What is the antidote for methotrexate (MTX) toxicity?

Methotrexate Toxicity Antidote

Leucovorin (folinic acid) is the primary antidote for methotrexate toxicity and should be administered as promptly as possible after methotrexate overdose to effectively counteract toxicity. 1

Mechanism of Action and Administration

• Leucovorin works by providing reduced folate that bypasses the dihydrofolate reductase enzyme inhibited by methotrexate, allowing for DNA synthesis and cellular function to continue despite methotrexate presence 1, 2
• The effectiveness of leucovorin decreases as the time interval between methotrexate administration and leucovorin initiation increases, making prompt administration critical 1
• For systemic methotrexate toxicity, leucovorin is typically administered at doses of 15-25 mg every 6 hours until methotrexate levels decrease to safe levels (<0.1 μmol/L) 3
• Higher doses of folic acid and leucovorin may be used as rescue therapy for significant methotrexate toxicities 4

Management Algorithm for Methotrexate Toxicity

Immediate Actions

1. Discontinue methotrexate administration 1
2. Begin leucovorin administration as soon as possible 1, 2
3. Monitor serum methotrexate concentration to determine optimal leucovorin dose and duration 1
4. Implement hydration and urinary alkalinization to prevent precipitation of methotrexate in renal tubules 1

For Severe Toxicity

• For patients with delayed methotrexate clearance due to impaired renal function, glucarpidase (carboxypeptidase G2) may be indicated 1
• Important: Do not administer leucovorin within two hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 1
• For massive overdose cases, consider high-dose leucovorin (up to 8 g/day) as the sole therapy, which has shown efficacy in managing severe methotrexate toxicity 2

For Intrathecal Overdose

• Accidental intrathecal overdose requires intensive systemic support, high-dose systemic leucovorin, alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion 1
• Central nervous system symptoms of intrathecal overdose include headache, nausea, vomiting, seizures, and acute toxic encephalopathy 1

Special Considerations

• Neither hemodialysis nor peritoneal dialysis has consistently shown improvement in methotrexate elimination, though high-flux dialyzers have shown some efficacy in acute, intermittent hemodialysis 1
• Patients with renal insufficiency are at higher risk for methotrexate toxicity and require dose adjustments - avoid methotrexate in patients with creatinine clearance <20 mL/min and reduce dose by 50% for those with clearance between 20-50 mL/min 4
• Folinic acid has demonstrated protective effects against methotrexate-induced genetic damage in both animal and human studies 5, 6

Monitoring and Prevention

• Monitor complete blood count, liver function tests, and renal function tests regularly during methotrexate therapy to detect early signs of toxicity 7
• Preventive folic acid supplementation (1 mg/day) is recommended for patients on regular methotrexate therapy to reduce adverse effects 4
• For patients receiving intrathecal methotrexate, oral leucovorin (10 mg) may be administered twice daily beginning on the day of treatment and continuing for 3 days to mitigate systemic toxicity 4

By understanding methotrexate pharmacokinetics and implementing appropriate monitoring and rescue protocols with leucovorin, toxicity can be effectively managed in most clinical scenarios 8.