Leucovorin, also known as folinic acid or calcium folinate, is a medication used primarily as an antidote to counteract the toxic effects of methotrexate and other folate antagonists. Methotrexate is a chemotherapy drug that works by inhibiting the enzyme dihydrofolate reductase, which is necessary for the synthesis of DNA, RNA, and proteins. However, it can also affect normal cells that require folate for their functions.

Leucovorin works by providing a form of folate that bypasses the need for dihydrofolate reductase, thereby helping to maintain the normal functions of cells, particularly in the bone marrow and gastrointestinal tract, which are often affected by methotrexate toxicity. It's also used in combination with 5-fluorouracil (5-FU) to enhance the effectiveness of this chemotherapy agent.

Leucovorin or calcium folinate is the reduced or activated form of folic acid that restores folate stores required for the synthesis of RNA and DNA. It is used in the treatment of the following conditions:

• For the palliative treatment of advanced Colorectal cancer in combination with 5-fluorouracil.

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• As a rescue drug to reduce the toxicity of high-dose Methotrexate treatment in patients with osteosarcoma.

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• For the treatment of megaloblastic anemia due to folate deficiency when oral therapy is not feasible.

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• Off label Uses of Leucovorin in Adults include:
  • As a cofactor therapy in methanol toxicity
  • In the neoadjuvant treatment of Bladder cancer
  • Advanced or metastatic oesophagal cancer
  • Advanced or metastatic Gastric cancer
  • Metastatic Pancreatic cancer
  • For the prevention of pyrimethamine-induced hematologic toxicity
  • For the treatment of ectopic tubal Pregnancy in combination with methotrexate.

Leucovorin Dose in Adult

Note: If you need a dose higher than 25 mg, it's better to get it through injections rather than taking it by mouth, because the body can't absorb it as well in higher doses when taken orally.

Leucovorin Dose in the treatment of advanced Colorectal cancer:  

• Leucovorin is typically given intravenously (IV).
• The dosage varies depending on the specific regimen used.
• One common regimen involves administering 200 mg/m²/day over at least 3 minutes for 5 days every 4 weeks for 2 cycles, followed by maintenance therapy every 4 to 5 weeks.
• Another regimen involves a lower dosage of 20 mg/m²/day for 5 days every 4 weeks for 2 cycles, followed by maintenance therapy every 4 to 5 weeks.

Note: These dosages are usually combined with fluorouracil, another chemotherapy drug. It's important to consult appropriate literature or guidelines for more detailed information on the various leucovorin-containing regimens available for treating colorectal cancer.

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Leucovorin Use in the treatment of Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose:  

• In cases of overdose with folic acid antagonists like trimethoprim or pyrimethamine, leucovorin is typically administered orally.
• The recommended dose ranges from 5 to 15 mg taken once daily.

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Leucovorin Use in the treatment of Folate-deficient megaloblastic anemia:  

• Leucovorin is typically administered via intramuscular (IM) or intravenous (IV) injection.
• The recommended dose is generally less than or equal to 1 mg given once daily.

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Leucovorin Use in the treatment of High-dose methotrexate-rescue:  

• Initial Dose:
  • Start with 15 mg (~10 mg/m²) orally, intramuscularly (IM), or intravenously (IV).
  • Begin 24 hours after starting methotrexate infusion.
  • Repeat every 6 hours for a total of 10 doses, until methotrexate level is less than 0.05 micromolar.
• Normal Methotrexate Elimination:
  • If methotrexate elimination is normal, with serum levels decreasing appropriately, continue with 15 mg every 6 hours for 60 hours (10 doses) starting 24 hours after methotrexate infusion begins.
• Delayed Late Methotrexate Elimination:
  • If methotrexate elimination is delayed, continue with 15 mg (oral, IM, or IV) every 6 hours until methotrexate level is less than 0.05 micromolar.
• Delayed Early Methotrexate Elimination and/or Acute Renal Injury:
  • If there's delayed early methotrexate elimination or acute renal injury, use IV administration.
  • Start with 150 mg every 3 hours until methotrexate level is less than 1 micromolar.
  • Then switch to 15 mg every 3 hours until methotrexate level is less than 0.05 micromolar.

