Adult Dosing

Rescue after high-dose methotrexate therapy

• Normal methotrexate elimination
• 15 mg IM/IV q6 hrs over 60 hrs x 10 doses, Start at 24 hrs after start of methotrexate infusion
• Continue till methotrexate level is <0.05 micromolar
• Follow this regimen if methotrexate level is approx 10 micromolar at 24 hrs, 1 micromolar at 48 hrs or <0.2 micromolar at 72 hrs after infusion

• Delayed late methotrexate elimination
• 15 mg IM/IV q6 hrs, continue till methotrexate level <0.05 micromolar
• Follow this regimen if methotrexate level remains >0.2 micromolar at 72 hrs and >0.05 micromolar at 96 hrs after infusion

• Delayed late methotrexate elimination and/or acute renal injury
• 150 mg IV q3 hrs, continue till methotrexate level <1 micromolar
• Followed by 15 mg IV q3 hrs till methotrexate level <0.05 micromolar
• Follow this regimen if methotrexate level is 50 micromolar at 24 hrs or 5 micromolar at 48 hrs after infusion or 100% increase in serum Cr at 24 hrs after infusion

Impaired methotrexate elimination and overdosage

• 15 mg IM/IV q6 hrs, continue till methotrexate level is 0.01 micromolar
• Increase dose to 150 mg IM/IV q3 hrs if serum Cr >50% at 24 hrs or methotrexate level at 48 hrs is >0.9 micromolar
• Initiate rescue within 24 hrs of methotrexate infusion and concomitantly administer NaHCO3 to maintain urine pH 7

Combination with 5-Fluorouracil for colorectal cancer

• With 5-Fluorouracil 370 mg/m²/day IV
• 200 mg/m² slow IV over 3 minutes x 4-5 days, repeat q4 wks for 2 courses, then q4-5 wks

• With 5-Fluorouracil 425 mg/m²/day IV
• 20 mg/m² IV x 4-5 days, repeat q4 wks for 2 courses, then q4-5 wks

Folate deficient megaloblastic anemia

• Upto 1 mg IM/IV qd
• Max: 1 mg/day

Note:

• Reconstitute with sterile water for injection or bacteriostatic water for injection (benzyl alcohol preserved)
• IV infusion rate should not exceed 160 mg/minute
• Do not mix with 5-fluorouracil infusion
• Do not inject intrathecally

Pediatric Dosing

Rescue after high-dose methotrexate therapy

• Normal methotrexate elimination
• 15 mg IM/IV q6 hrs over 60 hrs x 10 doses, Start at 24 hrs after start of methotrexate infusion
• Continue till methotrexate level is <0.05 micromolar
• Follow this regimen if methotrexate level is approx 10 micromolar at 24 hrs, 1 micromolar at 48 hrs or <0.2 micromolar at 72 hrs after infusion

• Delayed late methotrexate elimination
• 15 mg IM/IV q6 hrs, continue till methotrexate level <0.05 micromolar
• Follow this regimen if methotrexate level remains >0.2 micromolar at 72 hrs and >0.05 micromolar at 96 hrs after infusion

• Delayed late methotrexate elimination and/or acute renal injury
• 150 mg IV q3 hrs, continue till methotrexate level <1 micromolar
• Followed by 15 mg IV q3 hrs till methotrexate level <0.05 micromolar
• Follow this regimen if methotrexate level is 50 micromolar at 24 hrs or 5 micromolar at 48 hrs after infusion or 100% increase in serum Cr at 24 hrs after infusion

Impaired methotrexate elimination and overdosage

• 15 mg IM/IV q6 hrs, continue till methotrexate level is 0.01 micromolar
• Increase dose to 150 mg IM/IV q3 hrs if serum Cr >50% at 24 hrs or methotrexate level at 48 hrs is >0.9 micromolar
• Initiate rescue within 24 hrs of methotrexate infusion and concomitantly administer NaHCO3 to maintain urine pH 7

Combination with 5-Fluorouracil for colorectal cancer

• Not indicated

Note:

• Reconstitute with sterile water for injection or bacteriostatic water for injection (benzyl alcohol preserved)
• IV infusion rate should not exceed 160 mg/minute
• Do not inject intrathecally

[Outline]

• Adult Dosing
• Pediatric Dosing

• Rescue in high dose methotrexate therapy in osteosarcoma
• Treatment of impaired methotrexate elimination and inadvertent overdosages of folic acid antagonists
• Treatment of megaloblastic anemias due to folic acid deficiency
• Combination therapy with 5-fluorouracil in palliative treatment of advanced colorectal cancer

