How to manage methotrexate toxicity in a patient with suspected overdose?

Management of Methotrexate Toxicity

Administer leucovorin (folinic acid) immediately upon suspicion of methotrexate toxicity, as this is life-saving and time-critical, with efficacy diminishing dramatically after 24 hours. 1

Immediate Management Protocol

First-Line Antidotal Therapy

• Leucovorin (folinic acid) is the cornerstone of treatment and must be initiated immediately, with initial dosing of up to 100 mg/m² IV (approximately 15 mg for average adult) if methotrexate level is unknown 1, 2
• Administer subsequent doses of 10-15 mg/m² every 6 hours (oral or IV) until methotrexate levels fall below 0.05 µmol/L or toxicity resolves 1, 2
• Do NOT confuse folic acid with folinic acid (leucovorin) - only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote 1
• The FDA label emphasizes that leucovorin administration should begin as promptly as possible, as effectiveness decreases with delayed initiation 2

Supportive Measures for Recent Ingestion

• For recent oral ingestion (≥1 mg/kg within 1 hour), administer activated charcoal immediately 1
• Initiate aggressive IV hydration to enhance renal elimination of methotrexate 1, 2, 3
• Perform urinary alkalinization using sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 2, 3
• Monitor serum methotrexate concentration to determine optimal dose and duration of leucovorin treatment 2

Management of Specific Toxicities

Hematologic Toxicity (Most Lethal Complication)

• Myelosuppression accounts for 67 out of 164 methotrexate-associated fatalities, making it the most lethal complication 1
• Immediately discontinue methotrexate if total white cells <3.5×10⁹/L or neutrophils <2×10⁹/L 1
• For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) subcutaneously at 5 µg/kg daily to accelerate myeloid recovery 1, 4
• Monitor for sepsis with high vigilance, as mortality risk is substantial 1
• Provide broad-spectrum antibiotics if febrile, along with red cell and platelet transfusion as needed 4

Hepatotoxicity

• Stop methotrexate immediately if transaminases exceed twice the upper limit of normal 1
• Monitor liver function tests closely, repeating in 2-4 weeks 5
• Liver function abnormalities can be transitory, with many normalizing without stopping methotrexate, and only 5% requiring permanent discontinuation 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
• Pulmonary symptoms usually resolve with discontinuation of methotrexate 1

Neurotoxicity and Seizures

• Immediately discontinue methotrexate and initiate antiepileptic treatment for seizure control 6
• Obtain urgent brain MRI with T2-weighted and diffusion-weighted sequences to assess for methotrexate-induced leukoencephalopathy 6
• Subacute neurotoxicity is often reversible with appropriate management, typically showing MRI improvement within days to weeks 6

Advanced Interventions for Severe Cases

Glucarpidase (Carboxypeptidase-G2)

• The FDA indicates glucarpidase for treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function 2
• Glucarpidase decreases serum MTX concentrations by 90%-95% within 15 minutes 7
• Do NOT administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 2
• Its use is limited by significant cost and lack of availability 7

Hemodialysis

• Effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer 2
• Consider when glucarpidase is not available and renal impairment is present 7

Intrathecal Overdose Management

• Accidental intrathecal overdose may require intensive systemic support, high-dose systemic leucovorin, alkaline diuresis, and rapid CSF drainage with ventriculolumbar perfusion 2
• Symptoms include headache, nausea, vomiting, seizures, and acute toxic encephalopathy 2

Critical Risk Factors to Assess

Patient-Related Factors

• Advanced age (>50-70 years) significantly increases toxicity risk 5, 1
• Renal insufficiency is the primary risk factor due to impaired drug clearance 5, 1, 3
• Lack of folate supplementation increases toxicity risk 5, 1
• Hypoalbuminemia increases free methotrexate levels 5

Drug Interactions (Absolutely Critical)

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk 1
• NSAIDs reduce renal elimination and are particularly dangerous with high-dose methotrexate 1, 3
• Penicillins and other drugs competing for renal tubular secretion increase toxicity risk 1

Common Pitfalls to Avoid

• Delaying leucovorin administration is the most critical error - efficacy is doubtful if initiated >24 hours after last methotrexate dose 1
• Do not assume low serum levels exclude toxicity - serum methotrexate levels do not always correlate with toxicity; treat based on clinical presentation 1
• Do not administer folic acid instead of folinic acid - only leucovorin bypasses methotrexate's metabolic block 1
• Do not stop antibiotics prematurely - methotrexate should remain discontinued until infection resolves and antibiotic course is complete 1
• Do not rely on the folinic acid rescue therapy nomogram in acute ingestions, as it may underestimate toxicity 4

Prevention Strategies

Mandatory Supplementation

• All patients on methotrexate must receive folate supplementation (1-5 mg daily, except on the day of methotrexate administration) to reduce gastrointestinal, liver, and hematologic toxicity 1, 8

Monitoring Protocol

• Monitor complete blood count, liver function tests, and renal function tests at weeks 2,4,8, and 12 after initiation, then every 3-4 months thereafter 1, 8
• Increase monitoring frequency to every 2-4 weeks after any dose increase, as pancytopenia can occur as late as 6 weeks post-adjustment 8
• Obtain baseline chest X-ray for all patients starting methotrexate 1, 8

Patient Education

• Educate patients that methotrexate is taken WEEKLY, not daily - most oral overdoses result from accidental daily administration 2, 4, 9
• Warn patients to present immediately for unusual fatigue, malaise, fever, chills, or mouth sores 1