Methotrexate Monitoring Protocol
Regular laboratory monitoring is essential when prescribing methotrexate to detect potential toxicity early and prevent serious complications including bone marrow suppression, hepatotoxicity, and renal toxicity. 1
Pre-Treatment Assessment
- Complete blood count (CBC) with differential and platelet counts
- Liver function tests (AST, ALT, alkaline phosphatase, albumin, bilirubin)
- Renal function tests (serum creatinine, BUN, GFR)
- Chest X-ray
- Consider serum PIIINP (procollagen III peptide) for patients with psoriasis
- Hepatitis B and C serologic studies
- Consider baseline liver biopsy only for patients with:
Monitoring Schedule
Initial Phase (First 1-6 months)
- CBC, liver function tests, and renal function: Every 1-2 weeks for the first month
- Once stable: Every 2-3 weeks for the next 1-2 months 1
Maintenance Phase
- CBC, liver function tests, renal function: Every 1-3 months
- For patients with psoriasis: Monitor PIIINP every 3 months 1
- More frequent monitoring with dose increases or during periods of increased risk (dehydration, drug interactions) 2
Specific Monitoring Parameters
Hematologic Toxicity
- Monitor for: WBC <3×10⁹/L, neutrophils <1×10⁹/L, platelets <100×10⁹/L, MCV >105 fL
- Action for abnormal results: Withhold/decrease methotrexate dose and consider hematology consultation 1
Hepatotoxicity
- Monitor for: AST/ALT elevations, decreased serum albumin
- Action for mild elevations (<2× normal): Repeat in 2-4 weeks
- Action for significant elevations (≥2-3× normal): Withhold methotrexate, repeat tests, consider gastroenterology consultation
- For persistent elevations in 5 of 9 AST measurements over 12 months or decline in serum albumin below normal range: Consider liver biopsy 1, 3
- For psoriasis patients: Consider referral if PIIINP >8 mg/L on two occasions, or >10 mg/L on one occasion 1
Pulmonary Toxicity
- Monitor for: New or increasing dyspnea or dry cough
- Action: Withhold methotrexate, obtain chest X-ray and pulmonary function tests, consult respiratory team 1
Renal Function
- Adjust dose for impaired renal function
- More frequent monitoring in patients with renal impairment 2, 4
Drug Interactions Requiring Monitoring
- NSAIDs: Can increase methotrexate levels and toxicity
- Penicillins: Can reduce renal clearance of methotrexate
- Probenecid: Decreases renal tubular transport
- Trimethoprim/sulfamethoxazole: Can increase bone marrow suppression
- Salicylates, phenylbutazone, phenytoin, sulfonamides: Can displace methotrexate from albumin 2
Patient Education
- Emphasize weekly dosing schedule (not daily)
- Explain need for regular blood tests
- Advise to seek urgent medical attention for signs of toxicity:
- Fever/flu-like illness
- Mouth ulceration
- Unexplained bruising or bleeding
- Nausea, vomiting, abdominal pain
- Breathlessness or cough 1
- Advise about limiting alcohol intake
- Warn about potential drug interactions
Common Pitfalls and Caveats
- Dosing errors: Ensure patients understand weekly (not daily) dosing to prevent fatal toxicity
- Renal impairment: Significantly increases risk of toxicity; adjust dose accordingly
- Alcohol consumption: Increases risk of hepatotoxicity; advise limiting intake
- Drug interactions: Particularly with NSAIDs, can significantly increase toxicity
- Dehydration: Can increase methotrexate levels; advise maintaining adequate hydration
- Folic acid supplementation: Recommended to reduce side effects 1, 2
Management of Toxicity
If toxicity occurs:
- Withhold methotrexate
- For severe toxicity: Consider leucovorin (folinic acid) rescue, aggressive hydration, and urinary alkalinization
- For severe cases with delayed clearance: Consider glucarpidase 5, 2
By following this structured monitoring protocol, clinicians can minimize the risk of serious complications while maintaining the therapeutic benefits of methotrexate.