Usage
Calcium leucovorin, the calcium salt of folinic acid (also known as citrovorum factor), is prescribed for the following medical conditions:
- Leucovorin Rescue: Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and inadvertent overdosages of methotrexate and other folic acid antagonists. This is commonly used in high-dose methotrexate therapy for conditions like osteosarcoma.
- Megaloblastic Anemia: Treating megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. It is important to note that it’s not effective for pernicious anemia or other megaloblastic anemias caused by vitamin B12 deficiency.
- Advanced Colorectal Cancer: Used in combination with 5-fluorouracil to prolong survival in palliative treatment.
- Overdosage of Folic Acid Antagonists: Calcium folinate can be used to treat overdosages of folic acid antagonists like pyrimethamine or trimethoprim.
Pharmacological Classification: Antidote, vitamin, chemotherapeutic agent (in combination with 5-FU)
Mechanism of Action: Calcium leucovorin is a reduced folate, meaning it bypasses the metabolic step inhibited by methotrexate and other folate antagonists. This allows for continued synthesis of purines and pyrimidines, essential for DNA and RNA synthesis, thus rescuing normal cells from the toxic effects of the antifolate drugs. In combination with 5-fluorouracil, it enhances the cytotoxic effect by stabilizing the binding of 5-fluorouracil to its target enzyme, thymidylate synthase.
Alternate Names
- Folinic acid
- Citrovorum factor
Brand Names: Wellcovorin
How It Works
Pharmacodynamics: Calcium leucovorin readily enters cells and is converted to 5,10-methylenetetrahydrofolate, the active form of folate needed for DNA and RNA synthesis. In colorectal cancer treatment, it enhances the binding of 5-fluorouracil to thymidylate synthase, thereby increasing its cytotoxic effects.
Pharmacokinetics:
- Absorption: Rapidly absorbed following intramuscular (IM) and intravenous (IV) administration. Oral absorption is saturable and less efficient at higher doses.
- Metabolism: Converted to active metabolites, primarily 5-methyltetrahydrofolate, in the liver.
- Elimination: Primarily renal excretion, with a small percentage eliminated in bile.
Mode of Action: Calcium leucovorin is a reduced form of folic acid and bypasses the dihydrofolate reductase enzyme, which is inhibited by methotrexate and other antifolate drugs. It is readily converted to various cofactors essential for purine and thymidylate synthesis, allowing normal cells to continue DNA replication and other cellular processes even in the presence of folate antagonists. With 5-FU, it enhances cytotoxicity by stabilizing the complex of 5,10-methylenetetrahydrofolate, thymidylate synthase, and 5-fluorodeoxyuridylate, thereby potentiating the inhibition of thymidylate synthase.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Calcium leucovorin acts as a substrate for various enzymes involved in folate metabolism. It does not directly bind to receptors or modulate neurotransmitters. Its primary action is to overcome the effects of antifolate drugs by providing cells with the necessary reduced folates for metabolic processes. It enhances the inhibition of thymidylate synthase by 5-FU.
Elimination Pathways: Primarily renal excretion, both as unchanged drug and metabolites. Some biliary excretion also occurs.
Dosage
Standard Dosage
Adults:
- Leucovorin Rescue: 10-15 mg/m² IV every 6 hours for 10 doses, starting 24 hours after the beginning of methotrexate infusion. Oral administration may be used after the first IV dose. Dosage and duration may vary based on methotrexate levels.
- Megaloblastic Anemia: Up to 1 mg daily IM or IV. Oral dosages are typically 15 mg daily.
- Advanced Colorectal Cancer (with 5-FU): Various regimens exist, commonly involving 200 mg/m² IV infusion followed immediately by 5-fluorouracil.
Children:
Dosing is based on body surface area (BSA) and specific treatment protocols. Pediatric dosages are generally calculated in mg/m² similarly to adult dosing.
Special Cases:
- Elderly Patients: Dose adjustments may be necessary due to decreased renal function.
- Patients with Renal Impairment: Dose reduction or increased dosing intervals may be required based on creatinine clearance.
- Patients with Hepatic Dysfunction: Caution should be exercised, although specific dose adjustments are not typically recommended.
- Patients with Comorbid Conditions: Consider potential drug interactions and adjust dosages accordingly.
Clinical Use Cases
Dosage varies widely depending on the specific indication, clinical protocol, and patient factors. Please refer to the relevant protocol for specific recommendations.
Dosage Adjustments
Dose adjustments are made primarily based on renal function, methotrexate levels (in leucovorin rescue), and patient response. Close monitoring of renal function and serum methotrexate concentrations is crucial for safe and effective use.
Side Effects
Common Side Effects
- Nausea
- Vomiting
- Diarrhea
- Allergic reactions (rash, itching, hives)
Rare but Serious Side Effects
- Anaphylactic reactions
- Seizures (rarely)
- Severe mucositis or stomatitis (with 5-FU)
Long-Term Effects
No specific long-term effects have been identified with short-term use for leucovorin rescue or megaloblastic anemia.
