Methotrexate

Introduction

Methotrexate is a folate analogue that that competitively inhibits dihydrofolate reductase, stopping conversion of folate to tetrahydrofolate needed for purine nucleotide production and DNA/RNA synthesis. 

It is a chemotherapeutic agent used as an immunosuppressive in a variety of conditions and its major effects in both therapeutic and toxic scenarios are on rapidly dividing tissues, in particular bone marrow and gut lining. 

Typical scenarios for methotrexate toxicity are acute ingestion of an overdose, chronic accumulation with inadvertent daily administration instead of weekly, or high dosing of intravenous or intrathecal methotrexate. The majority of poison centre calls are for accidental daily oral dosing.[1]

Clinical manifestations of toxicity:

  • GIT: Mucositis, stomatitis, diarrhoea, hepatitis
  • Haem: Pancytopaenia
  • Renal: Impaired renal function
  • CNS (associated with high dose systemic or intrathecal): focal neurology, seizures, meningitis picture.

Toxicokinetics

Methotrexate absorption for the gut is by an active transport system that is saturable and is also used to transport folinic acid. The risk of toxicity following an acute ingestion is reduced by both its saturable absorption and its rapid renal clearance. 

Methotrexate toxicity correlates better to duration of exposure rather than peak plasma concentration, This means the risk of toxicity is higher in chronic accumulation following staggered exposures, particularly if there is impaired renal clearance (eGFR <45 mls/min).[2, 3]

Risk Assessment

The risk of toxicity following oral ingestion is low due to the limited absorption and rapid renal clearance. A single ingestion <1g of methotrexate (<5mg/kg children) with normal renal function is very unlikely to lead to toxicity and folinic acid rescue therapy is not recommended. 

Patients with a history of inadvertent daily doses, or those with symptoms of toxicity should be investigated for potential complications particularly bone marrow suppression and hepatitis.

Investigations should include:

  • FBC
  • Chem20

Methotrexate levels do not correlate well with toxicity and are not recommended.

 

Management

Decontamination

As methotrexate absorption is already limited, and activated charcoal also bind the antidote folinic acid if required, activated charcoal is not recommended.[2]

Supportive Measures

Provide good supportive care and keep the patient well hydrated.

In patients that develop myelosuppression, G-CSF analogues, transfusions and if febrile, broad spectrum antibiotics, may be required.[3]

Folinic Acid

Folinic acid (leucovorin) is useful in methotrexate toxicity by 2 pathways;

  • It directly competes with the active transporter decreasing methotrexate’s intestinal absorption 
  • It can be directly converted to tetrahydrofolate, bypassing dihydrofolate reductase. 

Folinic acid is given orally initially in order to compete with methotrexate absorption.  Subsequent doses are given intravenously. Folinic acid is recommended over folic acid as methotrexate blocks conversion of folate by dihydrofolate reductase, whereas folinic acid bypasses this step.

Recommendations for use in asymptomatic patients:[2]

ScenarioAny acute Ingestion & renal impairment (eGFR <45mls/min) Acute Ingestion >1gAny Staggered ingestion >36hrs
 Folinic Acid Oral 15mg followed by 15mg q6h IV for three days.  Oral 15mg q6h for 24 hours. Oral 15mg followed by 15mg q6h IV for three days.

For symptomatic patients:

Give 15mg folinic acid q6h IV/PO until cell counts recover and mucositis resolves

Disposition

Patients who show signs of toxicity or are at risk of developing toxicity should be admitted to hospital for folinic acid therapy.

Well patients with single ingestions <1g and normal renal function may be discharged, with advice to return should symptoms develop. 

They should be seen by their GP the following week with repeat bloods prior to restarting methotrexate therapy.

Further reading

  • Bateman, D.N. and C.B. Page, Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. Br J Clin Pharmacol, 2016. 81(3): p. 437-45.
  • Chan, B.S., A.H. Dawson, and N.A. Buckley, What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning? Clin Toxicol (Phila), 2017. 55(2): p. 88-96

References

1.         Bateman, D.N. and C.B. Page, Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.Br J Clin Pharmacol, 2016. 81(3): p. 437-45.

2.         Chan, B.S., A.H. Dawson, and N.A. Buckley, What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning?Clin Toxicol (Phila), 2017. 55(2): p. 88-96.

3.         Isoardi, K.Z., et al., Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose.Clin Toxicol (Phila), 2018. 56(12): p. 1204-1206.

4.         Chan, B.S., A.H. Dawson, and N.A. Buckley, Response to the letter regarding “Is it really safe to withhold folinic acid when less than 1000 mg/m(2) methotrexate is ingested?”.Clin Toxicol (Phila), 2017. 55(9): p. 1020.

5.         Hays, H., et al., Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review.Clin Toxicol (Phila), 2018. 56(2): p. 120-125.