What is the appropriate management of a suspected methotrexate overdose?

Treatment of Methotrexate Overdose

Immediate Life-Saving Intervention

Administer leucovorin (folinic acid) immediately upon recognition of methotrexate overdose—this is the cornerstone of treatment and efficacy diminishes dramatically after 24 hours, making early administration potentially life-saving. 1, 2, 3

Initial Leucovorin Dosing Protocol

• Start with leucovorin 100 mg/m² IV immediately if methotrexate level is unknown or the overdose is significant (≥1 mg/kg). 1, 4
• Continue leucovorin at 10-15 mg/m² (approximately 15 mg for average adult) IV or orally every 6 hours until methotrexate levels fall below 0.05 μmol/L or clinical toxicity resolves. 1, 2, 4
• For severe toxicity or delayed elimination, escalate to leucovorin 100 mg/m² IV every 3 hours until methotrexate level falls below 10⁻⁸ M. 4

Critical pitfall to avoid: Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote. Folic acid supplementation is for prevention, not treatment of acute toxicity. 2

Gastrointestinal Decontamination

• If the overdose occurred within 1 hour and is ≥1 mg/kg, administer activated charcoal immediately to reduce absorption. 1, 2, 5
• For ingestions >1000 mg, folinic acid therapy should be provided regardless of timing, as severe toxicity can occur even with normal renal function. 6

Supportive Care Measures

Hydration and Urinary Alkalinization

• Initiate aggressive IV hydration (approximately 3 L/day) to enhance renal elimination of methotrexate. 1, 2, 3
• Perform urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0, preventing methotrexate precipitation in renal tubules. 1, 2, 3, 7

Hospital Admission and Monitoring

• Admit the patient to hospital immediately for close monitoring. 1, 2
• Measure serum methotrexate levels at least 4 hours after ingestion and continue monitoring to guide leucovorin duration. 1, 3
• Monitor complete blood count with differential, liver function tests, and renal function daily to detect worsening cytopenias and organ dysfunction. 1, 2, 4

Important caveat: Serum methotrexate levels do not always correlate with toxicity in acute overdoses—treat based on clinical presentation and amount ingested, not solely on serum levels. 2, 6

Management of Specific Complications

Bone Marrow Suppression

• For severe neutropenia (<1×10⁹/L) or life-threatening bone marrow suppression, administer filgrastim (G-CSF) 5 μg/kg subcutaneously daily to accelerate myeloid recovery. 1, 2, 6
• Monitor vigilantly for sepsis, as myelosuppression accounts for the majority (67 of 164 cases) of methotrexate-associated fatalities. 2
• Provide broad-spectrum antibiotics if fever develops in neutropenic patients. 6

Mucositis and Gastrointestinal Toxicity

• Monitor for mucositis, oral ulceration, nausea, vomiting, and diarrhea, which typically manifest 6-23 days after exposure. 1, 2
• Continue leucovorin until mucosal ulceration resolves. 1

Advanced Rescue Measures

Glucarpidase (Carboxypeptidase-G2)

• For toxic methotrexate concentrations (>1 μmol/L) with delayed clearance due to impaired renal function, glucarpidase is indicated and can be obtained from the National Institutes of Health on a compassionate-use basis. 2, 3, 8
• Critical timing issue: Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase and will be degraded. 3

Hemodialysis Considerations

• Standard hemodialysis and peritoneal dialysis are generally ineffective for methotrexate elimination. 3
• However, acute intermittent hemodialysis using a high-flux dialyzer has shown effective methotrexate clearance in published reports. 3, 7

High-Risk Patient Factors Requiring Enhanced Vigilance

• Renal insufficiency is the primary risk factor due to 85% renal excretion—these patients require lower thresholds for intervention and enhanced monitoring. 2, 8
• Advanced age (>50-70 years) significantly increases toxicity risk. 2
• Third-space fluid collections (pleural effusions, ascites) require lower thresholds for leucovorin escalation. 4
• Concurrent NSAID use reduces renal elimination and dramatically increases toxicity risk. 2

Duration of Treatment

• Continue leucovorin every 6 hours until methotrexate levels are <0.05 μmol/L AND hematological abnormalities and mucosal ulceration have resolved. 1
• The expected timeline for symptom manifestation is 6-23 days after overdose, requiring prolonged monitoring. 1, 2

Critical Warning

Do not underestimate the severity of methotrexate overdose—there is high mortality risk even with appropriate treatment, and delayed leucovorin administration beyond 24 hours has doubtful efficacy. 1, 2, 4 Deaths have been reported from sepsis, septic shock, renal failure, aplastic anemia, and acute toxic encephalopathy following overdose. 3