Folinic Acid

Folinic acid (calcium folinate, leucovorin) is a reduced folate that bypasses dihydrofolate reductase. It is used to rescue normal cells from folate antagonists and to enhance fluorouracil. Levofolinate is the active isomer and is used at half the racemic dose.

Classification. Folate analogue; antidote to folate antagonists; biochemical modulator.

Mechanism. Provides tetrahydrofolate cofactors directly, so it restores one-carbon metabolism when dihydrofolate reductase is blocked by methotrexate, trimethoprim or pyrimethamine. With fluorouracil it stabilises the thymidylate synthase complex.

Pharmacokinetics. Converted rapidly to 5-methyltetrahydrofolate. Oral absorption saturates at doses above 25 mg, so higher doses are given intravenously. Half-life of the active metabolite is about 6 hours.

Methotrexate rescue after high-dose therapy.

• Dose: 15 mg (about 10 mg/m²) intravenously, intramuscularly or orally every 6 hours, starting 24 hours after the start of the methotrexate infusion (timing is regimen-specific).
• Duration: continue until methotrexate level is under 0.1 µmol/L (some regimens use under 0.05 µmol/L), usually for 10 or more doses.
• Titration for delayed excretion: increase to 100 mg/m² every 3 to 6 hours, or higher, directed by methotrexate levels and creatinine; add glucarpidase for toxic levels with kidney failure.
• Maximum: no fixed maximum; dose by methotrexate level.

Accidental methotrexate overdose. Start within 1 hour if possible; 10 mg/m² every 6 hours until methotrexate level is under 0.01 µmol/L, escalating if levels or creatinine are high.

Fluorouracil combinations (colorectal cancer). Racemic folinic acid 200 to 400 mg/m² (levofolinate 100 to 200 mg/m²) intravenously over 2 hours before fluorouracil, directed by the regimen.

Antifolate toxicity from trimethoprim or pyrimethamine. Folinic acid 10 to 25 mg orally daily, up to 50 mg in toxoplasmosis treatment, to reduce marrow toxicity.

Megaloblastic anaemia due to dihydrofolate reductase deficiency. 3 to 6 mg intramuscularly daily; not for pernicious anaemia.

Adjustments. Kidney: needs higher doses and longer courses if methotrexate clearance is delayed. Liver: none. Children: 10 mg/m² every 6 hours in rescue.

Contraindications. Pernicious anaemia and other cobalamin-deficiency anaemias; hypersensitivity. Not given intrathecally; deaths have followed intrathecal use.

Adverse effects. Allergic reactions, fever, gastrointestinal upset. With fluorouracil it increases toxicity (diarrhoea, mucositis, myelosuppression), so reduce the fluorouracil dose in older adults.

Interactions. Reduces the efficacy of co-trimoxazole in Pneumocystis pneumonia and of pyrimethamine against parasites if used at high dose. May lower phenytoin levels.

Pregnancy and breastfeeding. Used when needed; no evidence of harm.

Common errors. Starting rescue late or stopping too early; giving rapid infusions of calcium folinate (calcium load).

Preparation. Intravenous bolus or infusion in 0.9% sodium chloride or 5% glucose. Do not exceed 160 mg/min of calcium folinate because of the calcium content. Oral dosing is used only for doses up to 25 mg.

Baseline. Creatinine, electrolytes, liver function and methotrexate level.

Monitoring. Methotrexate level every 24 hours (more often if delayed), creatinine, urine pH above 7 and hydration with high-dose methotrexate; full blood count.

Referral and escalation. Methotrexate level above 1 µmol/L at 48 hours, rising creatinine or neurotoxicity: urgent specialist input, with glucarpidase if available.