Skip to content
ClinCalc Pro
Menu
Calculators Drugs Pathways AI Dx Donate Get the App
Antidote / Chemotherapy Support Pregnancy: §4.6: 'There are no adequate and well-controlled clinical studies conducted in pregnant or breast feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy.' The SPC adds that if treatment with methotrexate or other folate antagonists takes place despite pregnancy or lactation, 'there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects', while 5-fluorouracil use 'is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.' Breast-feeding: 'It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.'

Folinic Acid (Calcium Folinate / Leucovorin)

Brand names: Refolinon, Isovorin, Leucovorin Calcium

Folinic acid (calcium folinate, leucovorin) is a reduced folate used to counteract the toxicity of folate-antagonist drugs such as methotrexate and as an adjunct in certain regimens.

Adult dose

Dose: Leucovorin (calcium folinate) rescue after methotrexate — §4.2, verbatim: 'Depending upon the dose of methotrexate administered, dosage regimens of leucovorin calcium vary. Up to 120 mg leucovorin calcium are generally given, usually in divided doses over 12-24 hours by intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline. This is followed by 12-15 mg intramuscularly or 15 mg orally every 6 hours for 48 hours. Rescue therapy is usually started 24 hours after the commencement of methotrexate administration.' SUSPECTED METHOTREXATE OVERDOSE — §4.2, verbatim: 'If overdosage of methotrexate is suspected, the dose of leucovorin calcium should be equal to or greater than the dose of methotrexate and should be administered within one hour of the methotrexate administration.' MEGALOBLASTIC ANAEMIA (folate deficiency) — §4.2, verbatim: '15 mg (one tablet) leucovorin per day.' SCOPE: this SPC's §4.2 covers only these indications. It gives NO regimen for folinic acid used with fluorouracil as a cytotoxic modulator (§4.4 and §4.8 discuss that combination but state no dose), and no regimen for any other use, so none is published here.
Route: The rescue regimen is given by intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline, followed by intramuscular or oral dosing; megaloblastic anaemia is dosed orally. The sourced product itself is an oral tablet — §4.2 Method of administration: 'To be given orally.' CRITICAL ROUTE RESTRICTION, §4.2 verbatim: 'Although leucovorin calcium may also be available as a solution for injection, leucovorin calcium should not be administered intrathecally.'
Frequency: Rescue: the initial dose in divided doses over 12-24 hours, then every 6 hours for 48 hours; rescue therapy usually started 24 hours after methotrexate was commenced. Suspected methotrexate overdose: within one hour of the methotrexate administration. Megaloblastic anaemia: once a day.
Max: No maximum dose is stated for this indication, and no numeric cap is asserted here. The SPC gives 'Up to 120 mg' as the usual INITIAL rescue quantity over 12-24 hours, but the same section requires that in suspected methotrexate overdose the calcium folinate dose 'should be equal to or greater than the dose of methotrexate' — which may exceed that figure. A cap must never be applied to this record: capping folinic acid rescue would under-treat methotrexate toxicity.
TIMING IS THE SAFETY-CRITICAL VARIABLE, and the SPC states two different timings for two different situations: routine rescue is 'usually started 24 hours after the commencement of methotrexate administration', whereas suspected methotrexate OVERDOSE is treated 'within one hour of the methotrexate administration'. Do not read one for the other. The '12-15 mg intramuscularly or 15 mg orally every 6 hours for 48 hours' step follows the initial 'up to 120 mg' phase — it is not an alternative to it. §4.2 states the rescue regimen under the heading 'Adults and children', without a separate paediatric schedule and without any milligrams-per-kilogram figure. §4.4: 'Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.' §4.5: 'Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified' — and 'Calcium folinate may enhance the toxicity of fluorouracil.' EXCIPIENT, §4.4: 'Refolinon contains lactose. Patients with rare hereditary problems of galacatose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine' (spelling as printed in the SPC).