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Leucovorin Use in the treatment of High-dose methotrexate overexposure:  

• At 24 hours:
  • For methotrexate levels of ≥100 micromolar: Start with 1,000 mg/m² IV every 6 hours.
  • For methotrexate levels of ≥10 to <100 micromolar: Begin with 100 mg/m² IV every 3 or 6 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Administer 10 mg/m² IV or orally every 3 or 6 hours.
• At 48 hours:
  • For methotrexate levels of ≥100 micromolar: Continue with 1,000 mg/m² IV every 6 hours.
  • For methotrexate levels of ≥10 to <100 micromolar: Give 100 mg/m² IV every 3 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Provide 100 mg/m² IV every 6 hours or 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours.
• At 72 hours:
  • For methotrexate levels of ≥10 micromolar: Administer 100 to 1,000 mg/m² IV every 3 to 6 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Use 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours.
  • For methotrexate levels of ~0.1 to 1 micromolar: Dose at 10 mg/m² IV or orally every 3 to 6 hours.
  • If serum creatinine increases more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m² IV every 3 hours, then adjust according to methotrexate levels.
• Monitoring and Discontinuation:
  • Monitor methotrexate levels daily.
  • Discontinue leucovorin when methotrexate level is less than 0.1 micromolar.

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Leucovorin Use in the inadvertent treatment of Methotrexate overdose:

• Initial Dose:
  • Start with 10 mg/m² orally, intramuscularly (IM), or intravenously (IV) every 6 hours.
  • Continue until the methotrexate level is less than 0.01 micromolar.
• Adjustment:
  • If serum creatinine increases more than 50% above baseline 24 hours after methotrexate administration, or if the 24-hour methotrexate level is over 5 micromolar, or if the 48-hour methotrexate level is over 0.9 micromolar, increase leucovorin dose to 100 mg/m² IV every 3 hours.
  • Continue this increased dose until the methotrexate level is less than 0.01 micromolar.
• Caution:
  • Avoid intrathecal administration of leucovorin; it's not recommended.

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Leucovorin off-label use in the treatment of neoadjuvant Bladder cancer:  

• Leucovorin is typically administered intravenously (IV) or orally.
• The recommended dosage is 15 mg every 6 hours for 4 doses on days 2 and 9 of the treatment cycle.
• This regimen starts 24 hours after each dose of methotrexate and is usually used in combination with methotrexate, vinblastine, and cisplatin, as per the regimen outlined in Griffiths 2011.

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Leucovorin off-label use in the treatment of Cofactor therapy in methanol toxicity:

• Leucovorin is typically administered intravenously (IV).
• The recommended dosage is 1 mg per kilogram of body weight, with a maximum dose of 50 mg, given over 30 to 60 minutes.
• This administration should be repeated every 4 to 6 hours.
• Therapy should continue until methanol and formic acid have been completely eliminated from the body, as advised by Barceloux in 2002.

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Leucovorin off-label use in the treatment of advanced or metastatic Esophageal cancer:  

Leucovorin is typically administered intravenously (IV). The dosage and regimen depend on the specific combination therapy being used:

• With Fluorouracil and Irinotecan (FOLFIRI):
  • Administer 400 mg/m² over 2 hours once every 2 weeks. This regimen should continue until disease progression or unacceptable toxicity, as recommended by Guimbaud in 2014.
• With Fluorouracil and Oxaliplatin:
  • Administer 200 mg/m² over 2 hours once every 2 weeks. This regimen should also continue until disease progression or unacceptable toxicity, based on the guidance provided by Al-Batran in 2008.

