LEVOleucovorin is the active form of leucovorin calcium. It is used in patients with methotrexate toxicity or overdose and in patients on anti-folate chemotherapy.

LEVOleucovorin Uses:

• Metastatic Colorectal Cancer:

  • Treatment of advanced, metastatic colorectal cancer (in combination with fluorouracil)

• Folic acid antagonist overdose:

  • As an antidote to diminish toxicity in inadvertent overdosage of folic acid antagonists

• High-dose methotrexate rescue:

  • Rescue agent after high-dose methotrexate therapy in osteosarcoma treatment

• Impaired methotrexate elimination:

  • As an antidote to diminish the toxicity and counteract effects of impaired methotrexate elimination

• Limitations of use:

  • Levoleucovorin is not indicated for the treatment of pernicious anemia or megaloblastic anemias secondary to the lack of vitamin B12 (due to the risk of progressive neurologic manifestations despite hematologic remission).

LEVOleucovorin Dose in Adults:

Note:

• Levoleucovorin, when substituted in place of leucovorin calcium (the racemic form), is dosed at one-half the usual dose of leucovorin calcium:

LEVOleucovorin Dose in the treatment of metastatic Colorectal Cancer:

• IV:

  • The following regimens have been used (in combination with fluorouracil; fluorouracil doses may need to be adjusted for toxicity; no adjustment is required for the levoleucovorin dose):
    • 100 mg/m²/day over at least 3 minutes (followed by fluorouracil 370 mg/m²/day) for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks depending on recovery from toxicities, or
    • 10 mg/m²/day (followed by fluorouracil 425 mg/m²/day) for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks depending on recovery from toxicities, or

  • Substitution dosing:

    • Levoleucovorin, when substituted in place of leucovorin calcium within a chemotherapy regimen, is dosed at one-half the usual dose of leucovorin calcium

• High-dose methotrexate rescue: IV:

  • Usual dose:
    • 7.5 mg (~5 mg/m²) QID for 10 doses, beginning 24 hours after the start of the methotrexate infusion (based on a methotrexate dose of 12 g/m² IV over 4 hours).
    • Levoleucovorin (and hydration and urinary alkalinization to pH ≥7) should be continued and/or adjusted until the methotrexate level is <0.05 micromolar (5 x 10 M) as follows:

      • Normal methotrexate elimination (serum methotrexate levels ~10 micromolar at 24 hours post-administration, 1 micromolar at 48 hours and <0.2 micromolar at 72 hours post-infusion):

        • • 7.5 mg IV QID for 10 doses.

      • Delayed late methotrexate elimination (serum methotrexate levels >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours post methotrexate infusion):

        • • Continue 7.5 mg IV QID until methotrexate level is <0.05 micromolar

      • Delayed early methotrexate elimination and/or evidence of acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, ≥5 micromolar at 48 hours or a doubling or more of the serum creatinine level at 24 hours post methotrexate infusion [likely to develop reversible renal failure]):

        • • 75 mg IV every 3 hours until methotrexate level is <1 micromolar
          • Followed by 7.5 mg IV every 3 hours until methotrexate level is <0.05 micromolar

      • Significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment (as described above):

        • • Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses) in subsequent treatment cycles.

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

        • • May require higher levoleucovorin doses or prolonged administration.

  • Folic acid antagonist overdose:

    • IV:

      • 7.5 mg (~5 mg/m²) QID
      • Continue until the methotrexate level is <0.05 micromolar (5 x 10 M).
      • Initiate treatment as soon as possible after methotrexate overdose.
      • Monitor serum creatinine & methotrexate levels at least every 24 hours.
      • Increase the levoleucovorin dose to 50 mg/m IV every 3 hours if the 24-hour serum creatinine has increased 50% over baseline, or if the 24-hour methotrexate level is >5 micromolar (5 x 10 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10 M)
      • Continue levoleucovorin until the methotrexate level is <0.05 micromolar (5 x 10 M).
      • Hydration (aggressive [3 L/day]) & urinary alkalinization (urinary pH ≥7 with sodium bicarbonate) should also be maintained.

