What is the recommended dose of leucovorin (folinic acid) to prevent or treat methotrexate (MTX) toxicity in patients on low-dose methotrexate therapy?

From the Guidelines

The recommended dose of leucovorin (folinic acid) for preventing or treating methotrexate toxicity in patients on low-dose methotrexate therapy is at least 5 mg per week, as strongly recommended by multinational evidence-based guidelines 1.

Key Considerations

• The dose of leucovorin should be adjusted based on the patient's response and tolerance to methotrexate therapy.
• Leucovorin should not be administered simultaneously with methotrexate, as it can interfere with methotrexate's therapeutic effects.
• Patients with renal impairment may require higher doses or prolonged administration of leucovorin since methotrexate clearance is reduced.
• Leucovorin works by providing reduced folate that bypasses methotrexate's blockade of dihydrofolate reductase, thereby allowing normal DNA synthesis in healthy cells while not interfering with methotrexate's therapeutic action against target cells when properly timed.

Administration Timing

• Leucovorin is typically administered 24 hours after methotrexate to minimize interference with methotrexate's therapeutic effects.

Rescue Therapy

• For rescue therapy in cases of developing toxicity, higher doses of leucovorin may be given until toxicity resolves, with the specific timing and dosage depending on the severity of the toxicity and the patient's response to treatment, as indicated by more recent guidelines and studies 1.

Patient Monitoring

• Patients on methotrexate therapy should be closely monitored for signs of toxicity, including mucositis, myelosuppression, and elevated liver enzymes, and leucovorin rescue should be initiated promptly if toxicity occurs.

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 The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less, and 5 to 15 mg of leucovorin per day has been recommended by some investigators.

The recommended dose of leucovorin to prevent or treat methotrexate toxicity in patients on low-dose methotrexate therapy is 5 to 15 mg per day. However, the label does not explicitly state the dose for low-dose methotrexate therapy, it provides a dose for counteracting hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate. For high-dose methotrexate therapy, the dose is 15 mg (10 mg/m2) every 6 hours. 2

From the Research

Leucovorin Dose in Low-Dose Methotrexate Therapy

The recommended dose of leucovorin (folinic acid) to prevent or treat methotrexate (MTX) toxicity in patients on low-dose methotrexate therapy is not strictly established, as it can vary based on the severity of toxicity and patient-specific factors. However, some studies provide insights into the dosing strategies:

• A study published in 2023 3 compared two doses of leucovorin (15 mg and 25 mg every 6 hours) in patients with severe low-dose methotrexate toxicity. The results showed no significant difference in survival or time-to hematological recovery between the two doses.
• Another study from 2008 4 described the use of leucovorin in an outpatient setting for high-dose methotrexate therapy, with a standard dose of 10 mg orally every 6 hours, which could be escalated to 20-30 mg orally every 6 hours based on methotrexate levels.
• Earlier research from 1980 5 suggested that the leucovorin dose required for rescue can be calculated based on the methotrexate serum concentration, with higher doses needed if methotrexate elimination is retarded.
• A 1998 study 6 explored the concept of minimal-dose leucovorin for selective protection of normal tissue during high-dose trimetrexate therapy, finding that a dose as low as 2.5 mg/m2 could be effective.
• A case report from 2001 7 highlighted the successful use of high-dose leucovorin (1,200 mg continuous i.v. infusion every 24 hours) combined with thymidine rescue therapy in a patient with high-dose methotrexate-induced acute renal failure.

Key Considerations

• The dose of leucovorin may need to be adjusted based on the severity of methotrexate toxicity and the patient's individual response.
• Monitoring of methotrexate levels and patient toxicity is crucial in determining the appropriate leucovorin dose.
• The use of leucovorin in combination with other rescue therapies, such as thymidine, may be beneficial in certain cases.

Dosing Strategies

• For low-dose methotrexate toxicity, leucovorin doses ranging from 15 mg to 25 mg every 6 hours have been used 3.
• In outpatient settings for high-dose methotrexate, a standard dose of 10 mg orally every 6 hours, with potential escalation to 20-30 mg orally every 6 hours, has been described 4.
• For severe toxicity or delayed methotrexate elimination, higher doses of leucovorin may be required, as suggested by the formula provided in the 1980 study 5.