Both regimens involve combining leucovorin with other chemotherapy agents and are tailored to the individual patient's condition and treatment response.

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Leucovorin off-label use in the treatment of advanced or metastatic Gastric cancer:  

Leucovorin is typically administered intravenously (IV). The dosage and regimen depend on the specific combination therapy being used:

• With Fluorouracil and Irinotecan (FOLFIRI):
  • Administer 400 mg/m² over 2 hours once every 2 weeks. This regimen should continue until disease progression or unacceptable toxicity, as recommended by Guimbaud in 2014.
• With Fluorouracil and Oxaliplatin:
  • Administer 200 mg/m² over 2 hours once every 2 weeks. This regimen should also continue until disease progression or unacceptable toxicity, based on the guidance provided by Al-Batran in 2008.

Both regimens involve combining leucovorin with other chemotherapy agents and are tailored to the individual patient's condition and treatment response.

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Leucovorin off label use in the treatment of metastatic Pancreatic cancer:  

Leucovorin is typically administered intravenously (IV) in combination with other chemotherapy agents. The recommended dosage and regimen, based on the Conroy 2011 study, are as follows:

• Leucovorin Dose:
  • Administer 400 mg/m² over 2 hours once every 2 weeks.
• Combination Therapy:
  • Leucovorin is used in combination with fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX).
• Duration:
  • Treatment should be continued for at least 6 months.

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Leucovorin off label use in the treatment of Pemetrexed toxicity (cytopenias or mucositis):  

Leucovorin is typically administered intravenously (IV). The recommended dosage and regimen, based on clinical trial data as outlined in the Alimta prescribing information from 2017, are as follows:

• Leucovorin Dose:
  • Start with 100 mg/m² as an initial IV dose.
  • Followed by 50 mg/m² IV every 6 hours for a total of 8 days.
• Indications for Use:
  • This regimen is used in cases of:
    • CTC grade 4 leukopenia for 3 or more days.
    • CTC grade 4 neutropenia for 3 or more days.
    • CTC grade 4 thrombocytopenia, bleeding associated with grade 3 thrombocytopenia, or grade 3 or 4 mucositis (to be administered immediately).

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Leucovorin off label use in the treatment of Prevention of pyrimethamine-induced hematologic toxicity in HIV-infected patients:

Leucovorin is typically administered orally in combination with pyrimethamine. The recommended doses for various conditions, as outlined in the HHS Guidelines for Opportunistic Infections in Adults from 2015, are as follows:

Isosporiasis (Isospora belli):

• Treatment: 10 to 25 mg once daily (in combination with pyrimethamine).
• Chronic Maintenance (Secondary Prophylaxis): 5 to 10 mg once daily (in combination with pyrimethamine).

Pneumocystis pneumonia (PCP):

• Prophylaxis (Primary and Secondary):
  • 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or
  • 10 mg once daily (in combination with pyrimethamine [with atovaquone]).

Toxoplasma gondii encephalitis:

• Primary Prophylaxis:
  • 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or
  • 10 mg once daily (in combination with pyrimethamine [with atovaquone]).
• Treatment:
  • 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, atovaquone, or azithromycin]).
  • Note: Leucovorin dose may be increased to 50 to 100 mg/day in divided doses in cases of pyrimethamine toxicity (rash, nausea, bone marrow suppression).
• Chronic Maintenance (Secondary Prophylaxis):
  • 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine or clindamycin]) or
  • 10 mg once daily (in combination with pyrimethamine [with atovaquone]).

These dosages aim to minimize hematologic toxicity associated with pyrimethamine therapy and should be administered as part of a comprehensive treatment.