Adverse Drug Reactions (ADR)
- Anaphylactoid reactions require immediate medical attention.
- Severe diarrhea or mucositis, particularly in patients receiving 5-FU, can be life-threatening and require prompt intervention.
Contraindications
- Pernicious anemia or other megaloblastic anemias caused by vitamin B12 deficiency
- Hypersensitivity to calcium leucovorin or any components of the formulation
Drug Interactions
- 5-fluorouracil: Leucovorin enhances the toxicity of 5-fluorouracil. Do not mix in the same infusion.
- Anticonvulsants (phenobarbital, phenytoin, primidone): Leucovorin may decrease anticonvulsant levels and increase seizure risk.
- Methotrexate: Monitor methotrexate levels closely when using leucovorin for rescue.
- Trimethoprim, Pyrimethamine: These drugs may interfere with leucovorin’s action.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C
- Fetal Risks: Animal reproduction studies have not been conducted. Use only if clearly needed and benefits outweigh potential risks.
- Breastfeeding: It is unknown if leucovorin is excreted in human milk. Exercise caution when administering to breastfeeding women.
Drug Profile Summary
- Mechanism of Action: Provides reduced folate needed for DNA/RNA synthesis, bypassing the block caused by antifolate drugs. Enhances the effect of 5-FU by stabilizing its binding to thymidylate synthase.
- Side Effects: Nausea, vomiting, diarrhea, allergic reactions. Rarely: anaphylaxis, seizures.
- Contraindications: Pernicious anemia, B12 deficiency anemia, hypersensitivity.
- Drug Interactions: 5-FU, anticonvulsants, methotrexate, trimethoprim, pyrimethamine.
- Pregnancy & Breastfeeding: Pregnancy Category C; unknown if excreted in breast milk.
- Dosage: Varies widely depending on indication and patient factors.
- Monitoring Parameters: Renal function, serum methotrexate levels (during leucovorin rescue), complete blood count, and signs of toxicity (e.g., diarrhea, mucositis).
Popular Combinations
- 5-fluorouracil: for advanced colorectal cancer
Precautions
- General Precautions: Monitor for hypersensitivity reactions, renal function, and other potential adverse events.
- Pregnant Women: Use only if clearly needed.
- Breastfeeding Mothers: Exercise caution.
- Children & Elderly: Dosage adjustments may be necessary.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Calcium Leucovorin?
A: The dosage varies significantly based on the indication. For leucovorin rescue after high-dose methotrexate, 10-15 mg/m² IV every 6 hours for 10 doses is commonly used. For megaloblastic anemia, up to 1 mg daily IM or IV is administered. In colorectal cancer, 200 mg/m² IV is commonly used with 5-FU. Always consult relevant protocols and adjust dosing based on patient factors.
Q2: How should Calcium Leucovorin be administered?
A: Calcium leucovorin can be administered intravenously, intramuscularly, or orally. The route of administration depends on the clinical situation. IV administration is preferred for leucovorin rescue in patients with potential absorption issues.
Q3: Can Calcium Leucovorin be used to treat all types of megaloblastic anemia?
A: No. It is not effective for pernicious anemia or other megaloblastic anemias caused by vitamin B12 deficiency.
Q4: What are the most serious side effects to watch for with Calcium Leucovorin?
A: The most serious adverse reactions include allergic reactions (including anaphylaxis), and severe diarrhea or mucositis, especially in patients receiving concurrent 5-fluorouracil.
Q5: Is Calcium Leucovorin safe to use during pregnancy?
A: Calcium leucovorin is Pregnancy Category C. It should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus.
Q6: What is the role of Calcium Leucovorin in colorectal cancer treatment?
A: It enhances the cytotoxicity of 5-fluorouracil by stabilizing its interaction with thymidylate synthase. It is administered prior to 5-FU in certain treatment regimens for advanced colorectal cancer.
Q7: How does Calcium Leucovorin interact with anticonvulsant medications?
A: It may reduce the plasma levels of some anticonvulsants (e.g., phenytoin, phenobarbital, primidone), potentially leading to a loss of seizure control.
Q8: Why is it important to monitor methotrexate levels during leucovorin rescue?
A: Methotrexate levels are monitored to guide leucovorin dosing and duration. Delayed methotrexate excretion can increase the risk of toxicity, and higher doses or prolonged administration of leucovorin may be required in such cases.
Q9: Are there any specific precautions for elderly patients receiving Calcium Leucovorin?
A: Elderly patients are more susceptible to adverse drug reactions, and they frequently have decreased renal function. Dose adjustments and close monitoring are often necessary in this population.
Q10: How quickly should Calcium Leucovorin be administered in the case of a methotrexate overdose?
A: As soon as possible after an overdose is suspected, preferably within the first hour. Timely administration is critical for maximizing the effectiveness of leucovorin rescue.
