What is the treatment approach for an adult patient with a history of cancer, autoimmune disease, or inflammatory condition suspected of having methotrexate toxicity?

Management of Methotrexate Toxicity

Immediately administer leucovorin (folinic acid) as soon as methotrexate toxicity is suspected—this is life-saving and time-critical, with efficacy diminishing dramatically after 24 hours. 1

Immediate Recognition and Initial Management

Critical First Steps

• Discontinue methotrexate immediately upon suspicion of toxicity, regardless of serum methotrexate levels, as serum concentrations do not correlate with clinical toxicity 1, 2
• Administer leucovorin (folinic acid) urgently: Initial dose of 10-15 mg/m² (approximately 15 mg for average adult) IV or orally, repeated every 6 hours until toxicity resolves 1
• For suspected recent oral overdose (≥1 mg/kg within 1 hour), give activated charcoal immediately 1
• Initiate aggressive IV hydration to enhance renal elimination 1, 3
• Implement urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 3

Common Pitfall to Avoid

Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote; folic acid is for prevention, not acute treatment 1

Risk Factor Assessment

Identify high-risk patients who require enhanced monitoring and lower thresholds for intervention:

• Renal insufficiency (most critical risk factor due to 85% renal excretion) 4, 1, 2
• Advanced age (>50-70 years) 1, 2
• Lack of folate supplementation 1, 2
• Drug interactions, particularly NSAIDs, trimethoprim-sulfamethoxazole, penicillins, salicylates, and sulfonamides 4, 5, 2
• Hypoalbuminemia (increases free drug levels) 1
• Dosing errors (especially accidental daily instead of weekly dosing) 1

Management of Specific Toxicities

Hematologic Toxicity (Most Lethal Complication)

Myelosuppression accounts for 67 of 164 methotrexate-associated fatalities 1

• Monitor complete blood count with differential immediately and daily during acute toxicity 1, 6
• Withhold methotrexate if: WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 4, 1
• For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily to accelerate myeloid recovery 1
• Warn patients to present immediately for antibiotics ± G-CSF if febrile 4
• Continue leucovorin every 6 hours until blood counts recover 1

Hepatotoxicity

• Stop methotrexate if transaminases exceed 2× upper limit of normal on repeat testing 4, 1
• Liver function abnormalities can be transitory; many normalize without permanent discontinuation (only 5% require stopping) 4
• For patients with BMI >28 kg/m² or alcohol intake >14 drinks/week, perform transient elastography (FibroScan) screening 4
• Routine liver biopsy after prolonged use is not necessary, as cirrhosis risk is much lower than previously thought 4

Pulmonary Toxicity

Pulmonary fibrosis accounts for 30 of 164 methotrexate-associated fatalities 1

• Suspect in patients presenting with dyspnea, dry cough, and fever 4, 1
• Obtain chest X-ray immediately (baseline chest X-ray should have been performed before starting therapy) 4, 1
• Most cases are reversible on withdrawal of methotrexate 4
• Continue leucovorin rescue therapy during acute pulmonary toxicity 1

Gastrointestinal and Mucosal Toxicity

• Mucositis, stomatitis, diarrhea, and abdominal pain are common manifestations 1, 2
• These symptoms may appear 6-23 days after exposure in severe toxicity (methotrexate aminopterin syndrome) 1
• Continue leucovorin rescue and supportive care with IV fluids and electrolyte replacement 1

Monitoring During Acute Toxicity

• Complete blood count with differential: Daily until recovery 1
• Renal function (creatinine, BUN): Daily, as renal dysfunction perpetuates toxicity 3
• Liver function tests: Every 2-4 days 1
• Serum methotrexate levels (if available): Monitor clearance, though levels do not correlate with toxicity severity 2
• Urine output and pH: Maintain urine output >100 mL/hour and pH >7.0 with alkalinization 3

Advanced Interventions for Severe Toxicity

When Standard Measures Fail

• Glucarpidase (carboxypeptidase G2): For plasma methotrexate levels >1 µmol/L with delayed elimination and renal dysfunction 7, 3
  • Available through compassionate use from National Institutes of Health 1
  • Rapidly cleaves methotrexate to inactive metabolites 3
• High-flux hemodialysis: Consider for severe renal failure with persistent elevated methotrexate levels 5, 3
  • Standard dialysis is relatively ineffective; requires high-flux dialyzer 5

Critical Drug Interactions to Address

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk 1
• NSAIDs reduce renal elimination—particularly dangerous with any dose of methotrexate 4, 1, 5
• Penicillins reduce renal clearance—monitor closely and consider alternative antibiotics 4, 5
• Salicylates and sulfonamides displace methotrexate from albumin binding, increasing free drug levels 4, 5

Prevention of Future Toxicity

Once acute toxicity resolves and if methotrexate is to be restarted:

• Mandatory folic acid supplementation: 1-5 mg daily (except on methotrexate day) or 5 mg weekly 4, 1, 8
• Baseline monitoring before restart: CBC with differential, comprehensive metabolic panel, liver function tests, chest X-ray 1, 6
• Enhanced monitoring schedule: Weeks 2,4,8, and 12 after restart, then every 3 months 4, 6
• Dose reduction: Consider 50% dose reduction in patients with creatinine clearance 20-50 mL/min; avoid if <20 mL/min 8, 7
• Patient education: Emphasize weekly (not daily) dosing to prevent fatal dosing errors 5, 9

Special Considerations

Pregnancy and Teratogenicity

• Methotrexate is highly teratogenic and must be discontinued immediately if pregnancy is discovered 4
• Women should avoid conception for 6 months after stopping methotrexate 4
• Men should wait 3 months after discontinuation before attempting conception 4

Renal Impairment

• Methotrexate is contraindicated if eGFR <30 mL/min in rheumatoid arthritis patients 7
• Renal dysfunction is the primary risk factor for toxicity, as 85% of methotrexate is renally excreted 4, 1
• Even mild renal impairment dramatically increases toxicity risk and requires dose adjustment 8, 2