leucovorin (Rx)

Methotrexate Overdose

Administer as soon as possible and within 24 hr methotrexate level is >10^-6 M or 48 hour level is >9 x 10^-7 M, the dose of leucovorin should be increased to 100 mg/m² IV every 3 hours until methotrexate level is <10^-8 M

Dosing considerations

• Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly; bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater

High Dose Methotrexate Rescue

10 mg/m² IV q6hr for 10 doses; starts 24 hours after beginning of methotrexate infusion  

May give PO after 1st IV dose

Adjust dose as follows:

Normal methotrexate elimination

• Serum methotrexate level approximately 10 micromolar, 24 hr after administration, 1 micromolar at 48 hr, <0.2 micromolar at 72 hr
  • Administer 15 mg PO, IM, or IV q6hr for 60 hr (10 doses starting at 24 hr after start of methotrexate infusion

Delayed late methotrexate elimination

• Serum methotrexate level remaining above 0.2 micromolar at 72 hr, and more than 0.05 micromolar at 96 hr after administration
  • Continue 15 mg PO, IM, or IV q6hr, until methotrexate level <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury

• Serum methotrexate level of 50 micromolar or more at 24 hr, or 5 micromolar or more at 48 hr after administration, or a 100% or greater increase in serum creatinine level at 24 hr after methotrexate administration (eg, increase from 0.5 mg/dL to a level of 1 mg/dL or more)
  • Administer 150 mg IV q3hr until methotrexate level is <1 micromolar; then 15 mg IV q3hr until methotrexate level is <0.05 micromolar

Dosing considerations

• In presence of gastrointestinal toxicity, nausea or vomiting, administer leucovorin parenterally; do not administer leucovorin intrathecally; serum creatinine and methotrexate levels should be determined at least once daily
• Administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until methotrexate level is below 5 x 10^-8 M (0.05 micromolar)

Megaloblastic Anemia Due to Folate Deficiency

Up to 1 mg daily; there is no evidence that doses >1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg

Coadministration with Trimetrexate (Discontinued)

20 mg/m² IV/PO q6hr (for PO, round dose up to next 25 mg increment)  

Dose adjustment for both trimetrexate & leucovorin may be necessary if hematologic toxicity occurs

Advanced Colorectal Carcinoma (with 5FU)

Recommended 20 mg/m² IV followed by 425 mg/m² fluorouracil  

Dose reduction treatment pause may be necessary based on hematologic toxicity

Methanol Poisoning

1 mg/kg (50-70 mg adults) IV q4-6hr

Trimethoprim Toxicity

10 mg/m² PO q6hr

Other Indications & Uses

Bone marrow suppression due to folic acid antagonism

Methotrexate Overdose

Administer as soon as possible and within 24 hr methotrexate level is >10^-6 M or 48 hour level is >9 x 10^-7 M, the dose of leucovorin should be increased to 100 mg/m² IV every 3 hours until methotrexate level is <10^-8 M

Dosing considerations

• Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly; bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater

High Dose Methotrexate Rescue

10 mg/m² IV q6hr for 10 doses; starts 24 hr after beginning of methotrexate infusion

May give PO after 1st IV dose

Adjust dose as follows:

Normal methotrexate elimination

• Serum methotrexate level approximately 10 micromolar, 24 hr after administration, 1 micromolar at 48 hr, <0.2 micromolar at 72 hr
  • Administer 15 mg PO, IM, or IV q6hr for 60 hr (10 doses starting at 24 hr after start of methotrexate infusion

Delayed late methotrexate elimination

• Serum methotrexate level remaining above 0.2 micromolar at 72 hr, and more than 0.05 micromolar at 96 hr after administration
  • Continue 15 mg PO, IM, or IV q6hr, until methotrexate level <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury

• Serum methotrexate level of 50 micromolar or more at 24 hr, or 5 micromolar or more at 48 hr after administration, or a 100% or greater increase in serum creatinine level at 24 hr after methotrexate administration (eg, increase from 0.5 mg/dL to a level of 1 mg/dL or more)
  • Administer 150 mg IV q3hr until methotrexate level is <1 micromolar; then 15 mg IV q3hr until methotrexate level is <0.05 micromolar

Dosing considerations

• In presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally; do not administer leucovorin intrathecally; serum creatinine and methotrexate levels should be determined at least once daily
• Administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until methotrexate level is below 5 x 10^-8 M (0.05 micromolar)

Megaloblastic Anemia Due to Folate Deficiency

Up to 1 mg daily; there is no evidence that doses > 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg

Trimethoprim Toxicity

10 mg/m² PO q6hr

Contraindicated (0)

Serious - Use Alternative (1)

• trimethoprim

  leucovorin decreases effects of trimethoprim by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Monitor for trimethoprim treatment failure or decreased efficacy when coadministered with leucovorin, especially when used with sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients who are HIV positive .

Monitor Closely (3)

• capecitabine

  leucovorin increases effects of capecitabine by pharmacodynamic synergism. Use Caution/Monitor.

• fluorouracil

  leucovorin increases toxicity of fluorouracil by pharmacodynamic synergism. Use Caution/Monitor.

• glucarpidase

  glucarpidase will decrease the level or effect of leucovorin by increasing metabolism. Modify Therapy/Monitor Closely. Leucorvorin, reduced folates, and folate antimetabolites are substrates for glucarpidase (hydrolyzes glutamate residue from folic acid and antifolates)

Minor (0)

• capecitabine

  Monitor Closely (1)leucovorin increases effects of capecitabine by pharmacodynamic synergism. Use Caution/Monitor.

• fluorouracil

  Monitor Closely (1)leucovorin increases toxicity of fluorouracil by pharmacodynamic synergism. Use Caution/Monitor.

• glucarpidase

  Monitor Closely (1)glucarpidase will decrease the level or effect of leucovorin by increasing metabolism. Modify Therapy/Monitor Closely. Leucorvorin, reduced folates, and folate antimetabolites are substrates for glucarpidase (hydrolyzes glutamate residue from folic acid and antifolates)

• trimethoprim

  Serious - Use Alternative (1)leucovorin decreases effects of trimethoprim by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Monitor for trimethoprim treatment failure or decreased efficacy when coadministered with leucovorin, especially when used with sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients who are HIV positive .