Usage
Leucovorin Calcium is prescribed for:
- Diminishing the toxicity and counteracting the effects of methotrexate overdosage, including inadvertent overdoses of other folic acid antagonists.
- Treating megaloblastic anemia due to folic acid deficiency when oral therapy isn’t feasible.
- Prolonging survival in combination with 5-fluorouracil in the palliative treatment of advanced colorectal cancer.
It’s pharmacologically classified as a folate analog, specifically a reduced folate, and is a folic acid derivative.
Leucovorin Calcium acts by providing the reduced folate needed for purine and pyrimidine biosynthesis, thereby counteracting the effects of folic acid antagonists like methotrexate, which inhibit dihydrofolate reductase. In the case of colorectal cancer treatment, it enhances the binding of 5-fluorouracil to its target enzyme, thymidylate synthase, increasing its cytotoxic effects.
Alternate Names
- Folinic acid
- Calcium folinate
- Citrovorum factor
How It Works
Pharmacodynamics: Leucovorin Calcium readily enters cells and is converted to active forms of folate, bypassing the block caused by dihydrofolate reductase inhibitors. This allows for the synthesis of purines and pyrimidines, which are essential for DNA and RNA synthesis.
Pharmacokinetics:
- Absorption: Oral absorption is saturable, with doses above 25 mg showing limited increase in bioavailability. Parenteral administration provides complete bioavailability.
- Metabolism: Leucovorin is metabolized to 5-methyltetrahydrofolate (5-MTHF), the primary circulating form of folate.
- Elimination: Excreted primarily in the urine, both as unchanged drug and metabolites.
Mode of Action: Leucovorin enters cells and undergoes enzymatic conversion to 5,10-methylenetetrahydrofolate, which is essential for thymidylate synthesis. It counteracts the cytotoxic effects of methotrexate by replenishing reduced folate stores. When used with 5-fluorouracil, it enhances the inhibition of thymidylate synthase. This ultimately inhibits DNA synthesis and promotes cell death in cancer cells.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Leucovorin doesn’t directly bind to receptors or modulate neurotransmitters. Its action is through being a substrate for enzymes in the folate pathway, bypassing the dihydrofolate reductase inhibition by methotrexate and enhancing thymidylate synthase inhibition in the presence of 5-fluorouracil.
Elimination pathways: Leucovorin and its metabolites are primarily excreted renally.
Dosage
Standard Dosage
Adults:
The dosage varies greatly depending on the indication.
- Methotrexate rescue: 15 mg (approximately 10 mg/m²) IV or PO every 6 hours for 10 doses, starting 24 hours after the beginning of methotrexate infusion.
- Megaloblastic anemia: up to 1 mg daily IM or 15 mg orally daily.
- Advanced Colorectal Cancer (with 5-fluorouracil): 200 mg/m² IV, followed by 5-fluorouracil. Refer to 5-FU dosing guidelines and relevant protocols.
Children:
Dosing in children is also dependent on indication and calculated based on body surface area (BSA) or weight. Expert consultation is recommended.
- Methotrexate rescue: similar to adults, based on BSA (approx. 10 mg/m²) every 6 hours for 10 doses.
- Megaloblastic anemia: 0.25 mg/kg/day.
Special Cases:
- Elderly Patients: Monitor closely for toxicity, especially gastrointestinal, and consider dose reductions.
- Patients with Renal Impairment: Dose adjustments based on creatinine clearance are essential, as leucovorin is primarily renally excreted.
- Patients with Hepatic Dysfunction: Careful monitoring is advised, although specific dose adjustment recommendations are not universally established.
- Patients with Comorbid Conditions: Individualized assessment is necessary, considering potential drug interactions and underlying conditions.
Clinical Use Cases
Dosing in specific clinical scenarios should be guided by established protocols and expert consultation.
- Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations: No specific dosage recommendations for these situations; dosage is determined by the underlying indication for leucovorin use (e.g., methotrexate rescue).
Dosage Adjustments
Dosage adjustments are crucial in patients with renal impairment. Serum methotrexate level monitoring is essential for high-dose methotrexate therapy. Dose adjustments may also be necessary in the elderly and those with hepatic dysfunction or other comorbid conditions.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea
- Allergic reactions (rash, hives, itching)
Rare but Serious Side Effects
- Severe allergic reactions (anaphylaxis)
Long-Term Effects
No specific long-term effects have been consistently reported.
Adverse Drug Reactions (ADR)
Serious ADRs are rare but require immediate medical attention.
Contraindications
- Pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency.
- Hypersensitivity to leucovorin or any of its components.
Drug Interactions
- Anticonvulsants (phenytoin, phenobarbital, primidone): Leucovorin may decrease their efficacy.
- Fluorouracil: Leucovorin enhances its toxicity.
- Methotrexate: Used to mitigate toxicity, not interact negatively. However, concurrent high doses of leucovorin may reduce the effectiveness of intrathecally administered methotrexate.
Pregnancy and Breastfeeding
- Pregnancy Category: C. Use with caution if benefits outweigh risks.
- Breastfeeding: It’s unknown if leucovorin passes into breast milk. Consult with a physician before breastfeeding.
Drug Profile Summary
- Mechanism of Action: Bypasses dihydrofolate reductase inhibition, allowing for purine and pyrimidine synthesis; enhances 5-FU’s inhibition of thymidylate synthase.
- Side Effects: Nausea, vomiting, diarrhea, allergic reactions.
- Contraindications: Pernicious anemia due to B12 deficiency, hypersensitivity.
- Drug Interactions: Anticonvulsants, fluorouracil.
- Pregnancy & Breastfeeding: Category C; unknown if excreted in breast milk.
- Dosage: Varies widely based on indication; see detailed dosage section.
- Monitoring Parameters: Serum methotrexate levels (with high-dose methotrexate), renal function, complete blood counts.
Popular Combinations
- 5-fluorouracil: For advanced colorectal cancer.
Precautions
- Monitor renal function, especially in patients with pre-existing renal impairment.
- Avoid intrathecal administration.
- Close monitoring for toxicity in elderly and debilitated patients receiving leucovorin and 5-fluorouracil.
FAQs
Q1: What is the recommended dosage for Leucovorin Calcium?
A: Dosage varies widely depending on indication. Refer to the detailed dosage section above.
Q2: How is Leucovorin Calcium administered?
A: Intravenously (IV), intramuscularly (IM), or orally (PO).
Q3: What is the role of Leucovorin Calcium in methotrexate therapy?
A: It’s used to “rescue” patients from the toxic effects of high-dose methotrexate.
Q4: Can Leucovorin Calcium be used to treat all types of anemia?
A: No. It’s only effective for megaloblastic anemia caused by folate deficiency. It’s contraindicated in pernicious anemia caused by vitamin B12 deficiency.
Q5: What are the most common side effects patients experience with Leucovorin Calcium?
A: Nausea, vomiting, diarrhea, and allergic reactions like skin rash or hives.
Q6: Are there any specific precautions for elderly patients receiving Leucovorin Calcium?
A: Yes. Elderly patients, especially those receiving it in combination with 5-fluorouracil, should be closely monitored for signs of toxicity, particularly gastrointestinal.
Q7: Does Leucovorin interact with any other medications?
A: Yes. It can interact with anticonvulsants, potentially decreasing their effectiveness, and with fluorouracil, enhancing its toxicity.
Q8: Can Leucovorin be given intrathecally?
A: No. Intrathecal administration is contraindicated and may be harmful or fatal.
Q9: What monitoring parameters are important for Leucovorin Calcium?
A: Serum methotrexate levels during high-dose methotrexate therapy, renal function tests, and complete blood counts.
