What is the management of suspected methotrexate toxicity in a patient?

Management of Methotrexate Toxicity

Immediate Management: Leucovorin is Life-Saving and Time-Critical

Administer leucovorin (folinic acid) immediately upon suspicion of methotrexate toxicity—this is the cornerstone of treatment and efficacy diminishes dramatically after 24 hours, becoming doubtful if initiated later than 24 hours after the last methotrexate dose. 1, 2, 3

Initial Leucovorin Dosing Protocol

• Start with leucovorin 100 mg/m² IV immediately if methotrexate level is unknown 1, 2
• Continue with 10 mg/m² (approximately 15 mg for average adult) every 6 hours until methotrexate levels fall below 0.05 µmol/L or clinical toxicity resolves 1, 4, 2
• For severe toxicity or delayed elimination, escalate to 100 mg/m² IV every 3 hours until methotrexate level falls below 10⁻⁸ M 1
• Leucovorin can be administered orally or intravenously depending on severity 2

Critical First-Hour Interventions

• If ≥1 mg/kg methotrexate was ingested within 1 hour, administer activated charcoal first before starting leucovorin 1, 4, 2
• Admit to hospital immediately for monitoring 1, 2
• Measure serum methotrexate levels at least 4 hours after ingestion 2

Supportive Care: Hydration and Alkalinization

Initiate aggressive IV hydration (3 L/day) and urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 to prevent methotrexate precipitation in renal tubules and enhance elimination. 1, 4, 2, 3

• Continue hydration and alkalinization until methotrexate levels are safe 2, 5
• Monitor urine pH regularly to ensure adequate alkalinization 1

Management of Specific Toxicities

Hematologic Toxicity (Most Lethal Complication)

Myelosuppression accounts for 67 of 164 methotrexate-associated fatalities, making it the most lethal complication. 4

• Withhold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 4
• For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 mcg/kg subcutaneously daily to accelerate myeloid recovery 1, 4, 2
• Monitor complete blood count with differential daily to detect worsening cytopenias 1, 4
• Monitor closely for sepsis—mortality risk is substantial with methotrexate overdose 1, 2

Hepatotoxicity

• Stop methotrexate if transaminases exceed 2× upper limit of normal on repeat testing 4
• Monitor liver function tests daily during acute toxicity 1
• Many liver function abnormalities are transitory and normalize without permanent discontinuation (only 5% require permanent discontinuation) 4

Pulmonary Toxicity

Pulmonary fibrosis accounts for 30 of 164 methotrexate-associated fatalities. 4

• Suspect in patients presenting with dyspnea, dry cough, and fever 4
• Obtain chest X-ray immediately 4
• Discontinue methotrexate—pulmonary symptoms usually resolve with discontinuation 4

Renal Toxicity

Patients with renal impairment face substantially higher risk as 85% of methotrexate is renally excreted. 1, 4

• Enhanced hydration and alkalinization are critical in renal dysfunction 2, 5
• Monitor renal function daily 1
• Consider glucarpidase for toxic methotrexate concentrations with delayed clearance due to impaired renal function 3, 6

Advanced Rescue Measures

Glucarpidase (Carboxypeptidase-G2)

• Indicated for toxic methotrexate concentrations (>1 μmol/L) in patients with delayed clearance due to impaired renal function 3, 7, 6
• Decreases serum methotrexate concentrations by 90-95% within 15 minutes 6
• Do NOT administer leucovorin within 2 hours before or after glucarpidase because leucovorin is a substrate for glucarpidase 3
• Primary indication is intrathecal methotrexate poisoning 6

Hemodialysis

• Generally not effective for methotrexate elimination 3
• However, acute intermittent hemodialysis using a high-flux dialyzer has shown effective clearance 3
• Consider when glucarpidase is unavailable 6

Special Considerations for Intrathecal Overdose

• Requires intensive systemic support, high-dose systemic leucovorin, alkaline diuresis, and rapid CSF drainage with ventriculolumbar perfusion 3
• Administer leucovorin 10 mg orally twice daily for 3 days beginning on day of treatment to mitigate systemic toxicity 1
• Leucovorin does not cross the blood-brain barrier sufficiently to interfere with CSF methotrexate effect 1

High-Risk Populations Requiring Enhanced Vigilance

Renal Insufficiency (Primary Risk Factor)

• Avoid methotrexate entirely in patients with creatinine clearance <20 mL/min 1
• Lower thresholds for leucovorin escalation required 1, 4

Other High-Risk Factors

• Advanced age (>50-70 years) significantly increases toxicity risk 4
• Third-space fluid collections (pleural effusions, ascites) require lower thresholds for leucovorin escalation 1
• Lack of folate supplementation is a common preventable risk factor 4
• Hypoalbuminemia increases free drug levels 4

Critical Drug Interactions to Avoid

Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk. 4

• NSAIDs reduce renal elimination of methotrexate—particularly dangerous with any dose 4
• Other high-risk interactions: salicylates, sulfonamides, penicillins, probenecid, colchicine 4

Timeline of Toxicity Manifestations

Symptoms typically manifest 6-23 days after exposure, including: 4, 2

• Mucositis and oral ulceration
• Fever, malaise, fatigue
• Nausea, vomiting, diarrhea
• Myelosuppression
• Erythema and cutaneous ulceration

Common Pitfalls to Avoid

• Never delay leucovorin administration while waiting for methotrexate levels—treat based on clinical presentation 4
• Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block 4
• Folic acid is for prevention, not treatment of acute toxicity 4
• Do not underestimate severity—high mortality risk exists even with appropriate treatment 2
• Serum methotrexate levels do not always correlate with toxicity—treat based on clinical presentation 4

Prevention of Future Toxicity

All patients on methotrexate must receive folate supplementation (1-5 mg daily, except on methotrexate day, or 5 mg weekly) to reduce gastrointestinal, liver, and hematologic toxicity. 1, 4

• Prescribe only 2.5 mg tablets to make daily dosing physically impossible 4
• Write dose in full uppercase letters 4
• Use patient-held record books documenting weekly dosing schedule 4
• Review medications constantly for potential interactions 4