What is the management of methotrexate toxicity?

Management of Methotrexate Toxicity

Immediate management of methotrexate toxicity requires prompt administration of leucovorin (folinic acid), aggressive hydration, urinary alkalinization, and close monitoring of serum methotrexate levels to prevent life-threatening complications. 1, 2

Recognition of Toxicity Types

• Common minor toxicities include nausea, anorexia, stomatitis, and fatigue that typically occur around the time of methotrexate administration 3
• Major life-threatening toxicities include myelosuppression (most common cause of death), pulmonary fibrosis, and hepatotoxicity 3
• Pulmonary toxicity should be suspected in patients with new pulmonary symptoms such as dry cough; this is more common in rheumatoid arthritis than psoriasis patients 3, 4

Risk Factors for Methotrexate Toxicity

• Renal insufficiency (primary risk factor due to impaired drug clearance) 3, 5
• Advanced age 3, 4
• Lack of folate supplementation 3, 6
• Methotrexate dosing errors 3
• Drug interactions, especially with NSAIDs and sulfonamides 3, 4
• Hypoalbuminemia 3
• Greater than moderate alcohol intake 3

Immediate Management of Methotrexate Overdose

• Administer leucovorin (folinic acid) as soon as possible - this is life-saving and time-critical 1, 2
• For recent oral ingestion (within 1 hour) of ≥1 mg/kg, administer activated charcoal 1
• Initiate aggressive hydration with intravenous fluids 1, 2
• Perform urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 2
• Measure serum methotrexate levels at least 4 hours after ingestion 1
• Initial leucovorin dose should be up to 100 mg/m² IV if methotrexate level is unknown 1
• Continue leucovorin with subsequent doses every 6 hours based on methotrexate levels 1

Management of Specific Toxicities

Hematologic Toxicity

• Monitor complete blood counts closely 3
• If total white cells <3.5×109/L or neutrophils <2×109/L, withhold methotrexate until counts recover 3
• For severe neutropenia (<1×109/L), patients should be warned to present for antibiotics ± GCSF if febrile 3
• For bone marrow suppression, administer filgrastim (G-CSF) at 5 μg/kg daily to accelerate myeloid recovery 1

Hepatotoxicity

• Monitor liver function tests regularly 3
• If transaminases exceed twice the upper limit of normal, stop methotrexate 3
• Consider transient elastography for patients with risk factors (BMI >28 kg/m², alcohol intake >14 drinks/week) 3

Pulmonary Toxicity

• Obtain baseline chest x-ray for all patients starting methotrexate 3, 4
• Monitor for symptoms of interstitial pneumonitis (dyspnea, dry cough, fever) 4
• Discontinue methotrexate if pulmonary symptoms develop and investigate promptly 4

Gastrointestinal Toxicity

• Minor GI symptoms may be minimized by administering methotrexate by intramuscular or subcutaneous injection, splitting the dose, folate supplementation, or administering with food or at bedtime 3
• Monitor for mucositis and stomatitis 1

Special Situations

Severe Toxicity with Delayed Methotrexate Clearance

• For patients with high methotrexate levels and impaired renal function, glucarpidase is indicated 2, 7
• Glucarpidase rapidly decreases serum methotrexate concentrations by 90-95% within 15 minutes 8
• Do not administer leucovorin within two hours before or after glucarpidase as leucovorin is a substrate for glucarpidase 2
• Continue leucovorin until methotrexate levels are <0.05 μmol/L or until hematological abnormalities and mucosal ulceration have resolved 1

Intrathecal Methotrexate Overdose

• Requires intensive systemic support, high-dose systemic leucovorin, alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion 2
• Intravenous and intrathecal glucarpidase treatment may be considered 2

Prevention of Toxicity

• All patients on methotrexate should receive folate supplementation (1-5 mg daily, except on the day of methotrexate administration) 3, 6
• Regular monitoring of complete blood counts, liver function tests, and renal function is essential 6
• Use a test dose (typically 2.5 or 5 mg) with CBC evaluation 5-6 days later in patients with risk factors for hematologic toxicity 3
• More frequent monitoring is suggested with methotrexate dosage increases 3

Common Pitfalls to Avoid

• Do not delay leucovorin administration while waiting for methotrexate levels - early treatment is critical 1
• Do not underestimate the severity of methotrexate overdose - there is high mortality risk even with appropriate treatment 1
• Neither hemodialysis nor peritoneal dialysis has been consistently shown to improve methotrexate elimination; glucarpidase is preferred when available 2, 9
• Recognize that pancytopenia can occur at any time during treatment, even after single doses of methotrexate 3