What is the management of suspected methotrexate toxicity in a patient?

Management of Methotrexate Toxicity

Immediate Recognition and Action

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

Critical First Steps

• Administer leucovorin immediately at 10-15 mg/m² (approximately 15 mg for average adult) IV or orally, then repeat every 6 hours until toxicity resolves or methotrexate levels fall below 0.05 µmol/L 1, 2
• If methotrexate levels are unknown or elevated, give up to 100 mg/m² IV leucovorin initially 1
• Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote 1
• For recent oral ingestion (≥1 mg/kg within 1 hour), administer activated charcoal immediately 1

Supportive Measures

• Initiate aggressive IV hydration to enhance renal elimination 1, 2
• Perform urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules 1, 2
• Obtain urgent complete blood count with differential, comprehensive metabolic panel including liver and renal function tests 1

Recognition of Toxicity Types

Life-Threatening Major Toxicities

Myelosuppression accounts for the majority (67 out of 164) of methotrexate-associated fatalities and is the most lethal complication 1:

• Symptoms typically manifest 6-23 days after exposure 1
• Monitor for fever, unusual fatigue, bleeding, or signs of infection 1
• If WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L, withhold methotrexate 1
• For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily 1

Pulmonary toxicity accounts for 30 of 164 methotrexate-associated fatalities 1:

• Suspect in patients with new dyspnea, dry cough, or fever 1
• Obtain chest X-ray immediately 1
• Pulmonary symptoms usually resolve with discontinuation 1

Hepatotoxicity:

• Stop methotrexate if transaminases exceed 2× upper limit of normal on repeat testing 1
• Many liver function abnormalities are transitory and normalize without stopping methotrexate (only 5% require permanent discontinuation) 1

Common Minor Toxicities

• Nausea, anorexia, stomatitis, and fatigue typically occur around the time of methotrexate administration 1
• Mucositis, oral ulceration, vomiting, and diarrhea are common early manifestations 1

Risk Factors Requiring Enhanced Vigilance

Renal insufficiency is the primary risk factor due to 85% renal excretion and impaired drug clearance 1:

• Patients with any degree of renal impairment require enhanced monitoring and lower thresholds for intervention 1
• Methotrexate is contraindicated if eGFR <30 mL/minute 3

Other critical risk factors 1:

• Advanced age (>50-70 years)
• Lack of folate supplementation
• Methotrexate dosing errors (especially daily instead of weekly dosing)
• Drug interactions, particularly NSAIDs (reduce renal elimination), trimethoprim-sulfamethoxazole (absolutely contraindicated—causes severe bone marrow suppression), sulfonamides, and penicillins
• Hypoalbuminemia
• Volume depletion

Management of Specific Clinical Scenarios

Accidental Daily Dosing (Instead of Weekly)

• Immediate hospital admission for evaluation and monitoring 1
• Measure serum methotrexate levels at least 4 hours after last ingestion 1
• Administer leucovorin rescue therapy immediately—do not wait for laboratory confirmation 1
• Symptoms typically manifest 6-23 days after the dosing error begins 1
• Monitor closely for signs of sepsis and treat accordingly 1

Severe Hematologic Toxicity

• For life-threatening bone marrow suppression, administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily to accelerate myeloid recovery 1
• Monitor for sepsis with high vigilance, as mortality risk is substantial 1
• Warn patients with severe neutropenia to present immediately for antibiotics ± G-CSF if febrile 1

Refractory Cases with Elevated Methotrexate Levels

• If plasma methotrexate levels remain elevated despite standard measures, glucarpidase (carboxypeptidase-G2) should be obtained 1, 2
• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 2
• Glucarpidase is indicated for toxic methotrexate concentrations (>1 µmol/L) in patients with delayed clearance due to impaired renal function 2, 3

Neurotoxicity with Seizures

• Immediately discontinue methotrexate and initiate antiepileptic treatment 4
• Obtain urgent brain MRI with T2-weighted and diffusion-weighted sequences to assess for methotrexate-induced leukoencephalopathy 4
• Administer leucovorin up to 100 mg/m² IV 4
• Subacute neurotoxicity is often reversible with appropriate management 4

Prevention of Future Toxicity

Mandatory Interventions

All patients on methotrexate must receive folate supplementation 1:

• Dosing: 1-5 mg daily (except on methotrexate day) OR 5 mg weekly 1
• This reduces gastrointestinal, liver, and hematologic toxicity without compromising efficacy 1

Monitoring Schedule

Initial 3 months 1:

• Complete blood count, liver function tests, and creatinine at least monthly

After stabilization 1:

• Complete blood count and liver function tests every 3 months
• Baseline chest X-ray for all patients starting methotrexate 1

Patient Education to Prevent Dosing Errors

• Prescribe only 2.5 mg tablets to make daily dosing physically impossible 1
• Write dose in full uppercase letters on prescription 1
• Use patient-held record books documenting weekly dosing schedule 1
• Emphasize that methotrexate is taken weekly, not daily—mistaken daily use has led to fatal toxicity 2
• Prescriptions should not be written or refilled on a PRN basis 2

Critical Pitfalls to Avoid

• Delaying leucovorin administration—efficacy is doubtful if initiated >24 hours after last methotrexate dose 1
• Assuming low serum levels exclude toxicity—serum methotrexate levels do not correlate with toxicity; treat based on clinical presentation 1, 5
• Administering folic acid instead of folinic acid—only leucovorin bypasses methotrexate's metabolic block 1
• Concurrent use of trimethoprim-sulfamethoxazole—absolutely contraindicated due to severe bone marrow suppression risk from dual folic acid antagonism 1
• Using NSAIDs with methotrexate—reduces renal elimination and is particularly dangerous at any dose 1
• Stopping antibiotics prematurely—methotrexate should remain discontinued until infection resolves and antibiotic course is complete 1

Special Considerations

Pregnancy Exposure

• If conception occurs while taking methotrexate, stop the drug immediately and initiate or continue folic acid supplementation 6
• Termination of pregnancy is not mandatory 6
• Refer to an obstetrician to discuss risks of teratogenicity and further management 6

Hemodialysis Considerations

• Neither standard hemodialysis nor peritoneal dialysis effectively improves methotrexate elimination 2
• However, acute intermittent hemodialysis using a high-flux dialyzer has been reported to achieve effective clearance 2