Drug Essentials Levoleucovorin, a Cytoprotectant

Approved Drugs: Levoleucovorin (Fusilev)

Indications

Drug is indicated for rescue of normal cells following high dose methotrexate administration for osteosarcoma. It is also indicated to diminish and counteract methotrexate toxicity if the drug is not effectively eliminated, or for inadvertent overdose of folic acid antagonists.

Mechanism of Action

Drug is a folate analogue and the active isomer of 5-formyl tetrahydrofolic acid. This drug “rescues normal cells” as it provides tetrahydrofolic acid directly to normal cells so that they can resume active cell division after having been stopped by methotrexate.

Cells that divide frequently, such as those lining the intestines, need tetrahydrofolic acid to make DNA and RNA.

Methotrexate is a folate antagonist which blocks the enzyme dihydrofolate reductase (DHFR) and prevents folic acid from being converted to tetrahydrofolic acid.

High dose methotrexate is a lethal dose of chemotherapy and patients depend upon levoleucovorin or leucovorin to rescue the normal cells so that normal body cells can continue to divide.

Metabolism

Peak levels of total tetrahydrofolate are found 0.9 hours after drug administration, with a mean terminal half-life of 5.1 hours.

Drug Administration

• A 50 mg vial of drug is aseptically reconstituted with 5.3 mL of 0.9% Sodium Chloride for Injection USP, yielding 10 mg/mL. Withdraw ordered amount.
• Drug is given starting exactly 24 hours after high dose methotrexate is initiated, and dosage depends on the excretion of the methotrexate (MTX) from the blood. The usual dose is 5 mg/m² every 6 hours for 10 doses; for example, for a methotrexate dose of 12 grams/m², along with urine alkalinization (urine pH > 7.0) and aggressive IV hydration, a levoleucovorin dose of 7.5 mg (5 mg/m²) is given every 6 hours for 10 doses until MTX level is < 5 × 10^-8 M.
• Serum creatinine levels should be monitored, as this determines the excretion of methotrexate, as well as serum MTX levels daily.
• Do not administer >16 mL of reconstituted drug (160 mg levoleucovorin) per minute (large amount of calcium).

Guidelines for Levoleucovorin Dosage and Administration based on clinical situation:

• Normal MTX Excretion: At 24 hours, expect serum MTX level to be 10 micromolar; at 48 hours 1 micromolar and at 72 hours < 0.2 micromolar. Levoleucovorin dose 7.5 mg IV q 6 hr × 60 hr (10 doses starting at 24 h after start of MTX infusion).
• Delayed Late MTX Elimination: (At 72 hours, serum MTX remains > 0.2 micromolar, and more than 0.05 micromolar 96 h after MTX administration); Levoleucovorin 7.5 mg is continued every 6 hours until the methotrexate level is < 0.05 micromolar.
• Delayed Early MTX Elimination and/or Evidence of Acute Renal Injury: (serum MTX is ≥ 50 micromolar at 24 hr, ≥ 5 micromolar at 48 h after administration; or 100% greater increase in serum creatinine at 24 h after MTX administration (eg, increase from 0.5 mg/dL to > 1.0 mg/dL): Levoleucovorin dose is 75 mg IV every 3 h until MTX level is < 1 micromolar, then 7.5 mg IV every 3 h until MTX level is < 0.05 micromolar.
• Inadvertent MTX Overdosage: Begin levoleucovorin as soon as possible, and within 24 h of MTX administration when there is delayed MTX excretion. Dose 7.5 mg (5 mg/m²) IV every 6 h until serum MTX < 10^-8 M.
• Monitor serum creatinine and MTX levels q 24 hr; if serum creatinine has increased 50% over baseline, or if 24 hr MTX level is > 5 × 10^-6 M, or the 48 hr MTX level is > 9 × 10^-7 M, the dose of levoleucovorin should be increased to 50 mg/m² q 3 hr until MTX level is < 10^-8 M.
• Ensure daily hydration of at least 3 liters, and urine should be alkalinized with sodium bicarbonate to keep the urine pH at ≥ 7.0.

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Adverse Reactions by System (most common are in boldface type)

CNS: Confusion, taste perversion
GI:Stomatitis, vomiting, nausea, diarrhea, dyspepsia, typhlitis
Neuro: neuropathy
Respiratory: Dyspnea
Skin: Dermatitis

Patient Education

Teach patient: Purpose of levoleucovorin and frequent blood tests (serum creatinine and MTX).

Interactions

Do not mix with other agents in the same admixture, as they may precipitate. Levoleucovorin has interactions with certain drugs:

• 5-fluorouracil (5-FU): enhanced toxicity of 5-FU.
• Trimethoprim-sulfamethoxazole: may reduce treatment effectiveness when used together in the treatment of
  HIV-infected patients with Pneumocystis carinii pneumonia.
• Phenobarbitol, phenytoin, pyrimidone: may counteract effects of the anticonvulsant.

Special Considerations

• Levoleucovorin is indicated for intravenous administration ONLY; do not give intrathecally.
• Drug is dosed at one-half the dose of the racemic (leucovorin) dose.

Contraindications/Precautions

Patients who have had allergic reactions to folic or folinic acid. Administer cautiously to nursing mothers, as it is not known if drug is excreted in human milk.