profile and a notable lack of major safety concerns.]

6.1 Adverse Reactions

[Data from clinical trials, primarily from the 135 patients treated with Vistogard®, show that adverse reactions are predominantly gastrointestinal in nature and are typically mild to moderate in severity.][7]

• Common Adverse Reactions (>2% incidence):
• Vomiting:[ Occurred in approximately 10% of patients.][27]
• Nausea:[ Occurred in approximately 5% of patients.][27]
• Diarrhea:[ Occurred in approximately 3% of patients.][27]
• Serious Adverse Reactions:[ Serious side effects attributable to the drug are rare. One patient in the clinical trials experienced Grade 3 nausea and vomiting. Discontinuation of therapy due to adverse reactions was infrequent, occurring in only 2 of 135 patients (1.4%).][27][ Some sources list more severe symptoms like confusion, severe headache, or vision changes; however, these are more likely manifestations of the underlying severe fluoropyrimidine toxicity that Vistogard® is intended to treat, rather than side effects of the antidote itself.][3]

6.2 Contraindications, Warnings, and Precautions

[A defining feature of uridine triacetate's safety profile is the complete absence of any listed contraindications, warnings, or precautions in the official FDA-approved prescribing information for both Vistogard® and Xuriden®.][7][ This underscores its high safety margin and suitability for emergency use where a detailed patient history may not be available. While standard precautions regarding hypersensitivity to the active ingredient or excipients apply to any medication, no specific contraindications have been identified.][22]

6.3 Use in Special Populations

• Pediatric Use:[ The safety and effectiveness of uridine triacetate have been established in pediatric patients. Dosing is adjusted based on body surface area for Vistogard® and body weight for Xuriden® to ensure appropriate exposure.][7]
• Geriatric Use:[ Clinical studies of Vistogard® included a substantial proportion of elderly patients (30% were 65 years, and 11% were 75 years). No overall differences in the safety or efficacy profile were observed compared to younger patients, although the total number of geriatric subjects studied was limited.][7]
• Pregnancy:[ There are no adequate and well-controlled studies in pregnant women. However, animal reproduction studies conducted in pregnant rats administered uridine triacetate at doses approximately half the maximum recommended human dose (MRHD) revealed no evidence of teratogenicity or adverse effects on embryofetal development.][7][ In the clinical setting of a life-threatening fluoropyrimidine overdose, the decision to use the drug must balance the clear and immediate risk of maternal death against the unknown but likely low risk to the fetus.]
• Lactation:[ It is not known whether uridine triacetate or its metabolite, uridine, is excreted in human milk. The potential risks and benefits must be carefully weighed, considering the mother's critical clinical need for the life-saving therapy.][7]

6.4 Drug Interaction Profile

[Uridine triacetate has a very low potential for clinically significant drug-drug interactions.]

• Cytochrome P450 (CYP) System:[ ][In vitro][ studies have shown that uridine triacetate does not meaningfully inhibit or induce major CYP450 enzymes. Therefore, interactions with drugs metabolized through these common pathways are not expected.][27][ Multiple sources confirm that there are no known significant drug interactions.][3]
• P-glycoprotein (P-gp):[ ][In vitro][ data suggest that uridine triacetate is a weak inhibitor of the P-gp drug transporter. Because oral administration can lead to high concentrations of the drug within the gastrointestinal tract, there is a theoretical potential for it to interfere with the absorption of narrow therapeutic index P-gp substrates, such as digoxin. However, there are no ][in vivo][ human data to confirm this interaction, and no clinical cases have been reported.][7][ Nevertheless, this remains a point for clinical vigilance when co-administering with such drugs.]

Section 7: Global Regulatory Status and Market Access

[The global availability of uridine triacetate is inconsistent, reflecting the complex challenges that orphan drugs and emergency antidotes face in navigating different regulatory and reimbursement landscapes. A patient's access to this life-saving medication is highly dependent on their geographic location.]

7.1 United States (FDA)

[The United States represents the most mature market for uridine triacetate, with full marketing approval for both of its indications.]

• Xuriden®:[ Approved by the FDA in September 2015 for the treatment of hereditary orotic aciduria. It was granted Orphan Drug and Breakthrough Therapy designations, which helped expedite its review and approval.][5]
• Vistogard®:[ Approved by the FDA on December 11, 2015, for the emergency treatment of fluorouracil or capecitabine overdose or severe toxicity. It also received Orphan Drug designation and was granted Priority Review status due to its potential to provide a significant improvement in safety or effectiveness for a serious condition.][28]

7.2 Europe (EMA)

[The regulatory journey for uridine triacetate in the European Union is less advanced.]

