Reduced folate
Pregnancy: §4.6: there are no adequate and well-controlled clinical studies in pregnant or breast-feeding women, and 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. Where treatment with methotrexate or another folate antagonist takes place despite pregnancy or lactation, there are no limitations on using calcium folinate to diminish toxicity or counteract the effects. 5-fluorouracil is generally contraindicated in pregnancy and contraindicated in breast-feeding, and this applies also to combined use with calcium folinate. Breast-feeding: it is not known whether calcium folinate is excreted into human breast milk; it can be used during breast-feeding when considered necessary according to the therapeutic indications.
Folinic acid (calcium folinate)
Brand names: Refolinon, Lederfolin
Folinic acid (calcium folinate) is a reduced folate used as rescue therapy after high-dose methotrexate and to counteract the toxicity of folate-antagonist drugs.
Adult dose
Dose: LEUCOVORIN (FOLINIC ACID) RESCUE AFTER METHOTREXATE — adults and children. §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. 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.'
Route: The sourced product is Refolinon 15 mg TABLETS and §4.2 states 'Method of administration: To be given orally.' The same §4.2 also states the parenteral figures quoted above for the rescue phase — intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline — which require an injectable calcium folinate product not fetched in this bundle. NEVER INTRATHECAL: §4.2 verbatim — 'Although leucovorin calcium may also be available as a solution for injection, leucovorin calcium should not be administered intrathecally.'
Frequency: Rescue: divided doses over 12-24 hours, then 12-15 mg IM or 15 mg orally every 6 hours for 48 hours, starting usually 24 hours after methotrexate. Suspected methotrexate overdose: within one hour of the methotrexate. Megaloblastic anaemia: once daily.
Max: Up to 120 mg leucovorin calcium for the initial 12-24 hour rescue phase, in divided doses — the only ceiling figure stated. For suspected methotrexate overdose the SPC instead sets the dose relative to the antifolate: the calcium folinate dose should be equal to or greater than the dose of methotrexate, with no numeric ceiling given.
Source: UK SPC (eMC) for Refolinon 15mg tablets, §4.2 posology plus §4.3, §4.4/4.5, §4.6 and §4.8 (https://www.medicines.org.uk/emc/product/1369/smpc). SCOPE: Refolinon is the first brand named on this page; the second (Lederfolin) was not fetched. The product sourced is an oral 15 mg tablet, so the tablet strength pins the 15 mg oral figures; the IM/IV figures above are quoted from the same §4.2 but would be given with an injectable calcium folinate product whose own SPC was not fetched — check that product's label for its concentration and administration instructions. §4.4 verbatim: 'Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.' Refolinon contains lactose. NOTE ON SOURCES: providers.openfda and providers.who are both null in this bundle — no US label and no WHO entry were used.
Paediatric dose
Route: Oral (15 mg tablets). §4.2 also states intramuscular, IV bolus and IV infusion routes for the rescue phase — using an injectable product not fetched here. Never intrathecal.
Frequency: As for adults — rescue: divided doses over 12-24 hours, then every 6 hours for 48 hours. Megaloblastic anaemia: once daily.
NOT WEIGHT-BASED IN THIS SOURCE, so dosePerKg is null and the weight calculator is deliberately left unset. §4.2 gives ONE combined heading — 'Adults and children:' — for both the leucovorin rescue regimen and the megaloblastic anaemia dose, and states no separate paediatric figure, no per-kg or per-m2 figure and no age band. Children therefore take the same regimens quoted in the adult dose above. NOTE: paediatric methotrexate-rescue dosing in oncology practice is commonly protocol- and surface-area-based; nothing of that kind appears in this SPC and none has been invented here. Verify against a children's formulary and the treating oncology protocol before use.
Dose adjustments
Renal
Not stated in the product information we used — check the full SPC.
Hepatic
Not stated in the product information we used — check the full 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
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Pernicious anaemia or other megaloblastic anaemia where vitamin B12 is deficient
- PRECAUTION (§4.4, not a §4.3 contraindication): contains lactose — patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine
Side effects
- Adverse reactions to leucovorin calcium are rare, but occasional pyrexial reactions have been reported following intravenous and intramuscular administration
- In combination with 5-fluorouracil, the most common dose-limiting adverse reactions are stomatitis and diarrhoea
- Haematological adverse reactions such as leucocytopenia and thrombocytopenia may occur — these are dose-dependent and their occurrence can usually be decreased by reducing the dose of the cytotoxic drug
- Anaphylactoid and urticarial allergic reactions have been reported
Interactions
- 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
- Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures
- Concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the haematopoietic response to folic acid
- Calcium folinate may enhance the toxicity of fluorouracil
Monitoring
- §4.8: close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and of serum electrolytes (e.g. Na, K, Ca) and creatinine levels — these control the dose-dependent haematological reactions seen with calcium folinate plus 5-fluorouracil
- Methotrexate levels are not mentioned in the fetched sections; the §4.2 rescue schedule is time-based (every 6 hours for 48 hours, starting 24 hours after methotrexate). Follow the local protocol for level-guided rescue
- §4.4: use with methotrexate and 5-fluorouracil only under clinicians experienced in cancer chemotherapy
Clinical monograph
How it works
As an already-reduced folate it bypasses the dihydrofolate reductase step blocked by methotrexate, restoring folate-dependent synthesis in normal cells and so limiting antifolate toxicity.
Prescribing in practice
- Folinic acid rescue must be given at the correct time and dose relative to methotrexate, because delayed or inadequate rescue can result in life-threatening methotrexate toxicity.
- It is used to treat overdose or accidental overexposure to folate-antagonist drugs and certain methotrexate-induced toxicities.
- It does not reverse the antifolate effect of trimethoprim-sulfamethoxazole on a treated infection in the way that simple folate supplementation would, and product-specific guidance should be followed.
Monitoring
In methotrexate rescue, monitor methotrexate plasma levels and renal function to determine the duration and intensity of folinic acid cover.
Counselling the patient
- This is a rescue medicine that protects healthy cells from chemotherapy toxicity.
- It must be taken exactly on schedule after methotrexate.
- Report mouth ulcers, vomiting or feeling very unwell after methotrexate treatment.
Evidence & guidelines
Folinic acid (calcium folinate) rescue is the established standard for limiting toxicity after high-dose methotrexate and in folate-antagonist overdose.
Reference: UKHCDO; 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
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