What is the treatment for oral methotrexate (MTX) toxicity in a patient with potential pre-existing renal or liver disease?

Treatment of Oral Methotrexate Toxicity with Leucovorin

For oral methotrexate toxicity, especially in patients with renal or liver disease, leucovorin (folinic acid) should be administered immediately at 10 mg/m² every 6 hours, with the dose escalated to 100 mg/m² every 3 hours if severe toxicity develops or methotrexate levels remain dangerously elevated. 1, 2, 3

Immediate Recognition and Action

Time is critical - leucovorin effectiveness decreases dramatically as time passes after methotrexate administration, becoming doubtful if initiated later than 24 hours after the last methotrexate dose. 4 Early treatment may be life-saving, particularly given the high mortality risk associated with methotrexate overdose. 4

Initial Assessment and Dosing

When methotrexate toxicity is suspected (fever, mouth ulcers, unexplained bruising, severe nausea, or signs of bone marrow suppression), immediately:

• Start leucovorin 10 mg/m² IV, IM, or PO every 6 hours until serum methotrexate level is less than 10⁻⁸ M (0.01 micromolar). 2, 3
• If gastrointestinal toxicity, nausea, or vomiting is present, administer leucovorin parenterally rather than orally. 2, 3
• Never administer leucovorin intrathecally - this is explicitly contraindicated. 2, 3

Risk Factors Requiring Heightened Vigilance

Patients with pre-existing renal or liver disease face substantially higher risk:

• Renal impairment: 85% of methotrexate is renally excreted, so any renal dysfunction causes drug accumulation and prolonged toxic exposure. 1 The British Association of Dermatologists recommends avoiding methotrexate entirely in patients with creatinine clearance <20 mL/min. 1, 5
• Liver disease: Active or recurrent hepatitis, elevated liver function tests, and chronic liver disease are relative contraindications that increase toxicity risk. 1
• Drug interactions: Numerous medications increase methotrexate toxicity by decreasing renal tubular excretion (NSAIDs, penicillins, trimethoprim, sulfonamides) or albumin binding (salicylates). 1

Escalation Protocol Based on Severity

For Moderate Toxicity

If significant clinical toxicity develops (worrisome decrement in leukocyte, platelet, or red cell count):

• Increase leucovorin to 10 mg/m² every 6 hours and continue until recovery. 1
• Monitor complete blood count, renal function (BUN, creatinine), and liver function tests daily. 1

For Severe Toxicity or Delayed Elimination

If 24-hour serum creatinine increases 50% over baseline, OR 24-hour methotrexate level >5 × 10⁻⁶ M, OR 48-hour level >9 × 10⁻⁷ M:

• Escalate to leucovorin 100 mg/m² IV every 3 hours until methotrexate level falls below 10⁻⁸ M. 2, 3
• This high-dose leucovorin can be used as sole therapy for methotrexate toxicity with tolerable morbidity, even with very high methotrexate levels. 6

Essential Supportive Measures

Leucovorin rescue must be combined with aggressive supportive care:

• Aggressive IV hydration: 3 liters per day to enhance renal clearance. 4, 2, 3
• Urinary alkalinization: Administer sodium bicarbonate to maintain urine pH ≥7.0, which prevents methotrexate crystallization in renal tubules. 4, 2, 3, 7
• Monitor for sepsis: High mortality risk exists with methotrexate overdose, requiring vigilant infection surveillance. 4

Duration of Treatment

• Continue leucovorin administration until serum methotrexate level falls below 5 × 10⁻⁸ M (0.05 micromolar). 2, 3
• In cases of delayed elimination, methotrexate levels may remain elevated for 7-17 days, requiring prolonged leucovorin rescue. 6
• The frequency of leucovorin dosing should be maintained every 6 hours (or every 3 hours for severe cases) throughout this period. 2, 3

Additional Rescue Measures for Severe Cases

For life-threatening toxicity with profound bone marrow suppression:

• Filgrastim (G-CSF) 5 mcg/kg/day subcutaneously may accelerate myeloid recovery. 4
• Thymidine 8 g/m²/day by continuous IV infusion can be added to leucovorin rescue in severe cases with renal dysfunction. 8, 9
• Higher doses of folic acid and leucovorin may be used as rescue therapy for significant methotrexate toxicities including painful stomatitis. 1

Prevention of Mucosal Toxicity

When methotrexate levels remain persistently elevated (>2.4 micromolar):

• Leucovorin eye drops and mouth washes should be started to prevent conjunctivitis and mucositis. 9
• These topical applications provide local rescue while systemic leucovorin addresses bone marrow and other organ toxicity. 9

Common Pitfalls to Avoid

• Do not delay leucovorin administration waiting for laboratory confirmation - clinical suspicion of toxicity warrants immediate treatment. 1, 4
• Do not use oral leucovorin if the patient has nausea, vomiting, or gastrointestinal toxicity - switch to parenteral administration. 2, 3
• Do not underestimate the duration of rescue needed - patients with renal impairment may require 10-17 days of leucovorin therapy. 6
• Do not forget urinary alkalinization - leucovorin alone is insufficient without maintaining urine pH ≥7.0. 2, 3, 7
• Do not use trimethoprim-containing antibiotics during or after methotrexate toxicity, as synergistic antifolate effects can cause fatal bone marrow suppression. 10

Monitoring Requirements During Rescue

• Serum creatinine and methotrexate levels: Measure at least once daily, preferably at 24-hour intervals. 2, 3
• Complete blood count with differential: Daily monitoring to detect worsening cytopenias. 1
• Urine pH: Check frequently to ensure maintenance at ≥7.0. 2, 3
• Fluid and electrolyte status: Close monitoring required until methotrexate level normalizes and renal function recovers. 2, 3