1. Clinical Overview
Calcium Leucovorin is the calcium salt of leucovorin (folinic acid), a reduced form of folic acid. It is a crucial antidote for folic acid antagonists like methotrexate and pyrimethamine, and a chemoprotectant/modulator in oncology. It serves as a source of active folate, bypassing the dihydrofolate reductase (DHFR) enzyme blockade, allowing for the synthesis of thymidylate and purines essential for DNA/RNA synthesis. In India, it is a critical drug in oncology, hematology, and toxicology protocols.
| Onset | Duration | Bioavailability |
|---|---|---|
| Oral: 20-30 minutes; Intravenous: Immediate. | Approximately 3 to 6 hours, depending on route and dose. | Oral: Approximately 97% under fasting conditions. Reduced with food. |
2. Mechanism of Action
Leucovorin is a 5-formyl derivative of tetrahydrofolic acid (THF). It is readily converted intracellularly to other reduced folate cofactors, including 5,10-methylenetetrahydrofolate. This bypasses the metabolic block induced by dihydrofolate reductase (DHFR) inhibitors like methotrexate. By providing a source of reduced folates, it 'rescues' normal cells from the toxic effects of these antagonists, allowing for continued synthesis of thymidylate, purines, and ultimately DNA/RNA.
3. Indications & Uses
- Rescue therapy after high-dose methotrexate therapy in osteosarcoma, leukemia, and lymphoma.
- Adjunctive therapy with fluorouracil (5-FU) in palliative treatment of metastatic colorectal cancer.
- Treatment of megaloblastic anemia due to folic acid deficiency when oral therapy is not feasible.
- Treatment of overdose or impaired elimination of folic acid antagonists (e.g., methotrexate, trimethoprim, pyrimethamine).
4. Dosage & Administration
Adult Dosage: **Highly variable.** Methotrexate Rescue: Typically 15 mg (approx. 10 mg/m2) IV/IM/PO every 6 hours starting 24 hours after methotrexate infusion, continued until methotrexate level <0.05 micromolar. Dosing guided by methotrexate levels and creatinine. **Colorectal Cancer with 5-FU:** Various regimens, e.g., 200 mg/m2 IV over 2 min followed by 5-FU bolus, or 20 mg/m2 IV before 5-FU. **Folate Antagonist Overdose:** 10 mg/m2 IV/IM/PO, then 10 mg/m2 orally every 6 hours.
Administration: **Oral:** Can be taken without regard to meals, but food may decrease bioavailability. Tablets can be crushed. **IV:** Can be administered as a slow IV push (over 1-3 min for rescue doses) or as a short infusion (over 10-15 min for high doses with 5-FU). **IM:** Deep intramuscular injection. **DO NOT ADMINISTER INTRATHECALLY.** For methotrexate rescue, timing relative to methotrexate dose is critical.
5. Side Effects
Common side effects may include:
- Allergic skin reactions (rash, pruritus, urticaria).
- Nausea, vomiting, diarrhea (especially with high oral doses).
- Fatigue, malaise.
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Methotrexate | Leucovorin rescues normal cells from methotrexate toxicity. However, if given concurrently or too early, it can interfere with methotrexate's antitumor efficacy. | Major |
| Fluorouracil (5-FU) | Leucovorin potentiates the cytotoxicity and toxicity (e.g., diarrhea, stomatitis, myelosuppression) of 5-FU by stabilizing its active complex. | Major |
| Phenytoin, Phenobarbital, Primidone | Anticonvulsants may reduce serum folate levels. Leucovorin may decrease serum levels of these anticonvulsants, potentially leading to increased seizure frequency. Monitor levels closely. | Moderate |
| Sulfamethoxazole-Trimethoprim (Co-trimoxazole) | Trimethoprim is a DHFR inhibitor. Leucovorin may counteract its antibacterial effect in certain infections (e.g., Pneumocystis jirovecii pneumonia). | Moderate |
| Pyrimethamine | Leucovorin is used to counteract its hematologic toxicity in toxoplasmosis treatment without impairing its antiparasitic effect at appropriate doses. | Moderate |
7. Patient Counselling
- DO take the exact dose at the exact times prescribed, especially for methotrexate rescue. Timing is critical.
- DO inform all your doctors and pharmacists that you are taking leucovorin.
- DO report any signs of allergic reaction (rash, itching, swelling, trouble breathing) immediately.
- DO NOT take any over-the-counter vitamins, especially folic acid supplements, unless specifically instructed by your oncologist.
- DO NOT miss any scheduled blood tests to monitor methotrexate levels, kidney function, or blood counts.
8. Toxicology & Storage
Overdose: Overdose is unlikely to cause direct severe toxicity. However, excessive doses in the context of methotrexate rescue could theoretically reduce the chemotherapeutic efficacy of methotrexate. Symptoms would be related to hypercalcemia (if given as calcium salt rapidly IV: nausea, vomiting, confusion, polyuria, kidney stones) or hypersensitivity.
Storage: Store below 25°C. Protect from light and moisture. Keep the container tightly closed. Do not use if the solution is discolored or contains particulate matter. Keep out of reach of children.