Pharmacology · Chemotherapy supportive agents
Calcium folinate !
An already-reduced folate (leucovorin) that rescues normal cells from methotrexate and strengthens fluorouracil. Never given intrathecally.
Updated 2026-11-01
Also called: leucovorin, folinic acid, 5-formyltetrahydrofolate
Mechanism of action
Calcium folinate is 5-formyl-tetrahydrofolate, a folate that is already reduced. It does not need dihydrofolate reductase, so it refills the one-carbon folate pool even while methotrexate blocks that enzyme, rescuing normal cells. With fluorouracil it acts the other way: it is converted to 5,10-methylene-tetrahydrofolate, which locks fluorouracil's active metabolite (FdUMP) onto thymidylate synthase and makes the block stronger.
- Folinate is a reduced folate: no DHFR needed
- It refills the folate pool despite methotrexate
- With fluorouracil, it locks FdUMP onto thymidylate synthase
Pharmacokinetics
- Absorption
- Intravenous, intramuscular or oral; oral absorption is saturable, so larger doses are given intravenously.
- Metabolism
- Rapidly converted to 5-methyl-tetrahydrofolate (after oral use, mainly in the intestinal mucosa).
- Half-life
- Total reduced folates: about 6 hours.
Indications
- Rescue after high-dose methotrexate (for example in osteosarcoma), impaired methotrexate elimination or overdose of folate antagonists.
- Megaloblastic anaemia due to folate deficiency when oral therapy is not feasible. Megaloblastic anaemia (B12 or folate deficiency) →
- Advanced colorectal cancer, combined with fluorouracil. Colorectal cancer →
Adverse effects
Common
- Allergic sensitisation (hives, anaphylactoid reactions), uncommon
- With fluorouracil: more diarrhoea, mouth sores and low blood counts
Contraindications
- Pernicious anaemia and other megaloblastic anaemias from vitamin B12 deficiency (the blood improves while nerve damage progresses)
Key interactions
- Methotrexate
- Counteracts its effects (the purpose of rescue); high doses may reduce the effect of intrathecal methotrexate.
- Fluorouracil
- Enhances both its antitumour effect and its toxicity.
- Trimethoprim–sulfamethoxazole for Pneumocystis pneumonia in HIV
- The combination was linked to more treatment failure and morbidity.
- Phenobarbital, phenytoin, primidone
- Large amounts of folate may reduce their antiseizure effect in susceptible children.
What is monitored
- Serum methotrexate levels and creatinine during rescue (they decide the dose and how long it continues)
- Blood count, electrolytes and liver tests when combined with fluorouracil
Administration and safety
- Never given intrathecally.
- Rescue doses are given on time: the longer the delay after methotrexate, the less it protects.
- Not mixed in the same infusion as fluorouracil (a precipitate may form).
- Injected slowly because of its calcium content; for larger doses it is reconstituted with sterile water rather than diluents containing benzyl alcohol.
Nursing care
- Check that calcium folinate (leucovorin) is not confused with folic acid: they are different drugs.
- Keep the rescue schedule exactly and check each methotrexate level result.
- If the patient vomits, an oral dose may not be absorbed: report it so the route can be changed.
- Encourage fluids and check urine output during methotrexate rescue.
Pregnancy and breastfeeding
Effects in pregnancy are not known; it is used only if clearly needed.
Test yourself
Think of the answer, then tap the question to see it.
Why can calcium folinate rescue normal cells from methotrexate?
It is already reduced, so it bypasses the dihydrofolate reductase that methotrexate blocks.
Why is calcium folinate given with fluorouracil?
It forms 5,10-methylene-tetrahydrofolate, which stabilises FdUMP binding to thymidylate synthase and enhances inhibition.
Why is calcium folinate improper therapy for pernicious anaemia?
It can correct the blood picture while the neurological damage of vitamin B12 deficiency continues.
What happens to the protective effect when methotrexate rescue is delayed?
It decreases: the longer the interval, the less folinate counteracts toxicity.
Related drugs
Related conditions
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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - LEUCOVORIN CALCIUM injection, powder, lyophilized, for solution (DailyMed (U.S. National Library of Medicine), 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 70 (McGraw Hill, 2023); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026); eEML - Electronic Essential Medicines List (World Health Organization, 2025).
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