  • Impaired methotrexate elimination:

    • IV:
      • 7.5 mg (~5 mg/m² ) QID
      • Continue until the methotrexate level is <0.05 micromolar (5 x 10 M).
      • Initiate treatment within 24 hours of methotrexate administration if elimination is impaired.
      • Monitor serum creatinine and methotrexate levels at least every 24 hours.
      • Increase the levoleucovorin dose to 50 mg/m IV every 3 hours if the 24-hour serum creatinine has increased 50% over baseline, or if the 24-hour methotrexate level is >5 micromolar (5 x 10 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10 M)
      • Continue levoleucovorin until the methotrexate level is <0.05 micromolar (5 x 10 M).
      • Hydration (aggressive [3 L/day])& urinary alkalinization (urinary pH ≥7 with sodium bicarbonate) should also be maintained.

LEVOleucovorin Dose in Childrens:

Note:

•  Levoleucovorin, when substituted in place of leucovorin calcium (the racemic form), is dosed at one-half the usual dose of leucovorin calcium.

High-dose methotrexate rescue:

• Children and Adolescents:

  • IV:
    • 7.5 mg (~5 mg/m²) QID, beginning 24 hours after the start of the methotrexate infusion (based on a methotrexate dose of 12 g/m IV over 4 hours).
    • Levoleucovorin (and hydration and urinary alkalinization) should be continued and/or adjusted until the methotrexate level is <0.05 micromolar (5 x 10 M).
    • In trials, the youngest reported patients were 4 to 6 years of age.
    • The dosage & frequency should be determined based on methotrexate elimination and serum level:

      • Normal methotrexate elimination (serum methotrexate levels ~10 micromolar at 24 hours post-administration, 1 micromolar at 48 hours, and <0.2 micromolar at 72 hours post-infusion):

        • • 7.5 mg IV QID for 10 doses

      • Delayed late methotrexate elimination (serum methotrexate levels >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours post-methotrexate infusion):

        • • Continue 7.5 mg IV QID until methotrexate level is <0.05 micromolar

      • Delayed early methotrexate elimination and/or evidence of acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, ≥5 micromolar at 48 hours, or a doubling or more of the serum creatinine level at 24 hours post-methotrexate infusion):

        • • 75 mg IV every 3 hours until methotrexate level is <1 micromolar, followed by 7.5 mg IV every 3 hours until methotrexate level is <0.05 micromolar

      • Significant clinical toxicity in the presence of less severe abnormalities in methotrexate elimination or renal function (as described above):

        • • Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses) in subsequent treatment cycles.

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

        • • May require higher levoleucovorin doses or prolonged administration.

  • Methotrexate overdose (inadvertent):

    • Children and Adolescents:
      • 5 mg (~5 mg/m²) QID; continue until the methotrexate level is <0.01 micromolar (10 M).
      • Initiate treatment as soon as possible after methotrexate overdose.
      • Increase the levoleucovorin dose to 50 mg/m² IV every 3 hours if the 24-hour serum creatinine has increased 50% over baseline, or if the 24-hour methotrexate level is >5 micromolar (5 x 10 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10 M); continue levoleucovorin until the methotrexate level is <0.01 micromolar (10 M).
      • Hydration (aggressive) and urinary alkalinization (with sodium bicarbonate; goal urine pH ≥7) should also be maintained.

Pregnancy Risk Category: C

• Levoleucovorin refers to the Levo isomeric version of racemic leucovorin. It is a biologically active form folic acid.
• Folic acid should be taken in adequate amounts during pregnancy.
• Refer to Folic Acid Monograph.
• The information available on the treatment of colorectal carcinoma in pregnancy is not extensive.

Use of LEVOleucovorin during breastfeeding

• It is unknown if breast milk contains levoleucovorin.
• Levoleucovorin refers to the Levo isomeric version of racemic leucovorin. It is a biologically active form folic acid.
• Breastfeeding women should consume adequate amounts of Folic Acid.
• Refer to Folic Acid Monograph.
• Combination of fluorouracil or methotrexate can be used to administer levoleucovorin.
• Refer to Methotrexate and Fluorouracil monographs.

