From the FDA Drug Label
Leucovorin 15 mg (10 mg/m2) should be administered IM, IV, or PO every 6 hours until serum methotrexate level is less than 10 -8 M If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10 -6 M or the 48 hour level is greater than 9 x 10 -7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10 -8 M.
The recommended leucovorin dose for low-dose methotrexate toxicity in patients with impaired renal function is 15 mg (10 mg/m2) every 6 hours, which may be increased to 150 mg (100 mg/m2) IV every 3 hours if the patient's condition worsens, as indicated by increased serum creatinine or methotrexate levels 1.
From the Research
For low-dose methotrexate toxicity in patients with impaired renal function, leucovorin (folinic acid) should be administered at a dose of 15-25 mg every 6 hours until methotrexate levels fall below 0.05 μmol/L, as supported by the most recent study 2. In severe cases with significant renal impairment, higher doses of 50-100 mg every 6 hours may be required. Treatment should begin as soon as toxicity is suspected, ideally within 24-48 hours of methotrexate administration. The duration of leucovorin rescue typically ranges from 3-5 days but should continue until methotrexate levels are undetectable or symptoms resolve. Some key points to consider in the management of low-dose methotrexate toxicity include:
- Intravenous administration is preferred initially, especially in patients with gastrointestinal symptoms, with transition to oral dosing when appropriate.
- Hydration and urinary alkalinization (maintaining urine pH >7) should be implemented concurrently to enhance methotrexate excretion.
- Leucovorin works by providing reduced folate that bypasses the methotrexate-induced blockade of dihydrofolate reductase, allowing for continued DNA synthesis in normal cells while counteracting methotrexate's toxic effects.
- Methotrexate levels should be monitored regularly during treatment to guide leucovorin dosing adjustments, as seen in studies such as 3 and 4. It's also important to note that while carboxypeptidase-G2 can be used in cases of severe methotrexate toxicity, as reported in 5, leucovorin remains the primary treatment for low-dose methotrexate toxicity. Overall, the management of low-dose methotrexate toxicity requires careful monitoring and adjustment of leucovorin dosing, as well as supportive care measures to minimize toxicity and prevent long-term complications.