• Hypersensitivity to any of the ingredients of the product
• Treatment of pernicious anemia
• Treatment of other megaloblastic anemias secondary to vitamin B-12 deficiency
• Intrathecal administration

• N/A

Renal Dose Adjustment

• Renal impairment: Dose adjustments not defined

Hepatic Dose Adjustment

• Hepatic impairment: Dose adjustments not defined

• Use of leucovorin for treatment of pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12 is contraindicated due to risk of hematologic remission
• In case of accidental overdosage of folic acid antagonists, prompt administration of leucovorin is advised. Any delay would decrease its effectiveness in counteracting hematologic toxicity
• Avoid intrathecal administration as it may be fatal
• Monitor serum methotrexate concentration to determine the optimal dose and treatment duration of leucovorin
• Fluid accumulation, renal insufficiency or inadequate hydration may delay excretion of methotrexate. Higher doses of leucovorin or extended administration is advised in such cases
• Doses >10 mg/m² should be reconstituted with sterile water for injection and used immediately as some diluents may contain benzyl alcohol
• Do not inject more that 160 mg/minute via IV due to calcium content of leucovorin
• Leucovorin may enhance the toxicity of 5-flurouracil. Use lower doses of 5-flurouracil when used in combination
• Risk of gastro-intestinal toxicities (stomatitis and diarrhea) increases with combination therapy of leucovorin and flurouracil, especially in elderly and debilitated patients. Monitor patients with diarrhea until diarrhea has resolved to avoid risk to clinical worsening which may be fatal
• Rare cases of seizures and/or syncope have been reported in cancer patients the using leucovorin, usually in combination with fluoropyrimidine
• Concurrent use of trimethoprim-sulfamethoxazole for treatment of pneumonia in HIV patients may result in increased mortality and failure of treatment
• Monitor electrolytes, liver function, CBC with differential and platelets before and during therapy. Adjust dose of flurouracil as per WBC and platelet counts
• Discontinue flurouracil therapy if tumor progression is observed or WBC and platelets levels do not reach 4,000/mm³ and 130,000/mm³ respectively within two weeks
• Leucovorin/5-flurouracil should be administered by medical personnel experienced in use of antimetabolite chemotherapy due to risk of toxicity

Cautions: Use cautiously in

• Renal insufficiency
• Fluid accumulation
• Diarrhea
• CNS metastates
• Elderly
• Debilitated patients

Pregnancy Category:C

Breastfeeding: Safety unknown. As many drugs are excreted in human milk, manufacturer advises caution while administering to nursing women.

• CV: Syncope
• CNS: Seizures
• GI: Nausea, vomiting, diarrhea, stomatitis, constipation, anorexia
• HEMA: Leukopenia, thrombocytopenia
• DERM: Alopecia, dermatitis
• HYPERSENSITIVITY: Allergic sensitization, anaphylactoid reactions, urticaria
• MISC: Infection, lethargy, malaise, fatigue, toxicity

• Antidote; serves as a cofactor in reactions utilizing folates, thereby counteracting the toxic effects of methotrexate and folic acid antagonists. Also enhances action of flurouracil by binding to enzyme thymidylate synthetase
• Metabolized in liver and intestine to active metabolite 5-methyltetrahydrofolate
• Excreted in urine (80-90%) and feces
• Half-life: 6.2 hrs

US Trade Name(s)

• Only generic available

US Availability

leucovorin (generic)

• INJ: 10 mg/mL (50 mL vial)
• PWDR for INJ: 50 mg/vial
• PWDR for INJ: 100 mg/vial
• PWDR for INJ: 200 mg/vial
• PWDR for INJ: 350 mg/vial
• PWDR for INJ: 500 mg/vial

Canadian Trade Name(s)

• Only generic available

Canadian Availability

leucovorin (generic)

• INJ: 10 mg/mL (5, 30, 50 mL vials)

UK Trade Name(s)

• Refolinon

UK Availability

calcium folinate (generic)

• INJ: 3 mg/mL (1 mL ampoule)
• INJ: 7.5 mg/mL (2 mL ampoule)
• INJ: 10 mg/mL (10, 20, 30 mL vials)

Refolinon

• INJ: 3 mg/mL (2, 10 mL ampoules)

Australian Trade Name(s)

• Only generic available

Australian Availability

calcium folinate (generic)

• INJ: 50 mg/5 mL
• INJ: 100 mg/10 mL

leucovorin (generic)

• INJ: 15 mg/2 mL
• INJ: 50 mg/5 mL
• INJ: 100 mg/10 mL
• INJ: 300 mg/30 mL

[Outline]

Hematology/Oncology

Antidote

Detoxifying Agents

Emergency/Critical Care

Antidote

Detoxifying Agents