levoleucovorin (Rx)

High-dose Methotrexate Rescue

Indicated for rescue after high-dose methotrexate therapy in osteosarcoma

Recommended initial dose of 7.5 mg q6hr based on methotrexate IV dose of 12 g/m²

Monitor serum creatinine and methotrexate levels at least once daily; continue levoleucovorin, hydration, and urinary alkalinization (pH ≥7) until methotrexate level <5 x 10-8 M (0.05 micromolar)

Normal methotrexate elimination

• Serum methotrexate level ~10 micromolar at 24 hr, 1 micromolar at 48 hr, and <0.2 micromolar at 96 hr post methotrexate infusion
• Initiate at 7.5 mg (~5 mg/m²) q6hr 24 hr after beginning methotrexate infusion for 60 hr (10 doses)

Delayed late methotrexate elimination

• Serum methotrexate levels >0.2 micromolar at 72 hr and >0.05 micromolar at 96 hr post methotrexate infusion
• Continue 7.5 mg IV q6hr until methotrexate level <0.05 micromolar

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

• Serum methotrexate level ≥50 micromolar at 24 hr, ≥5 micromolar at 48 hr, or serum creatinine level increased ≥100% at 24 hr post methotrexate infusion
• 75 mg IV q3hr until methotrexate level is <1 micromolar, followed by 7.5 mg IV q3hr until methotrexate level is <0.05 micromolar
• Extend levoleucovorin treatment for an additional 24 hr (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment

Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration

• May require higher levoleucovorin doses or prolonged administration

Folic Acid Antagonists Overdose or Impaired Elimination

Indicated for diminishing toxicity and counteracting effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists

7.5 mg (~5 mg/m²) q6hr until methotrexate level is <0.05 micromolar

Start as soon as possible after methotrexate overdosage or 24 hr of delayed elimination

Increase dose 50 mg/m² q3hr until methotrexate level <0.05 micromolar for the following:

• If serum creatinine at 24 hr increases ≥50% compared to baseline
• If methotrexate level at 24 hr >5 x 10^6 M
• If methotrexate level at 48 hr >9 x 10^7 M
• Continue hydration (3 L/day) and urinary alkalinization with sodium bicarbonate Adjust bicarbonate dose to maintain urine pH at ≥7

Metastatic Colorectal Cancer

Indicated, in combination with 5-fluorouracil (5-FU), for palliative treatment in patients with advanced metastatic colorectal cancer

Regimens are used for treatment of colorectal cancer

• Levoleucovorin 100 mg/m² IV over a minimum of 3 min, followed by 5-FU 370 mg/m² qDay for 5 consecutive days OR
• Levoleucovorin 10 mg/m² IV followed by 5-FU 425 mg/m2 qDay for 5 consecutive days
• Repeat q4Weeks for 2 courses, then q4-5Weeks, if patient recovered from toxicity from the prior course
• Do not adjust levoleucovorin dosage for toxicity

Refer to fluorouracil prescribing information for information on dosage and dosage modifications for adverse reactions

Dosing Considerations

Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin

Limitations of use

• Not indicated for pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12
• Refer to prescribing information for complete monitoring instructions

High-dose Methotrexate Rescue

<6 years: Safety and efficacy not established

≥6 years

• Indicated for rescue after high-dose methotrexate therapy in osteosarcoma
• Recommended initial dose of 7.5 mg q6hr based on methotrexate IV dose of 12 g/m²
• Monitor serum creatinine and methotrexate levels at least once daily; continue levoleucovorin, hydration, and urinary alkalinization (pH ≥7) until methotrexate level <5 x 10-8 M (0.05 micromolar)

• Normal methotrexate elimination

  • Serum methotrexate level ~10 micromolar at 24 hr, 1 micromolar at 48 hr, and <0.2 micromolar at 96 hr post methotrexate infusion
  • Initiate at 7.5 mg (~5 mg/m²) q6hr 24 hr after beginning methotrexate infusion for 60 hr (10 doses)

• Delayed late methotrexate elimination

  • Serum methotrexate levels >0.2 micromolar at 72 hr and >0.05 micromolar at 96 hr post methotrexate infusion
  • Continue 7.5 mg IV q6hr until methotrexate level <0.05 micromolar

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

  • Serum methotrexate level ≥50 micromolar at 24 hr, ≥5 micromolar at 48 hr, or serum creatinine level increased ≥100% at 24 hr post methotrexate infusion
  • 75 mg IV q3hr until methotrexate level is <1 micromolar, followed by 7.5 mg IV q3hr until methotrexate level is <0.05 micromolar
  • Extend levoleucovorin treatment for an additional 24 hr (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment

• Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration

  • May require higher levoleucovorin doses or prolonged administration

Contraindicated (0)

Serious - Use Alternative (1)

• trimethoprim

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

Monitor Closely (0)

Minor (0)

• trimethoprim

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