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Key points

  • We recommend to consult your poison centre with the use of this antidote.
  • Folinic acid or leucovorin, the biologically active forms of folic acid, must be used for reversing toxicity due to dihydrofolate reductase inhibitors (methotrexate).
  • Folic acid, can be used interchangeably with folinic acid or leucovorin only in cases of methanol poisoning.
  • Folic acid or leucovorin facilitates the conversion of formates (toxic) resulting from the metabolism of methanol.
  • Leucovorin contains calcium: rapid intravenous administration can result in complications.
  • Never use the intrathecal route.
  • Methotrexate concentrations are not useful in assessing the degree of toxicity or the dosing regimen for leucovorin in non-oncologic overdoses, and they should not be measured. 

+ Synonyms and other terms

  • Folinic acid
  • Calcium folinate

+ Indications

Methotrexate poisoning:

  • Acute Oral methotrexate ingestion of a dose greater than 5 mg/kg in children and greater than 1000 mg in adults.
  • Acute methotrexate exposure (PO, IM or IV), regardless of dose, in patient with renal impairment (eGFR less than 45mL/min/1,73m2).
  • Acute methotrexate injection (IM, SC or IV) of a dose greater than 1mg/kg in children and adults, with NORMAL kidney function.
    • Acute methotrexate injection of a dose inferior to 1mg/kg can lead to mild toxicity. However severe toxicity is not expected. Call your poison centre.
  • Staggered methotrexate exposure (PO, IM or SC), regardless of dose and kidney function, over a period of 36 h or more.
  • High dose IV methotrexate (oncology):
    • Refer to local hospital oncologic protocol

Adjuvant in methanol poisoning

+ Dosage

+ Pediatric Dose

Methotrexate Poisoning:

  • Acute Oral methotrexate ingestion (greater than 5 mg/kg) with NORMAL kidney function and early presentation (24h) without signs of toxicity:
    • Leucovorin calcium: 15 mg (regardless of weight) PO every 6 h for 24h 
  • All other scenarios: acute oral ingestion (greater than 5 mg/kg) and delayed presentation (more than 24h) or signs of toxicity/ staggered exposure / acute exposure with abnormal kidney function / acute injection (greater than 1 mg/kg) with normal kidney function.
    • Leucovorin calcium: 15 mg (regardless of weight) PO followed 6 hours later by 15 mg (regardless of weight) direct IV* every 6 h for 3 days minimum and continue until resolution of symptoms (mucositis) and normalisation of laboratory abnormalities (cytopenia)
  • High dose IV methotrexate (oncology):
    • refer to local hospital oncologic protocol

*IV is preferred for inpatient management, discussion with your local poison centre is suggested to determine if oral is appropriate


Methanol Poisoning:

  • In the absence of metabolic acidosis:
    • 1 mg/kg (max: 50mg) IV every 6 hours.
  • In the presence of metabolic acidosis:
    • 2 mg/kg (max: 100mg) by IV infusion over 15 - 60 minutes every 4 - 6 hours.
    • Adjust the interval based on severity of the acidosis and medical history (malnutrition, alcoholism, etc.).

+ Adult Dose

Methotrexate Poisoning:

  • Acute Oral methotrexate ingestion (greater than 1000 mg) with NORMAL kidney function and early presentation (24h) without signs of toxicity:
    • Leucovorin calcium: 15 mg PO every 6 h for 24h 
  • All other scenarios: acute oral ingestion (greater than 1000 mg) and delayed presentation (more than 24h) or signs of toxicity/ staggered exposure/ acute exposure with abnormal kidney function / acute injection (greater than 1 mg/kg) with normal kidney function. 
    • Leucovorin calcium: 15 mg PO followed 6 hours later by 15 mg direct IV*every 6 h for 3 days minimum and continue until resolution of symptoms (mucositis) and normalisation of laboratory abnormalities (cytopenia)
  • High dose IV methotrexate (oncology):
    • refer to local hospital oncologic protocol

*IV is preferred for inpatient management, discussion with your local poison centre is suggested to determine if oral is appropriate

Methanol Poisoning:

  • In the absence of metabolic acidosis:
    • 1 mg/kg (max: 50mg) IV every 6 hours.
  • In the presence of metabolic acidosis:
    • 2 mg/kg (max: 100mg) by IV infusion over 15 - 60 minutes every 4 - 6 hours.
    • Adjust the interval based on severity of the acidosis and medical history (malnutrition, alcoholism, etc.).

+ Renal Impairment

No data suggests that the dose should be modified for short-term use.

+ Hepatic Impairment

No data suggests that the dose should be modified for short-term use.

+ Hemodialysis Patient

No data suggests that the dose should be modified for short-term use.

+ Pregnancy

  • Do not hesitate to use leucovorin calcium during pregnancy if the anticipated toxic effects pose a significant risk of morbidity or mortality.
  • No data suggests that the dose should be modified for short-term use.

+ Obese or Overweight Patient

No data suggests that the dose should be modified for short-term use.

+ Adverse effects

  • Allergic and anaphylactoid reactions
  • Seizures

+ Monitoring

  • No monitoring is required other than the monitoring of the poisoning under treatment.
  • Methotrexate poisoning:
    • Complete blood count (CBC)
    • Clinical toxicity signs: mucositis etc.

+ End of treatment

Methotrexate Poisoning:

  • Oral and parenteral (SC or IM) methotrexate poisoning:

    • A minimum of 24 h or 3 days of treatment depending on the indication (see dosage section)

    And

    • When signs and symptoms (mucositis and pancytopenia) are resolved without the need of the effect of Colony Stimulating Factor (ex: Filgrastim, Neupogen).
  • High dose IV methotrexate rescue therapy (oncology):
    • Refer to protocol available in your hospital.

