What is the treatment for methotrexate toxicity?

Management of Methotrexate Toxicity

Administer leucovorin (folinic acid) immediately upon recognition of methotrexate toxicity—this is life-saving and time-critical, with efficacy decreasing dramatically after 24 hours from the last methotrexate dose. 1, 2, 3

Immediate Management of Acute Overdose

First-Line Antidote: Leucovorin

• Leucovorin (folinic acid) is the preferred antidote for methotrexate poisoning and should be administered as soon as possible 1, 3, 4
• Initial dosing: Up to 100 mg/m² IV if methotrexate level is unknown 2
• For recent oral ingestion of ≥1 mg/kg within 1 hour, administer activated charcoal first, then immediately start leucovorin 1, 2
• Leucovorin is most effective when initiated within a few hours of the last methotrexate dose; efficacy becomes doubtful if initiated later than 24 hours 2
• Continue leucovorin until methotrexate levels fall below toxic range and clinical improvement occurs 3, 5

Critical Supportive Measures

• Aggressive IV hydration (3 L/day) to enhance renal clearance 1, 2, 3
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 to prevent methotrexate precipitation in renal tubules 1, 2, 3
• Admit all patients to hospital for close monitoring 2
• Monitor serum methotrexate concentrations to guide leucovorin dose and duration 3

Advanced Rescue Therapies

• Glucarpidase is indicated for toxic methotrexate concentrations (>1 μmol/L) in patients with delayed clearance due to impaired renal function 3, 4
• Glucarpidase decreases serum methotrexate by 90-95% within 15 minutes 5
• Critical timing consideration: Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 3
• Glucarpidase is primarily indicated for intrathecal methotrexate poisoning and high-dose methotrexate toxicity with renal injury 5
• High-flux hemodialysis can be effective for methotrexate removal when glucarpidase is unavailable 3, 5

Management of Specific Toxicities

Hematologic Toxicity (Most Common Cause of Death)

• Myelosuppression accounts for 67 out of 164 methotrexate-associated fatalities 1
• Withhold methotrexate if total white cells <3.5×10⁹/L or neutrophils <2×10⁹/L until counts recover 1
• For severe neutropenia (<1×10⁹/L), patients should present immediately for antibiotics ± G-CSF if febrile 1
• Filgrastim (G-CSF) 5 mcg/kg/day subcutaneously may be used for toxic bone marrow suppression to accelerate myeloid recovery 2
• Monitor for sepsis, as there is high mortality risk with methotrexate overdose 2

Hepatotoxicity

• Stop methotrexate immediately if transaminases exceed twice the upper limit of normal 1
• Liver function abnormalities can be transitory, with many normalizing without stopping methotrexate, and only 5% requiring permanent discontinuation 1
• For persistent elevations over 12 months or decreased serum albumin below normal range, consider gastroenterology consultation and/or liver biopsy 1
• Monitor liver function tests every 3-6 months during chronic therapy 6, 1

Pulmonary Toxicity

• Pulmonary fibrosis accounts for 30 out of 164 methotrexate-associated fatalities 1
• Monitor for acute interstitial pneumonitis presenting with dyspnea, dry cough, and fever 1
• Obtain baseline chest x-ray for all patients starting methotrexate 1
• Pulmonary symptoms usually resolve with discontinuation of methotrexate 6

Gastrointestinal Toxicity

• Common manifestations include nausea, anorexia, stomatitis, mucositis, oral ulceration, vomiting, and gastrointestinal bleeding 1, 3
• Critical pitfall: In patients treated for ectopic pregnancy, gastrointestinal symptoms may mimic acute ectopic rupture—rule out treatment failure before attributing symptoms to methotrexate toxicity 6

Prevention Strategies

Mandatory Folate Supplementation

• All patients on methotrexate must receive folic acid supplementation (1-5 mg daily, except on the day of methotrexate administration) 1, 7
• Folic acid reduces gastrointestinal, hepatic, and hematologic toxicity without compromising therapeutic efficacy 1, 7
• Lack of folate supplementation is a major risk factor for methotrexate toxicity 1
• Important exception: For ectopic pregnancy treatment with high-dose methotrexate, avoid folic acid as it may counteract methotrexate's therapeutic action 6, 7

Regular Monitoring

• Baseline testing: Complete blood count, renal function (creatinine, eGFR), liver function tests, and chest x-ray 1
• Monitoring frequency: Weeks 2,4,8, and 12 after initiation, then at least every 3 months thereafter 1
• Monitor for drug interactions, especially with NSAIDs and sulfonamides, which can increase toxicity risk 1

High-Risk Populations Requiring Extra Vigilance

• Renal insufficiency (primary risk factor due to impaired drug clearance) 1
• Advanced age 1
• Dosing errors (accidental daily instead of weekly administration) 3, 4
• Hypoalbuminemia 1
• Patients with eGFR <30 mL/minute: methotrexate is contraindicated 4
• Patients with eGFR 30-59 mL/minute: use lower initial dose with careful monitoring 4

Common Pitfalls to Avoid

• Do not delay leucovorin administration—every hour counts, and efficacy drops precipitously after 24 hours 2
• Do not confuse routine folic acid supplementation with leucovorin rescue therapy—leucovorin is the antidote for overdose and should be given immediately regardless of timing concerns 7
• Do not give leucovorin within 2 hours of glucarpidase if glucarpidase is used 3
• Do not attribute gastrointestinal symptoms to methotrexate toxicity in ectopic pregnancy patients without first ruling out treatment failure 6
• Do not use folic acid during high-dose methotrexate treatment for ectopic pregnancy, as it may counteract therapeutic effect 6, 7