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Leucovorin off label use in the treatment of Tubal ectopic pregnancy in combination with a multidose methotrexate regimen:

Leucovorin is typically administered intramuscularly (IM) according to the following protocol:

• Regimen:
  • Methotrexate is administered on days 1, 3, 5, and 7.
  • Leucovorin calcium is alternated with methotrexate, given on days 2, 4, 6, and 8.
• Dosage:
  • Leucovorin calcium is given at a dose of 0.1 mg/kg on the specified days.
• Monitoring:
  • Serum human chorionic gonadotropin (hCG) levels should be measured on each day of methotrexate administration.
• Response Assessment:
  • If serum hCG decreases by more than 15% from the previous measurement, methotrexate and leucovorin should be discontinued. The total treatment may involve between 1 and 4 doses of each.
  • If serum hCG decreases by less than 15% from the previous measurement, methotrexate administration continues (maximum 4 doses), followed by leucovorin calcium administration the next day.

This regimen aims to effectively treat tubal ectopic pregnancy while minimizing adverse effects and requires close monitoring of hCG levels throughout the treatment course.

Leucovorin Dose in Children

Leucovorin Use in the treatment of Folic acid antagonist (eg, pyrimethamine, trimethoprim) overdose:  

For Infants, Children, and Adolescents:

• Take leucovorin orally.
• The recommended daily dose ranges from 5 to 15 mg.

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Leucovorin Use in the treatment of Folinic-acid-dependent seizures: 

For Infants and Children:

• Start with an initial oral dose of 2.5 to 5 mg twice daily.
• Gradually increase the dose if seizures persist, up to a maximum of 8 mg per kilogram of body weight per day (for example, 25 mg three times daily).
• These dosages are based on limited data from case series and reports involving patients with refractory seizures who were on multiple anticonvulsants, with or without pyridoxine supplementation.

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Leucovorin Use in the treatment of Megaloblastic anemia secondary to folate deficiency:  

For Infants, Children, and Adolescents:

• Leucovorin is administered either intramuscularly (IM) or intravenously (IV).
• The recommended daily dose is less than or equal to 1 mg.
• This dosage aims to address megaloblastic anemia caused by folate deficiency.

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Leucovorin Use in the treatment of High-dose methotrexate rescue:  

For Infants, Children, and Adolescents:

• Initial Dose:
  • Administer 15 mg (~10 mg/m²) every 6 hours orally, intramuscularly (IM), or intravenously (IV).
  • Start 24 hours after the beginning of the methotrexate infusion. This is based on a methotrexate dose of 12 to 15 g/m² IV over 4 hours.
  • Leucovorin (along with hydration and urinary alkalinization) should be continued and/or adjusted until the methotrexate level is less than 0.05 micromolar (5 x 10^-5 M).
• Normal Methotrexate Elimination:
  • If methotrexate elimination is normal (serum levels decreasing appropriately), administer 15 mg every 6 hours for 10 doses beginning 24 hours after the start of methotrexate infusion.
• Delayed Late Methotrexate Elimination:
  • If methotrexate elimination is delayed (serum levels remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration), continue leucovorin calcium 15 mg every 6 hours until methotrexate level is less than 0.05 micromolar.
• Delayed Early Methotrexate Elimination and/or Acute Renal Injury:
  • If there's delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration), administer 150 mg every 3 hours intravenously until methotrexate level is less than 1 micromolar, then switch to 15 mg every 3 hours until methotrexate level is less than 0.05 micromolar.

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Leucovorin Use in the treatment of High-dose methotrexate overexposure:

Infants, Children, and Adolescents:

