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Antidote / Chemotherapy Support Pregnancy: C - use in MTX toxicity; benefit clearly outweighs risk

Folinic Acid (Calcium Folinate / Leucovorin)

Brand names: Refolinon, Isovorin, Leucovorin Calcium

Adult dose

Dose: MTX rescue: 15 mg/m2 IV/IM/PO every 6 h starting 24 h after MTX. High-dose MTX toxicity: 100-1000 mg/m2 IV every 3-6 h until MTX levels <0.05 umol/L
Route: IV / IM / PO
Frequency: Every 6 h (standard rescue) or every 3-6 h (high-dose toxicity) until MTX level safe
For co-trimoxazole / trimethoprim toxicity (megaloblastic anaemia): 5-15 mg/day PO. Methotrexate and folinic acid MUST NOT be given simultaneously - folinic acid rescues normal cells by bypassing DHFR block.

Paediatric dose

Route: IV / IM / PO
Frequency: Every 6 h per protocol
Max: Per oncology protocol
Same dose as adult per m2. For MTX rescue: start 24 h post-MTX infusion per oncology protocol.

Dose adjustments

Renal

Increase folinic acid dose and frequency if creatinine elevated >=50% above baseline (impaired MTX clearance).

Clinical pearls

  • CRITICAL: Folinic acid (leucovorin) is NOT the same as folic acid - only folinic acid bypasses DHFR blockade caused by MTX. Folic acid is INEFFECTIVE as rescue.
  • MTX toxicity features: mucositis, neutropenia, renal failure, hepatotoxicity. Monitor LFTs, FBC, creatinine, and MTX levels.
  • High-dose MTX (>1g/m2) always requires leucovorin rescue - start 24 h post-infusion.
  • Increase folinic acid dose significantly if MTX levels remain high at 24 h, 48 h, 72 h post-infusion.
  • Glucarpidase (carboxypeptidase G2) is an additional antidote for severe MTX toxicity with renal failure - specialist use.
  • Used as part of FOLFOX/FOLFIRI regimens in colorectal cancer - same drug, different clinical context.

Contraindications

  • Do NOT use folic acid (folate) as a substitute - folic acid requires DHFR for activation, which MTX blocks
  • Pernicious anaemia as sole treatment (masks B12 deficiency)

Side effects

  • Pyrexia (IV administration)
  • Allergic reactions (rare)
  • Seizures at very high doses (rare)

Interactions

  • Methotrexate: NEVER co-administer - defeats the purpose of rescue therapy
  • 5-fluorouracil (5-FU): folinic acid potentiates 5-FU activity (used therapeutically in CRC regimens)
  • Phenobarbital / Phenytoin / Primidone: folinic acid may reduce anticonvulsant levels

Monitoring

  • Serum MTX levels (24h, 48h, 72h post-infusion)
  • FBC with differential
  • Renal function (creatinine, urea)
  • LFTs
  • Mucositis assessment

Reference: BNFc; TOXBASE; UKMI; SPC Refolinon; NICE CG151; BNF 84; ESMO Methotrexate Guidelines. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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