LEVOleucovorin Dose in Kidney Disease:

• No initial dosage adjustments provided in the manufacturer’s labeling
• In patients with impaired methotrexate elimination, dose adjustment should be based on methotrexate levels.

LEVOleucovorin Dose in Liver disease:

• No initial dosage adjustments provided in the manufacturer’s labeling.

• Adverse reactions reported with levoleucovorin either as a part of combination chemotherapy or following chemotherapy.

Common Side Effects of LEVOleucovorin:

• Central nervous system:

  • Fatigue
  • Malaise

• Dermatologic:

  • Dermatitis
  • Alopecia

• Gastrointestinal:

  • Stomatitis
  • Diarrhea
  • Nausea
  • Vomiting
  • Anorexia
  • Decreased appetite
  • Abdominal pain

• Neuromuscular & skeletal:

  • Asthenia

Less Common Side Effects of LEVOleucovorin:

• Central nervous system:

  • Confusion
  • Neuropathy

• Gastrointestinal:

  • Dysgeusia
  • Dyspepsia
  • Typhlitis

• Renal:

  • Renal insufficiency

• Respiratory:

  • Dyspnea

Contraindications to LEVOleucovorin:

• Hypersensitivity to leucovorin products, folic acid, folic acids, or any other component of the formulation.

Warnings and precautions

• Gastrointestinal toxicities:

  • Fluorouracil's toxicity is increased by levoleucovorin and leucovorin Calcium
  • Patients receiving weekly doses of leucovorin calcium and fluorouracil have experienced death from diarrhea, severe enterocolitis, and dehydration.
  • Fluorouracil is often combined with levoleucovorin to treat colorectal carcinoma.
  • The fluorouracil dose can be reduced when taken together (compared to fluorouracil without levoleucovorin).
  • Fluorouracil-related gastrointestinal toxicities, such as diarrhea and stomatitis, may be more frequent than usual.
  • Before you start treatment (initial, repeat), it is important to resolve any symptoms of gastrointestinal toxicities.

• Syncope and seizure:

  • Syncope and seizures have been reported after taking leucovorin Calcium.
  • This is usually in patients who have CNS metastases or are at higher risk for other health problems.

LEVOleucovorin: Drug Interaction

Monitoring parameters:

• High-dose methotrexate therapy, impaired methotrexate elimination, or methotrexate overdose (inadvertent):

  • Serum methotrexate and creatinine levels at least every 24 hours.
  • Monitor urine pH.
  • Monitor fluid & electrolyte status in patients with delayed methotrexate elimination (likely to experience renal toxicity).
  • For colorectal cancer, monitor for diarrhea and stomatitis.

How to administer LEVOleucovorin?

IV:

• For IV administration only; do not administer intrathecally.
• Administer by slow IV push or infusion over at least 3 minutes.
• Do not exceed 160 mg/minute for products containing calcium.

For colorectal cancer:

• Levoleucovorin has also been administered (off-label administration rate) as an IV infusion over 2 hours.

Mechanism of action of LEVOleucovorin:

• Levoleucovorin is used to counteract the toxic and therapeutic effects of folic acids antagonists (eg methotrexate), which inhibit dihydrofolate reductase.
• Levoleucovorin, the Levo isomeric pharmacologic active leucovorin form (levo-leucovorin doesn't require dihydrofolate reduction).
• Leucovorin is a reduced derivative of Folic Acid. It supplies the cofactor that methotrexate lacks.
• Leucovorin increases the activity and toxicity of fluorouracil. It stabilizes the binding of 5-fluoro-2’deoxyuridine-5’-monophosphate to thymidylate synthetase, thereby causing inhibition.

Metabolism:

• Converted to the active reduced form of folate, 5-methyl-tetrahydrofolate (5-methylTHF; active)

Half-life elimination:

• Total-tetrahydrofolate: 5.1 hours; (6S)-5-methyl-5,6,7,8-tetrahydrofolate: 6.8 hours

Time to peak serum:

• IV (healthy volunteers; 15 mg dose): 0.9 hours

International Brands of LEVOleucovorin:

• Fusilev
• Khapzory
• Elvorine
• Isovorin

LEVOleucovorin Brand Names in Pakistan:

No Brands Available in Pakistan.