• At 24 hours:
  • For methotrexate levels of ≥100 micromolar: Initiate leucovorin at 1,000 mg/m² IV every 6 hours.
  • For methotrexate levels of ≥10 to <100 micromolar: Begin with 100 mg/m² IV every 3 or 6 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Administer 10 mg/m² IV or orally every 3 or 6 hours.
• At 48 hours:
  • For methotrexate levels of ≥100 micromolar: Continue with 1,000 mg/m² IV every 6 hours.
  • For methotrexate levels of ≥10 to <100 micromolar: Administer 100 mg/m² IV every 3 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Provide 100 mg/m² IV every 6 hours or 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours.
• At 72 hours:
  • For methotrexate levels of ≥10 micromolar: Administer 100 to 1,000 mg/m² IV every 3 to 6 hours.
  • For methotrexate levels of ~1 to 10 micromolar: Use 10 mg/m² IV or orally to 100 mg/m² IV every 3 hours.
  • For methotrexate levels of ~0.1 to 1 micromolar: Dose at 10 mg/m² IV or orally every 3 to 6 hours.
  • If serum creatinine increases more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m² IV every 3 hours, then adjust according to methotrexate levels above.
  • Monitor methotrexate levels daily, and consider discontinuing leucovorin when methotrexate level is below 0.1 micromolar; some suggest below 0.08 micromolar as preferable (Bleyer, 1978).

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Leucovorin Use in the treatment of inadvertent Methotrexate overdose:

For Infants, Children, and Adolescents:

• Administer leucovorin orally, intramuscularly (IM), or intravenously (IV).
• Start with a dose of 10 mg/m² every 6 hours until the methotrexate level is less than 0.01 micromolar.
• If serum creatinine increases more than 50% above baseline 24 hours after methotrexate administration, if the 24-hour methotrexate level is greater than 5 micromolar, or if the 48-hour methotrexate level is greater than 0.9 micromolar, increase the leucovorin dose to 100 mg/m² IV every 3 hours until the methotrexate level is less than 0.01 micromolar.

Note: Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised based on recommendations from Jardine (1996) and Smith (2008).

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Leucovorin Use in the treatment of Megaloblastic anemia secondary to congenital deficiency of dihydrofolate reductase:  

For Infants, Children, and Adolescents:

• Administer leucovorin either intramuscularly (IM) or orally.
• The recommended daily dose ranges from 3 to 6 mg.
• This dosage is used for the treatment of megaloblastic anemia secondary to congenital deficiency of dihydrofolate reductase, based on information from Nelson (1996).

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Leucovorin Use in the prevention of hematologic toxicity due to Pyrimethamine:

• For Treatment of Congenital Toxoplasmosis (Toxoplasma gondii):
  • HIV-exposed/-positive Infants:
    • Leucovorin administered intramuscularly (IM) or orally at 10 mg with every pyrimethamine dose.
    • Treatment duration: 12 months.
  • Non-HIV-exposed/-positive Infants:
    • IM or oral administration of 10 mg three times weekly for 12 months.
• For Treatment of Acquired Toxoplasmosis (Toxoplasma gondii):
  • HIV-exposed/-positive Infants, Children, and Adolescents (Acute Induction):
    • Oral administration of 10 to 25 mg once daily for at least 6 weeks.
    • Note: Adolescent doses may be increased to 50 to 100 mg/day in divided doses in case of pyrimethamine toxicity (rash, nausea, bone marrow suppression).
  • Non-HIV-exposed/-positive Infants, Children, and Adolescents (Chorioretinitis):
    • Oral administration of 10 to 20 mg three times weekly.
• For Prophylaxis of Toxoplasmosis (Toxoplasma gondii):
  • Primary Prophylaxis for HIV-exposed/-positive Infants and Children:
    • Oral administration of 5 mg once every 3 days.
  • Primary Prophylaxis for HIV-exposed/-positive Adolescents:
    • Oral administration of 25 mg once weekly (with pyrimethamine and dapsone) or 10 mg once daily (with pyrimethamine and atovaquone).
  • Hematopoietic Stem Cell Transplantation Recipients (Children):
    • Oral administration of 5 mg every 3 days after engraftment and as long as the patient remains on immunosuppressive therapy.
  • Hematopoietic Stem Cell Transplantation Recipients (Adolescents):
    • Oral administration of 10 to 25 mg once daily after engraftment and as long as the patient remains on immunosuppressive therapy.
  • Secondary Prophylaxis for HIV-exposed/-positive Infants and Children:
    • Oral administration of 5 mg once every 3 days.
  • Secondary Prophylaxis for HIV-exposed/-positive Adolescents:
    • Oral administration of 10 to 25 mg once daily or 10 mg once daily.
  • Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) (Adolescents):
    • Oral administration of 25 mg once weekly or 10 mg once daily.
• For Isosporiasis (Isospora belli):
  • Treatment for Acute Infection (Infants, Children, and Adolescents):
    • Oral administration of 10 to 25 mg once daily.
  • Secondary Prophylaxis (Infants, Children, and Adolescents):
    • Oral administration of 10 to 25 mg once daily (for Infants and Children) or 5 to 10 mg once daily (for Adolescents).

