Treatment for Methotrexate Overdose
In the event of a methotrexate overdose, early treatment with leucovorin (folinic acid) is life-saving and should be administered as promptly as possible, along with supportive measures including hydration and urinary alkalinization. 1
Initial Management
- If the overdose occurred within 1 hour and is ≥1 mg/kg, administer activated charcoal to reduce absorption 1
- Admit the patient to hospital immediately and measure serum methotrexate levels at least 4 hours after ingestion 1
- Begin leucovorin (calcium folinate) administration as soon as possible - effectiveness decreases as time interval between overdose and leucovorin initiation increases 2
- Initial leucovorin dose should be up to 100 mg/m² by intravenous infusion if methotrexate level is unknown 1
- Continue leucovorin with subsequent oral/intravenous doses every 6 hours based on methotrexate levels 1
Supportive Care
- Maintain aggressive hydration to improve renal elimination of methotrexate 1, 2
- Perform urine alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 2
- Monitor complete blood count, liver function, and renal function regularly 3
- Continue leucovorin until methotrexate levels are <0.05 μmol/L or until hematological abnormalities and mucosal ulceration have resolved 1
Management of Specific Complications
- For bone marrow suppression: administer filgrastim (granulocyte colony-stimulating factor) subcutaneously at 5 μg/kg daily to accelerate myeloid recovery 1, 4
- For severe cases with delayed methotrexate clearance due to renal impairment: consider glucarpidase (carboxypeptidase G2) 2, 5
- Do not administer leucovorin within two hours before or after glucarpidase as leucovorin is a substrate for this enzyme 2
- For intrathecal methotrexate overdose: consider CSF drainage and ventriculolumbar perfusion in addition to systemic leucovorin 2, 5
Monitoring and Follow-up
- Monitor serum methotrexate concentration regularly to determine optimal dose and duration of leucovorin treatment 2
- Watch carefully for signs of sepsis, which is a major cause of mortality in methotrexate overdose 2, 4
- Monitor for mucositis, fever, diarrhea, erythema, and ulceration, which may take 6-23 days to manifest 1
Special Considerations
- In patients with renal insufficiency, neither hemodialysis nor peritoneal dialysis significantly improves methotrexate elimination, though high-flux dialyzers may be effective 2
- Large acute oral methotrexate poisoning (>1000 mg) should receive folinic acid therapy even with normal renal function 4
- For intrathecal overdose, intensive systemic support with high-dose leucovorin, alkaline diuresis, and CSF drainage is required 2, 5
Common Pitfalls to Avoid
- Do not delay leucovorin administration while waiting for methotrexate levels - early treatment is critical 1, 6
- Do not rely solely on the folinic acid rescue therapy nomogram in acute ingestions, as it may underestimate toxicity 4
- Avoid intrathecal administration of leucovorin as it has been associated with severe neurotoxicity and death 7
- Do not underestimate the severity of methotrexate overdose - there is high mortality risk even with appropriate treatment 1