What is the management approach for an adult patient with a methotrexate overdose?

Management of Methotrexate Overdose

Administer leucovorin (folinic acid) immediately upon recognition of methotrexate overdose—this is life-saving and time-critical, with efficacy decreasing dramatically after 24 hours. 1, 2

Immediate Management Algorithm

First-Line Interventions (Within First Hour)

• Give activated charcoal if the overdose is ≥1 mg/kg and occurred within 1 hour of presentation to reduce absorption 1, 2
• Start leucovorin immediately—do not delay while waiting for methotrexate levels, as early treatment is critical for survival 1, 2
• Admit to hospital for intensive monitoring and supportive care 1

Initial Leucovorin Dosing

• Administer up to 100 mg/m² IV as the initial dose if methotrexate level is unknown 1, 2
• Continue leucovorin every 6 hours (oral or IV) based on methotrexate levels 1, 2
• For severe toxicity or delayed elimination, escalate to 100 mg/m² IV every 3 hours until methotrexate level falls below 10⁻⁸ M 2
• Continue until methotrexate levels are <0.05 μmol/L or until hematological abnormalities and mucosal ulceration resolve 1

Essential Supportive Measures

• Aggressive IV hydration with 3 L/day to enhance renal elimination of methotrexate 1, 2, 3
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0, preventing methotrexate precipitation in renal tubules 1, 2, 3
• Measure serum methotrexate levels at least 4 hours after ingestion and monitor serially 1

Laboratory Monitoring

• Complete blood count with differential monitored daily to detect worsening cytopenias 2
• Renal function tests (creatinine, BUN) monitored daily, as 85% of methotrexate is renally excreted 2
• Liver function tests monitored daily 2
• Serial methotrexate levels to guide leucovorin duration 1, 3

Management of Specific Complications

Bone Marrow Suppression

• Administer filgrastim (G-CSF) 5 μg/kg subcutaneously daily to accelerate myeloid recovery if toxic bone marrow suppression develops 1, 2
• Monitor closely for sepsis—myelosuppression accounts for 67 out of 164 methotrexate-associated fatalities, making this the most lethal complication 4
• Initiate broad-spectrum antibiotics if febrile neutropenia develops 5
• Provide red cell and platelet transfusions as needed for severe cytopenias 5

Renal Dysfunction

• Patients with pre-existing renal impairment face substantially higher risk, as impaired clearance leads to prolonged toxic exposure 2, 6
• If standard measures fail and methotrexate levels remain dangerously elevated, glucarpidase should be obtained from the National Institutes of Health on a compassionate-use basis 4, 3
• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 3
• Hemodialysis using a high-flux dialyzer has shown effective clearance in some cases, though generally not recommended as first-line 3

Clinical Monitoring for Toxicity

• Watch for mucositis, fever, diarrhea, erythema, and ulceration, which may take 6-23 days to manifest 1, 4
• Monitor for gastrointestinal symptoms including nausea, vomiting, stomatitis, oral ulceration, and GI bleeding 3
• Assess for neurologic symptoms if intrathecal overdose occurred, including headache, seizures, and acute toxic encephalopathy 3

Critical Pitfalls to Avoid

• Never delay leucovorin while waiting for methotrexate levels—efficacy becomes doubtful if initiated >24 hours after the last methotrexate dose 1, 2
• Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote 4
• Do not underestimate severity—there is high mortality risk even with appropriate treatment 1, 2
• Serum methotrexate levels do not always correlate with toxicity—treat based on clinical presentation and dose ingested, particularly in acute large ingestions >1000 mg 5
• The folinic acid rescue nomogram should not be relied upon in acute oral ingestions, as toxicity can occur below treatment thresholds 5

Special Considerations

High-Risk Patients

• Renal insufficiency is the primary risk factor due to impaired drug clearance 2, 4
• Advanced age increases toxicity risk 2, 4
• Lack of baseline folate supplementation increases risk 2, 4
• Drug interactions, especially with NSAIDs (reduce renal elimination) and trimethoprim-sulfamethoxazole (absolutely contraindicated—causes severe bone marrow suppression) 4

Intrathecal Overdose

• May require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis, and rapid CSF drainage with ventriculolumbar perfusion 3
• Intrathecal glucarpidase has been reported in published case reports for hastening clearance 3
• Monitor for cerebellar herniation with increased intracranial pressure and acute toxic encephalopathy 3