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Leucovorin Use as a cofactor in the treatment of Methanol toxicity:

For Infants, Children, and Adolescents:

• Administer intravenously (IV).
• The recommended dose is 1 mg/kg.
• Maximum dose: 50 mg.
• Infuse over 30 to 60 minutes.
• Frequency: Every 4 to 6 hours.
• Therapy should continue until methanol and formic acid have been completely eliminated.

Pregnancy Risk Factor C

• Leucovorin falls under Pregnancy Risk Factor C because there haven't been any studies on its effects on animal reproduction.
• Leucovorin is essentially a biologically active form of folic acid, and it's generally advised to ensure sufficient folic acid intake during pregnancy.
• For more details on folic acid recommendations during pregnancy, it's best to refer to the Folic Acid monograph.

Leucovorin use during breastfeeding:

• Leucovorin is essentially an active type of folic acid, and it's generally advised for breastfeeding women to have enough folic acid.
• However, caution is recommended when giving leucovorin to a breastfeeding woman, according to the manufacturer.
• For more detailed information, it's best to refer to the Folic Acid monograph.

Leucovorin Dose in Renal Disease:

• The manufacturer's labeling does not include any specific dosage adjustments for individuals with renal impairment.

Leucovorin Dose in Liver Disease:

• The manufacturer's labeling does not include any specific dosage adjustments for individuals with hepatic impairment.

Side effects of Leucovorin (Frequency of the side effects has not been defined):

• Dermatologic:
  • Erythema
  • Pruritus
  • Skin rash
  • Urticaria
• Hematologic & oncologic:
  • Thrombocythemia
• Hypersensitivity:
  • Anaphylactoid reaction
  • Hypersensitivity reaction
• Respiratory:
  • Wheezing

Contraindication to Leucovorin include:

• In Canadian labeling, there are additional contraindications not found in the US labeling.
• These include hypersensitivity to leucovorin or any component of the formulation, as well as intrathecal administration.

Warnings and Precautions

Hypersensitivity

• Hypersensitivity reactions, such as allergic reactions, anaphylactoid reactions, and urticaria, have been reported with leucovorin use.
• Since leucovorin is often given alongside other chemotherapy agents, identifying the exact cause of hypersensitivity reactions can be challenging.
• In a study involving 44 patients who experienced hypersensitivity to leucovorin-containing treatments, confirmation of hypersensitivity or infusion reaction to leucovorin was found in 5 patients.
• Additionally, reactions occurred again when the patients were rechallenged with LEVOleucovorin, as noted in research by Ureña-Tavera in 2015.

Seizures:

• Seizures or fainting episodes have been reported, albeit rarely, in cancer patients receiving leucovorin, particularly when used alongside fluoropyrimidine medications.
• These occurrences are most frequently observed in patients with central nervous system (CNS) metastases or other predisposing factors.
• However, it's important to note that a definitive causal relationship between leucovorin and seizures has not yet been established.

Anemias:

• Leucovorin is not suitable for treating pernicious anemia and other megaloblastic anemias caused by a deficiency in vitamin B12.
• While it may lead to a hematologic remission, it does not address the neurologic manifestations, which may continue to progress.
• Therefore, alternative treatments should be considered for these specific types of anemias.