Paediatric dose

Route: Intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline, then intramuscular or oral — never intrathecal ('leucovorin calcium should not be administered intrathecally').
Frequency: As for adults — the initial rescue quantity in divided doses over 12-24 hours, then every 6 hours for 48 hours, with rescue usually started 24 hours after methotrexate was commenced.
NOT A WEIGHT-BASED DOSE — dosePerKg is deliberately null. This SPC heads its rescue regimen 'Adults and children:' and then gives ONE regimen for both, with no milligrams-per-kilogram and no per-square-metre figure anywhere in §4.2, so there is no per-kilogram number to enter and no weight calculation is offered. The label's own paediatric instruction is therefore the adult regimen quoted in adultDose above ('Up to 120 mg... in divided doses over 12-24 hours... followed by 12-15 mg intramuscularly or 15 mg orally every 6 hours for 48 hours'), together with the overdose rule that the calcium folinate dose should equal or exceed the methotrexate dose. No age bands, no minimum age and no neonatal statement appear in the fetched sections, so none is asserted. Verify all paediatric dosing against a children's formulary and the local chemotherapy protocol.

Dose adjustments

Renal

Not stated — no renal-impairment dosing band appears in any fetched section of this SPC. §4.8 recommends that haematological adverse reactions 'can be controlled by close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels'. Verify against the full SPC before advising.

Hepatic

Not stated — no hepatic-impairment dosing band appears in any fetched section of this SPC.

Dose independently re-sourced from UK Summary of Product Characteristics (SPC) via the eMC — clinician-reviewed. Always confirm against the product SmPC and your local formulary before prescribing.

Contraindications

  • §4.3, verbatim: 'Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.'
  • §4.3, verbatim: 'Pernicious anaemia or other megaloblastic anaemia where vitamin B 12 is deficient.'
  • Route contraindication, §4.2: 'leucovorin calcium should not be administered intrathecally'
  • Not a contraindication but a §4.4 restriction: 'Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.'
  • Excipient restriction, §4.4: contains lactose — not for patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

Side effects

  • §4.8, verbatim: 'Adverse reactions to leucovorin calcium are rare, but following intravenous and intramuscular administration occasional pyrexial reactions have been reported.'
  • §4.8: with calcium folinate plus 5-fluorouracil, 'The most common dose-limiting adverse reaction... are stomatitis and diarrhoea.'
  • §4.8: haematological adverse reactions such as leucocytopenia and thrombocytopenia — 'These adverse reactions are dose-dependent and their occurrence can usually be decreased by reducing the dosage of cytotoxic drugs.'
  • §4.8: 'Anaphylactoid and urticaria allergic reactions have also been reported with the use of leucovorin.'

Monitoring

  • §4.8: 'close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels'
  • §4.5: do not give simultaneously with a folic acid antagonist when the intent is to reduce or prevent clinical toxicity — 'the therapeutic effect of the antagonist may be nullified'
  • §4.5: folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures
  • §4.5: concurrent chloramphenicol and folic acid in folate-deficient patients may antagonise the haematopoietic response to folic acid
  • §4.5: 'Calcium folinate may enhance the toxicity of fluorouracil.'

Clinical monograph

How it works

As a ready-made reduced folate, it bypasses the dihydrofolate reductase block produced by methotrexate, restoring folate-dependent synthesis in normal cells (folinic acid 'rescue').

Prescribing in practice

  • In methotrexate toxicity, start rescue promptly and continue according to methotrexate levels and renal function, as delay reduces its protective effect.
  • Do not use folinic acid to treat overdose of trimethoprim-related antifolates without specialist advice, and distinguish it from folic acid, which is not an adequate rescue agent.
  • Refer to current prescribing references and toxicology services for regimen selection in high-dose methotrexate and accidental overdose.

Monitoring

Monitor methotrexate levels, renal function and full blood count when used as rescue from antifolate toxicity.

Counselling the patient

  • Explain that this medicine protects healthy cells from the side effects of certain chemotherapy or methotrexate.
  • Stress the importance of taking rescue doses exactly on schedule.
  • Advise reporting mouth ulcers, sore throat or feeling unwell, which may indicate toxicity.

Evidence & guidelines

Folinic acid rescue is a well-established component of high-dose methotrexate therapy and of the management of methotrexate toxicity.

Reference: TOXBASE; UKMI; SPC Refolinon; NICE CG151; ESMO Methotrexate Guidelines; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

Calculators
Pathways
📚 MRCEM Revision

Featured in these MRCEM clinical pathways

Folinic Acid (Calcium Folinate / Leucovorin) is a core drug in the following exam-focused workups on our sister siteReviseMRCEM.

MRCEM Primary / Intermediate / OSCE candidates: each pathway includes exam-style questions, RCEM/NICE citations, and FAQ summaries.