Methanol Poisoning:

  • When metabolic acidosis has been corrected and the methanol eliminated.

+ Special Notes on Administration

Enteral route (PO)

  • The maximum absorbable dose of leucovorin calcium is 25 mg (absorption depends on a saturable active transporter)
  • Available as 5 mg tablet, round up dose to nearest 2.5 mg or 5 mg.
  • For doses higher than 25 mg, switch to IV route of administration.
  • IV formulation can be administered orally if needed and povides equivalent bioavailability to oral tablet.


Intravenous Route (IV)

  • Dose less than 100mg:
    • May be given undiluted (10mg/ml) direct IV.
    • Inject at a rate less than or equal to 160mg/min into the tubing of a freely running IV solution of D5W or NS.
  • Dose greater or equal to 100mg:
    • Dilute in 50mL (for doses up to 500mg) or 100-500ml (for higher doses) of a compatible IV solution.
    • Administer using a volumetric pump over 15 to 60 minutes. Make sure the rate of infusion is less or equal to 160mg/min.
  • Leucovorin contains calcium: too rapid IV administration can result in complications due to calcium content; maximum rate of infusion 160 mg/min

Subcutaneous Route (SC)

  • Not applicable.

Intramuscular Route (IM)

  • Not applicable

Intraosseous Route (IO)

  • No data available.

compatibility

Partial list only. Consult the pharmacist on duty at your health care facility.

  • Compatible solutions: NS, D5W, D10W, LR.
  • Y-site compatibility: alfentanil, aminophylline, calcium (acetate, chloride, gluconate), codeine, dexamethasone, digoxin, diltiazem, diphenhydramine, dobutamine, dopamine, enalapril, ephedrine, epinephrine, esmolol, famotidine, fentanyl, furosemide, haloperidol, standard heparin, hydrocortisone, hydromorphone, regular insulin, isoproterenol, labetalol, lidocaine, lorazepam, magnesium (sulfate), mannitol, meperidine, metoclopramide, metoprolol, midazolam, milrinone, morphine, nitroglycerin, nitroprusside, norepinephrine, octreotide, ondansetron, pentobarbital, phenobarbital, phentolamine, phenylephrine, potassium (acetate, chloride), procainamide, promethazine, propranolol, ranitidine, sufentanil, vasopressin, verapamil. 
  • Y-site incompatibility: amiodarone, bicarbonate (sodium), dantrolene, diazepam, droperidol, methylprednisolone, naloxone, pantoprazole, phenytoin, potassium (phosphate), thiopental.

Stability

  • Store vials in refrigerator at a temperature between 2°C and 8°C
  • Protect from light.
  • Solutions diluted in D5W or in NS will be stable for at least 24 h

+ Available products

  • Leucovorin calcium for injection, USP, 10 mg/ml, Inj., Sol., vials of 5 ml and 50 ml, Pfizer Canada Inc., DIN 02183005 and DIN 02182998  
  • Leucovorin calcium for injection, USP, 10 mg/ml, Inj., Sol., vials of 50 ml, Teva Canada Inc, DIN 02087316,
  • Leucovorin calcium tablet, USP, 5 mg, tablet, Pfizer, DIN 02170493

+ Amount required to treat a person weighting 70kg during 24 hours

  • At least 800 mg.

+ References

  • Bateman, D. Nicholas, and Colin B. Page. 2016. “Antidotes to Coumarins, Isoniazid, Methotrexate and Thyroxine, Toxins That Work via Metabolic Processes.” British Journal of Clinical Pharmacology 81 (3):437–45.
  • Hieger, Michelle A., and S. Rutherfoord Rose. 2016. “Folic and Folinic Acid.” In Critical Care Toxicology, edited by Jeffrey Brent, Keith Burkhart, Paul Dargan, Benjamin Hatten, Bruno Megarbane, and Robert Palmer, 38:1–9. Cham: Springer International Publishing.
  • Howard, Scott C., John McCormick, Ching-Hon Pui, Randall K. Buddington, and R. Donald Harvey. 2016. “Preventing and Managing Toxicities of High-Dose Methotrexate.” The Oncologist 21 (12):1471–82.
  • Roberts, Darren M., Christopher Yates, Bruno Megarbane, James F. Winchester, Robert Maclaren, Sophie Gosselin, Thomas D. Nolin, et al. 2015. “Recommendations for the Role of Extracorporeal Treatments in the Management of Acute Methanol Poisoning: A Systematic Review and Consensus Statement.” Critical Care Medicine 43 (2):461–72.
  • Betty S. Chan, Andrew H. Dawson and Nicholas A. Buckley.2017. “What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning?” Clinical Toxicology 55 (2) 88-96.
  • Silas W.Smith, Lewis S. Nelson. 2008. “Case Files of the New York City Poison Control Center: Antidotal strategies for the Management of Methotrexate toxicity.” Journal fo Medical Toxicology 4 (2): 132-140
  • Ottawa Parenteral Drug Therapy Manual 2019, Leucovorin calcium, p 392-393
  • Groupe d’oncologie du Québec (GEOQ), Guide d’administration Méthotrexate à haute dose (clientèle hospitalisée). Révision mars 2017.
  • Betty S. Chan et al, Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase, Br J Clin Pharmacol. 2024;1-8
     

 


Last updated : 2024-09-05