Renal impairment

• Leucovorin is eliminated from the body through the kidneys, so patients with renal impairment may have a higher risk of experiencing toxicities associated with leucovorin.
• Therefore, caution should be exercised when administering leucovorin to individuals with renal impairment, and appropriate dosage adjustments or monitoring may be necessary to minimize the risk of adverse effects.

Leucovorin: Drug Interaction

Risk Factor C (Monitor therapy)
Capecitabine	Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Capecitabine.
Floxuridine	Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Floxuridine.
Fluorouracil (Systemic)	Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil.
Fluorouracil (Topical)	Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Topical).
Fosphenytoin	Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Fosphenytoin.
PHENobarbital	Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of PHENobarbital.
Phenytoin	Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Phenytoin.
Primidone	Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active metabolites of primidone (e.g., phenobarbital).
Tegafur	Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil.
Risk Factor D (Consider therapy modification)
Glucarpidase	May decrease serum concentrations of the active metabolite(s) of Leucovorin Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolate concentrations may be reduced. Glucarpidase may decrease the serum concentration of Leucovorin CalciumLevoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours after glucarpidase administration, and dose based on methotrexate concentration thereafter.
Risk Factor X (Avoid combination)
Raltitrexed	Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Raltitrexed.
Trimethoprim	Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with trimethoprim (plus sulfamethoxazole) for Pneumocystis jirovecii pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy.

Monitoring Parameters:

High-dose Methotrexate Therapy:

• Monitoring Plasma Methotrexate Concentration:
  • Leucovorin is continued until the plasma methotrexate level is less than 0.05 micromolar.
  • Predictive Values: Plasma drug levels exceeding 50 and 1 micromolar at 24 and 48 hours post-infusion may indicate delayed methotrexate clearance.

Fluorouracil Therapy:

• Monitoring Parameters:
  • Complete Blood Count (CBC) with Differential and Platelets.
  • Liver Function Tests.
  • Electrolytes.

Tubal Ectopic Pregnancy (in Combination with Multidose Methotrexate) (Off-label Use):

• Pre-therapy Evaluation:
  • Serial hCG Measurements: Conduct 2 to 7 days apart to exclude viable intrauterine pregnancy.
  • Additional Tests: CBC with Differential, Liver Function Tests, Serum Creatinine, Blood Type, and Rh.
  • Assess for Absolute Contraindications: Evaluate for medical conditions that contraindicate methotrexate treatment of ectopic pregnancy.
• Monitoring during Therapy:
  • Serum hCG Measurements: Monitor on days of methotrexate administration.
  • Response Evaluation: Continuously measure serum hCG weekly until reaching a non-pregnant level. Consider surgical intervention if serum hCG does not decrease after 4 doses.

How to administer Leucovorin?

Rate of Administration:

• Do not exceed a rate of >160 mg/minute for IV solutions due to calcium content.

Route of Administration:

• Not intended for intrathecal use.
• Administer via IM, IV push, or IV infusion (duration: 15 minutes to 2 hours).

Timing with Methotrexate:

• Initiate leucovorin typically 24 hours after the start of methotrexate.
• Irreversible toxicity to normal tissues may occur if leucovorin is not initiated by approximately 40 hours after starting methotrexate.

Rescue After Folate Antagonists:

• Administer via IV bolus, IM, or orally.
• Avoid oral administration in the presence of nausea or vomiting.
• Oral absorption is saturable at doses >25 mg; avoid doses >25 mg orally (switch to parenteral therapy).

Combination Therapy with Fluorouracil:

• Administer fluorouracil after or at the midpoint of the leucovorin infusion.
• Leucovorin is typically given via IV bolus injection or short (10 to 120 minutes) IV infusion. Refer to individual protocols for alternative schedules.

Treatment of Methanol Toxicity:

• Infuse leucovorin over 30 to 60 minutes.

