Fluorouracil (5-FU) is a widely used chemotherapeutic agent for treating solid tumors. However, overdose or toxicity can lead to severe or life-threatening complications. Rapid and effective intervention is crucial to prevent mortality and mitigate adverse effects. This article outlines the critical steps in managing fluorouracil overdose, including the use of specific antidotes, supportive care measures, and emerging treatment options.
Pathophysiology of Fluorouracil Toxicity
Fluorouracil is a fluoropyrimidine analog that interferes with DNA and RNA synthesis, leading to cytotoxic effects. Overdose can result in severe myelosuppression, gastrointestinal toxicity, neurotoxicity, and cardiotoxicity. The severity of toxicity depends on factors such as dosage, infusion rate, and patient-specific enzyme deficiencies (e.g., dihydropyrimidine dehydrogenase [DPD] deficiency).
flowchart TD;
A[Fluorouracil Overdose] --> B[Myelosuppression]
A --> C[Gastrointestinal Toxicity]
A --> D[Neurotoxicity]
A --> E[Cardiotoxicity]
B --> F[Infections, Sepsis]
C --> G[Severe Diarrhea, Mucositis]
D --> H[Encephalopathy, Confusion]
E --> I[Myocardial Ischemia, Arrhythmias]Clinical Presentation
Symptoms of fluorouracil overdose may manifest within hours to days post-exposure and include:
- Gastrointestinal Symptoms: Severe nausea, vomiting, diarrhea, mucositis
- Hematologic Effects: Pancytopenia, increased risk of infections and hemorrhage
- Neurological Symptoms: Altered mental status, seizures, ataxia
- Cardiac Toxicity: Chest pain, arrhythmias, cardiogenic shock
Immediate Management Steps
- Discontinue Fluorouracil Infusion – Stop administration immediately to prevent further toxicity.
- Assessment and Monitoring – Conduct vital sign monitoring, complete blood count (CBC), electrolyte panel, and cardiac evaluation.
- Airway, Breathing, Circulation (ABC) Support – Provide respiratory support if needed, manage hypotension, and ensure hemodynamic stability.
- Gastrointestinal Decontamination – Not typically useful due to intravenous administration; activated charcoal may be considered in rare cases of oral ingestion.
Specific Antidote: Uridine Triacetate
Uridine triacetate (Vistogard) is the only FDA-approved antidote for fluorouracil and capecitabine overdose. It works by providing an alternative substrate for RNA synthesis, reducing fluorouracil incorporation into nucleic acids.
Dosage & Administration:
- Indication: Acute fluorouracil or capecitabine overdose, severe early-onset toxicity
- Adult & Pediatric Dose: 10 g orally every 6 hours for 20 doses (5 days)
- Administration: Should be started within 96 hours of overdose for optimal effectiveness
Supportive Care Measures
1. Hematologic Support
- Granulocyte colony-stimulating factor (G-CSF): Used to mitigate neutropenia and reduce infection risk.
- Blood transfusions: Considered in cases of severe anemia or thrombocytopenia.
2. Gastrointestinal Management
- IV fluids and electrolyte correction to prevent dehydration.
- Anti-emetics (ondansetron, granisetron) to control nausea and vomiting.
- Loperamide or octreotide for severe diarrhea.
3. Neurological and Cardiac Monitoring
- Cardiac telemetry for patients with arrhythmias or ischemic symptoms.
- Antiepileptic medications for seizure control if neurotoxicity occurs.
Prognosis and Recovery
Early recognition and prompt administration of uridine triacetate significantly improve survival rates. Patients who receive timely treatment generally recover within weeks, although prolonged bone marrow suppression may necessitate continued monitoring.
