What is the management approach for methotrexate toxicity?

Management of Methotrexate Toxicity

Immediate Recognition and Antidotal Therapy

Leucovorin (folinic acid) must be administered as soon as possible when methotrexate toxicity is suspected—this is life-saving and time-critical. 1, 2 The effectiveness of leucovorin decreases as the time interval between methotrexate administration and leucovorin initiation increases. 2

Acute Overdose Management

For acute methotrexate overdose, implement the following immediately:

• Administer leucovorin (folinic acid) without delay as the preferred antidote for methotrexate poisoning 1, 3
• Give activated charcoal if recent oral ingestion of ≥1 mg/kg has occurred 1
• Initiate aggressive intravenous hydration to promote renal clearance 1, 4
• Perform urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 5
• Monitor serum methotrexate concentrations continuously, as this is essential for determining optimal leucovorin dose and duration 2, 4

Glucarpidase for Severe Toxicity

Glucarpidase is indicated when plasma methotrexate levels exceed 1 μmol/L in patients with impaired renal function and delayed methotrexate clearance. 2, 3

Critical timing considerations:

• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase and will be degraded 2
• Some patients may require repeated doses of glucarpidase in addition to supportive measures like dialysis 6
• Early glucarpidase administration has been associated with shorter hospital stays and decreased grade 4 toxicities 7

Management of Specific Toxicity Types

Hematologic Toxicity (Myelosuppression)

Monitor complete blood counts closely and implement the following thresholds: 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), warn patients to present immediately for antibiotics ± G-CSF if febrile 1
• Myelosuppression accounts for the majority (67 of 164) of methotrexate-associated fatalities 8

Hepatotoxicity

Stop methotrexate immediately if transaminases exceed twice the upper limit of normal. 8, 1

Additional hepatic monitoring:

• Liver function abnormalities can be transitory; many normalize without stopping methotrexate (only 5% require permanent discontinuation) 8
• For patients with BMI >28 kg/m² or alcohol intake >14 drinks per week, screen using transient elastography (FibroScan) 8
• Routine liver biopsy after prolonged use is not necessary, as cirrhosis risk is much lower than previously thought 8

Pulmonary Toxicity

Obtain a baseline chest x-ray for all patients starting methotrexate. 8, 1

Monitor for acute interstitial pneumonitis presenting with:

• Dyspnea 8, 1
• Dry cough 8, 1
• Fever 8

Most cases are reversible on methotrexate withdrawal, though pulmonary fibrosis accounts for 30 of 164 methotrexate-associated fatalities. 8

Renal Toxicity

Nephrotoxicity results from methotrexate crystallization in renal tubular lumen, occurring in 2-12% of patients receiving high-dose methotrexate. 4

Management approach:

• Increase hydration and continue urinary alkalinization when delayed excretion or acute kidney injury occurs 4
• Escalate to high-dose leucovorin for impaired clearance 4
• Consider glucarpidase for persistent elevation despite preventive strategies 4
• Hemodialysis using a high-flux dialyzer can achieve effective methotrexate clearance in severe cases 2

Intrathecal Overdose

Intrathecal methotrexate overdose requires specialized management: 2

• Intensive systemic support 2
• High-dose systemic leucovorin 2
• Alkaline diuresis 2
• Rapid CSF drainage and ventriculolumbar perfusion 2

Symptoms include headache, nausea, vomiting, seizures, and acute toxic encephalopathy, with reported deaths from cerebellar herniation and increased intracranial pressure. 2

Prevention Strategies

Folate Supplementation

All patients on methotrexate must receive folate supplementation to reduce gastrointestinal, liver, and hematologic toxicity. 8, 1

Dosing options:

• 1 mg daily (taken 6 days per week, avoiding methotrexate day) 8, 1, 9
• 5 mg weekly (traditionally taken 1-2 days after methotrexate dose) 8

Monitoring Schedule

Baseline testing: FBC, U&E, LFT, and chest x-ray 8, 1

Monitoring frequency: 8

• Weeks 2,4,8, and 12 after initiation
• At least every 3 months thereafter (12-weekly ongoing monitoring)
• Repeat bloods 2 weeks after all dose increases

Risk Factor Identification

Toxicity risk increases with: 1, 3

• Renal insufficiency (impaired drug clearance) 1, 3
• Advanced age 1
• Lack of folate supplementation 1
• Dosing errors (particularly accidental daily instead of weekly administration) 1, 2
• Drug interactions with NSAIDs, sulfonamides, salicylates, and certain antibiotics 1, 10

Methotrexate is contraindicated if eGFR <30 mL/minute and requires dose reduction by 50% if eGFR is 20-50 mL/minute. 9, 3

Common Minor Toxicities

Nausea, anorexia, stomatitis, and fatigue typically occur at the time of methotrexate administration. 8, 1

Minimize these effects by: 8

• Administering methotrexate by intramuscular or subcutaneous injection
• Splitting the dose
• Ensuring folate supplementation
• Administering with food or at bedtime