Mechanism of action of Leucovorin:

• Cofactor Restoration: Leucovorin calcium acts as a reduced form of folic acid, supplying the necessary cofactor blocked by methotrexate.
• Competition with Methotrexate:
  • Active Competition: Leucovorin competes actively with methotrexate for transport sites and displaces it from intracellular binding sites.
  • Restoration of Folate Stores: It restores active folate stores essential for DNA/RNA synthesis.
• Enhancement of Fluorouracil Activity:
  • Stabilization: Leucovorin stabilizes the binding of 5-dUMP and thymidylate synthetase, thereby enhancing the activity of fluorouracil.
• Adjunct in Pyrimethamine Therapy:
  • Reduction of Hematologic Toxicity: When administered with pyrimethamine for opportunistic infection treatment, leucovorin reduces the risk of hematologic toxicity.

Methanol Toxicity Treatment:

• Metabolism of Formic Acid:
  • Normal Process: Formic acid, methanol’s toxic metabolite, is metabolized to carbon dioxide and water by 10-formyltetrahydrofolate dehydrogenase after binding to tetrahydrofolate.
  • Leucovorin Administration: Administering a source of tetrahydrofolate may assist the body in eliminating formic acid, aiding in the treatment of methanol toxicity.

Absorption:

• Oral, IM Absorption: Leucovorin is well absorbed through oral and intramuscular routes.

Metabolism:

• Intestinal and Hepatic Metabolism: It undergoes metabolism in the intestinal mucosa and liver to form 5-methyl-tetrahydrofolate (5MTHF), which is the active form.

Bioavailability:

• Saturable Oral Absorption: Bioavailability is saturable at oral doses exceeding 25 mg, with a decrease in bioavailability observed with increasing doses: 25 mg (97%), 50 mg (75%), 100 mg (37%).

Half-life Elimination:

• Duration in the Body: Leucovorin has an elimination half-life of approximately 4 to 8 hours.

Time to Peak:

• Oral Route: It reaches peak levels in about 2 hours after oral administration.
• Intravenous (IV) Route: Total folates reach peak levels in about 10 minutes, while 5MTHF peaks in about 1 hour.
• Intramuscular (IM) Route: Total folates peak in approximately 52 minutes, and 5MTHF peaks around 2.8 hours.

Excretion:

• Primary Excretion Route: Leucovorin is primarily excreted in the urine, with some excretion occurring in the feces.

Leucovorin (Calcium Folinate) International brand names:

• Acido Folinico/ Leucovorina
• Antrex
• Asovorin
• Cafona
• Cafonate
• Calcium folinate Faulding
• Calciumfolinat Pharmalink
• Calcium folinate
• Calciumfolinat-Ebewe
• Calfonat
• Chemovorin
• Dalisol
• Ferbon
• Folcasin
• Folical
• Folina 15
• Folinato de Calcio Dakota
• Farma
• Kalcij-folinat
• Kunyrin
• Lederfolin
• Lederfoline
• Ledervorin
• Calcium
• Leucan
• Leucocalcin
• Leuconolver
• Leucovorin
• Leucovorin Ca
• Leucovorin Calcium
• Leucovorine Abic
• Lifacor
• Likelin
• Lovorin
• Medifolin
• MPL Coverin
• Novorin
• Nyrin
• Refolinon
• Rescuvolin
• Robin
• Rontafur
• Tecnovorin

Leucovorin (calcium folinate injection) brand name in Pakistan:

Leucovorin (Calcium Folinate) [Inj 15 Mg]
Leucocin	Pharmedic (Pvt) Ltd.

 

Leucovorin (Calcium Folinate) [Inj 30 Mg]
Calcium Folinate	Bio Pharma

 

Leucovorin (Calcium Folinate) [Inj 50 Mg]
Calcium Folinate	Atco Laboratories Limited
Leucocin	Pharmedic (Pvt) Ltd.
Leucofolate	Consolidated Chemical Laboratories (Pvt) Ltd.