What are the guidelines for administering intravenous (IV) methotrexate?

Intravenous Methotrexate Administration Guidelines

For systemic inflammatory conditions, IV methotrexate is not a standard route of administration and should only be used in specific circumstances: when oral/subcutaneous routes have failed due to intolerance or inadequate bioavailability, or when high-dose protocols are required for oncologic indications. 1

Route Selection for Non-Oncologic Indications

• Oral methotrexate is the preferred initial route for psoriasis, rheumatoid arthritis, and inflammatory bowel disease, with typical weekly doses of 7.5-25 mg administered as a single dose 2

• Subcutaneous administration should be the next step before considering IV, as it provides superior bioavailability (nearly 100% vs. variable oral absorption) and may reduce gastrointestinal and mucosal toxicity 2

• IV methotrexate for inflammatory conditions is reserved for high-dose protocols (typically ≥500 mg/m²) in refractory cases that have failed conventional routes, requiring leucovorin rescue 1, 3

High-Dose IV Methotrexate Protocol (Oncologic or Refractory Inflammatory Disease)

Pre-Administration Requirements

• Delay administration if any of the following are present 1:

  • WBC count <1,500/μL
  • Neutrophil count <200/μL
  • Platelet count <75,000/μL
  • Serum bilirubin >1.2 mg/dL
  • SGPT >450 U
  • Active mucositis
  • Persistent pleural effusion (must be drained completely before infusion)

• Document adequate renal function: serum creatinine must be normal and creatinine clearance must be >60 mL/min before each course 1

• If serum creatinine increases by ≥50% from baseline, measure creatinine clearance to confirm it remains >60 mL/min even if creatinine is still within normal range 1

Hydration and Alkalinization Protocol

• Administer 1,000 mL/m² IV fluid over 6 hours prior to methotrexate infusion 1

• Continue hydration at 125 mL/m²/hr (3 liters/m²/day) during the infusion and for 2 days after completion 1

• Alkalinize urine to maintain pH >7.0 throughout methotrexate infusion and leucovorin therapy using oral or IV sodium bicarbonate 1

Dosing for High-Dose Protocols

• For refractory rheumatoid arthritis: 500 mg/m² IV every 2 weeks with leucovorin rescue has been studied, though this remains investigational 3

• For acute lymphocytic leukemia: 500-1,500 mg/m² IV (one-third by rapid infusion, two-thirds over 24 hours) with leucovorin rescue 4

• Reconstitute lyophilized powder immediately before use with preservative-free 5% dextrose or normal saline to 50 mg/mL concentration (1 gram vial with 19.4 mL diluent) 1

Leucovorin Rescue Protocol

Standard Rescue (Normal Methotrexate Elimination)

• Begin leucovorin 15 mg PO, IM, or IV every 6 hours starting 24 hours after methotrexate infusion, continuing for 60 hours (10 doses total) 1

• Expected methotrexate levels: approximately 10 μmol/L at 24 hours, 1 μmol/L at 48 hours, and <0.2 μmol/L at 72 hours 1

Delayed Late Elimination

• If methotrexate level remains >0.2 μmol/L at 72 hours or >0.05 μmol/L at 96 hours: continue leucovorin 15 mg every 6 hours until level falls below 0.05 μmol/L 1

Delayed Early Elimination or Acute Renal Injury

• If methotrexate level is ≥50 μmol/L at 24 hours, ≥5 μmol/L at 48 hours, OR serum creatinine increases by ≥100% at 24 hours 1:

  • Administer leucovorin 150 mg IV every 3 hours until methotrexate level <1 μmol/L
  • Then reduce to leucovorin 15 mg IV every 3 hours until methotrexate level <0.05 μmol/L
  • Continue aggressive hydration and urinary alkalinization
  • Consider high-flux hemodialysis if oliguric renal failure develops

• CRITICAL WARNING: Never administer leucovorin intrathecally 1

Monitoring Requirements

• Measure serum creatinine and methotrexate level 24 hours after starting methotrexate 1

• Continue daily measurements until methotrexate level falls below 0.05 μmol/L 1

• Monitor fluid and electrolyte status closely in patients with delayed elimination until renal function normalizes 1

Mandatory Folic Acid Supplementation

• Prescribe folic acid at least 5 mg weekly (or 1 mg daily) with all methotrexate regimens to reduce gastrointestinal, hepatic, and mucosal toxicity 2, 5

• Do not administer folic acid on the same day as methotrexate to avoid competitive cellular uptake 2, 5

Absolute Contraindications

• Pregnancy (teratogenic; women must use contraception and wait ≥3 months after discontinuation before attempting pregnancy) 2, 5
• Nursing mothers 2
• Alcoholism or chronic liver disease 2
• Immunodeficiency syndromes 2
• Bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia 2
• Hypersensitivity to methotrexate 2

Key Clinical Pitfalls

• The most common fatal error is daily instead of weekly dosing—always clearly document the specific day of the week for administration 5

• Renal impairment dramatically increases toxicity risk—even mild elevations in creatinine require dose adjustment or withholding 2, 1

• Drug interactions are frequently overlooked: NSAIDs, proton pump inhibitors, penicillins, and trimethoprim can all increase methotrexate toxicity by reducing renal clearance 2

• Pleural effusions and ascites act as "third spaces" that sequester methotrexate, causing prolonged elimination and severe toxicity—these must be drained before high-dose administration 1