• Marketing Authorization:[ The drug does not currently have marketing authorization from the European Medicines Agency (EMA) for either indication.][38]
• Orphan Designation:[ On June 28, 2024, uridine triacetate received a positive opinion from the EMA's Committee for Orphan Medicinal Products (COMP) for an orphan designation for the "treatment of hereditary orotic aciduria".][9][ This designation provides the developer with scientific and regulatory support to advance the medicine toward a formal marketing authorization application, but it does not constitute approval or availability for patients.][9]
• United Kingdom:[ In the UK, uridine triacetate is recommended as a treatment option through routine commissioning by NHS England for patients exhibiting early-onset severe toxicities from fluoropyrimidine administration.][40]

7.3 Australia (TGA)

[In Australia, uridine triacetate is not formally approved or listed on the Australian Register of Therapeutic Goods (ARTG).][38][ Access is managed through a pragmatic but non-standard pathway.]

• Special Access Scheme (SAS):[ The drug is available for emergency use under the Therapeutic Goods Administration's (TGA) Special Access Scheme.][10][ This scheme allows for the importation and supply of unapproved therapeutic goods for patients with serious or life-threatening conditions.]
• Centralized Distribution:[ To ensure rapid, 24-hour access to this critical antidote across the country, a unique distribution model has been established. The Peter MacCallum Cancer Centre in Melbourne serves as the sole national storage and distribution hub for Vistogard®, responding to requests from hospitals nationwide. This model overcomes the logistical challenge of stocking an expensive, rarely used drug at multiple sites.][10][ The cost per course of treatment is substantial, listed at A$133,500.][10]

7.4 Other Jurisdictions

[Based on available data, uridine triacetate has not received marketing approval in several other major jurisdictions, including Canada (Health Canada), China (NMPA), and Spain (CIMA AEMPS).][38][ This patchwork of global access underscores the significant disparities in regulatory pathways and market viability for drugs targeting ultra-rare diseases or emergency indications.]

Table 3: Global Regulatory Snapshot

Regulatory Body/Country	Brand Name(s)	Approved/Designated Indication(s)	Approval/Access Status	Key Dates/Notes
USA (FDA)	Vistogard® Xuriden®	Emergency treatment of fluoropyrimidine overdose/toxicity Treatment of hereditary orotic aciduria	Approved	Vistogard® approved Dec 2015 28Xuriden® approved Sep 2015 5
Europe (EMA)	Uridine triacetate	Treatment of hereditary orotic aciduria	Orphan Designation (No Marketing Authorization)	Orphan designation granted June 2024 9
United Kingdom (NHS)	Uridine triacetate	Treatment of early-onset severe fluoropyrimidine toxicities	Routinely Commissioned	Policy published March 2020 40
Australia (TGA)	Vistogard®	Emergency treatment of fluoropyrimidine overdose/toxicity	Special Access Scheme (SAS) (Not Registered on ARTG)	Available via centralized distribution from Peter MacCallum Cancer Centre 10

Section 8: Conclusion and Future Perspectives

[Uridine triacetate stands as a significant pharmaceutical agent, defined by its dual identity as a life-saving emergency antidote and a transformative therapy for an ultra-rare genetic disease. Its development is a testament to successful rational drug design, where the chemical modification of a natural nucleoside into a lipophilic prodrug overcame critical pharmacokinetic barriers to unlock its therapeutic potential.]

[The clinical evidence for Vistogard® in treating fluoropyrimidine overdose is unequivocal, demonstrating a profound survival benefit that has established it as the standard of care for this iatrogenic emergency. For patients with hereditary orotic aciduria, Xuriden® represents the first and only targeted therapy, offering a mechanism-based treatment that addresses the underlying biochemical defect of the disease. Its safety profile is remarkably benign for a drug of such critical importance, with a lack of major toxicities, contraindications, or significant drug interactions, further solidifying its clinical value.]

[For clinical practice, this report underscores the importance of rapid diagnosis and immediate administration of Vistogard® in cases of suspected fluoropyrimidine overdose or severe early-onset toxicity. The 96-hour window for initiation is a critical parameter based on the pivotal trial data, and healthcare systems must have protocols in place to ensure timely access. For Xuriden®, the key to successful management is consistent daily administration and careful monitoring of biochemical and hematologic markers to ensure an adequate therapeutic response.]

[Looking forward, several areas warrant further investigation. The most pressing clinical question is the potential efficacy of uridine triacetate in treating delayed-onset fluoropyrimidine toxicity beyond the 96-hour window. While compelling case reports exist, formal clinical trials or well-designed registry studies are needed to provide the robust evidence required to potentially expand its approved indication. Such an expansion could save additional lives, particularly among patients with partial DPD deficiency who may present with severe toxicity later in their treatment course. Further exploration of its neuroprotective properties and its potential to mitigate toxicity from other antimetabolites that interfere with pyrimidine pathways could also unveil new therapeutic applications.]

[Finally, the fragmented global regulatory status of uridine triacetate serves as a case study in the broader challenges facing orphan drugs and emergency antidotes. The disparities in access between regions highlight the need for more harmonized and expedited regulatory pathways for drugs that, while serving small patient populations, have a transformative impact on survival and quality of life.]

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