Methotrexate (MTX) is a folic acid antagonist widely employed as an antineoplastic and immunosuppressive agent. Toxicity following oral overdose is uncommon and usually involves dosing errors (often the weekly dose mistakenly being taken daily) or renal impairment.

The antidote folinic acid (leucovorin, calcium folinate) is effective in cases of toxicity and is available in IV and oral formulations.

High dose intravenous and intrathecal MTX is used in cancer chemotherapy and can cause severe toxicity – such cases should be discussed with a medical oncologist.

MTX’s therapeutic and toxic effects are a result of its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase. MTX enters cells through an active transport system used by folinic acid and binds to and inhibits the enzyme. Dihydrofolate reductase maintains reduced folate by recycling dihydrofolic acid which has been produced during thymidylate synthesis (see diagram). Dihydrofolate reductase reduces folic acid to tetrahydrofolate, an essential co-factor in the synthesis of purine nucleotides.

Simple methotrexate diagram

Reduced folates are also required by thymidylate synthetase to provide methyl donors for the formation of thymidylate, essential for DNA synthesis. The effects of MTX poisoning are most apparent in more rapidly dividing cells such as gastrointestinal tract and bone marrow.

Effects can also often be observed on the liver as higher concentrations of MTX are provided to the liver through the portal circulation as the drug is absorbed.
Acute renal failure can result from MTX precipitation in the renal tubule, particularly in patients who are inadequately hydrated.

Single Acute Ingestion
MTX has saturable absorption with low bioavailability, meaning neither accidental nor acute deliberate ingestion is likely to lead to toxicity.

Ingestions of <1000mg in adults or <5mg/kg in children are very unlikely to lead to toxicity, unless there is co-existent renal impairment.

Repeated supratherapeutic ingestion
MTX is generally prescribed as a once weekly dose. Errors in dosing, often when patients mistakenly take the dose daily, are far more likely to lead to toxicity. Ingestions of this nature lead to a prolonged exposure to MTX over at least several days, overcoming the protective effect of reduced bioavailability seen in single ingestions.

Toxicity is likely if MTX is taken for 3 or more consecutive days, or twice daily for a period of more than 36 hrs.

Absorption of MTX after oral administration is saturable. MTX is absorbed from the gastrointestinal tract via the active transport system which is used for folates. The bioavailability falls with increasing doses from > 50% to < 25% of the ingested dose. At doses less than 30 mg/m² , absorption is 90% whilst at doses greater than 80 mg/m2, absorption is less than 20%.

It is for this reason that high-dose MTX therapy must be administered parenterally to achieve the desired plasma concentrations. This saturable absorption may protect against toxicity following acute oral overdose.

The volume of distribution of MTX is about 0.6 L/kg. It is poorly lipid soluble and does not diffuse across lipid membranes. Its only method of entering cells is through active transport processes. It uses the folinic acid transport systems and thus folinic acid may compete for transport into cells as well as antagonising the effects inside cells.

MTX does not get transported into the CSF and CSF concentrations are generally < 5% of plasma concentrations. Once inside cells MTX is polyglutamated. The polyglutamation inhibits the efflux of MTX from the cells. Polyglutamated MTX may be retained inside cells between 1 to 4 weeks after serum MTX concentrations fall.

MTX is eliminated almost entirely by renal excretion. MTX is predominantly excreted unchanged in the urine within 48 hours by both glomerular filtration and active tubular secretion. Toxicity is dependent more on the duration of concentration than dose administered. Renal failure reduces MTX clearance and increases the duration of exposure to MTX.

Aspirin and probenecid inhibit MTX secretion in the proximal tubule and folinic acid blocks MTX reabsorption thus aspirin may increase toxicity and folinic acid may accelerate MTX excretion. The clearance of MTX is largely independent of urine flow rate.

The distribution half-life is 2 hours while elimination half-life of MTX is 8-10 hours. However, toxicity may continue after serum concentrations fall due to the trapping of polyglutamated MTX inside cells.

Clinical features of MTX toxicity are predominantly gastrointestinal, haematological and renal.

• Gastrointestinal: nausea, vomiting, mucositis, stomatitis, diarrhoea. GI bleeding and hepatotoxicity can be seen in severe cases.
• Haematological: bone marrow suppression (7-10 days post exposure) including neutropenia, agranulocytosis, anaemia and thrombocytopenia.
• Renal: Renal impairment due to MTX precipitation in renal tubules, especially in dehydrated patient.
  

• Renal function: important for assessing a patient’s risk of developing toxicity.
• Full blood count: either as baseline or to assess for bone marrow suppression if delayed presentation.
• Liver function: either as baseline or to assess for bone marrow suppression if delayed presentation.
• MTX serum concentration: MTX concentrations are not useful in either acute or chronic ingestions due to low bioavailability, rapid cellular uptake and short distribution half-life. They may be helpful following toxicity following intravenous dosing – this should be discussed with a medical oncologist.
  

Airway and Breathing

Compromise of airway and breathing are not expected with MTX toxicity.

Circulation

Cardiovascular toxicity is not expected following MTX poisoning. Dehydration and resultant hypotension may occur due to GI losses and should be managed with intravenous fluids.

Patients with clinically significant MTX poisoning and in particular myelosuppression should be managed under standard principals for this group of patients. They may require:

• barrier nursing
• antibiotics – especially in the setting on neutropenia
• antiemetics
• mouth care
• transfusions
• G-CSF or GM-CSF

The care is essentially that for any patient who has had severe adverse effects from chemotherapy.

Calcium folinate competes for absorption of MTX from the GI tract and therefore can be used to reduce absorption.

In patients ingesting >1000 mg MTX (child: >5 mg/kg)

Give: Calcium folinate 15mg orally

If calcium folinate is not readily available activated charcoal in standard doses can be used instead.

There is no role for enhanced elimination following MTX poisoning.

Administration of reduced folate in the form of folinic acid allows for continued purine synthesis in the MTX-toxic patient and is used in high-dose MTX therapy to limit the toxic effects.

Acute single ingestion

In patients taking >1000mg (child: >5mg/kg), who have normal renal function (eGFR>45). Give:

Calcium folinate 15mg orally, every 6 hours for 24 hours

In patients taking excess MTX of any dose, with impaired kidney function (eGFR <45). Give:

Calcium folinate 15mg orally (decontamination role)
Followed by
Calcium folinate 15mg intravenously, every 6 hours for 3 days

Repeated supratherapeutic ingestion

In patients taking their weekly dose for 3 or more days in a row or twice daily for more than 36 hours. Give:

Calcium folinate 15mg orally (decontamination role)
Followed by
Calcium folinate 15mg intravenously, every 6 hours for 3 days
Followed by
Calcium folinate 15mg orally, every 6 hours for 1 week or until systemic toxicity resolves.

Glucarpidase is an enzyme which rapidly deactivates methotrexate after injection. It has no role in the treatment of oral methotrexate toxicity but can be used in cases of high dose parenteral administration – for further information consult a medical oncologist.

Admit all patients with renal impairment or signs of systemic toxicity for antidotal therapy and supportive care until toxicity resolves.

Adults taking >1000mg or children taking >5mg/kg, with normal renal function can be discharged to complete a 24-hour course of oral folinic acid at home.

Patients ingesting less than the above amounts, without renal failure can be reassured and discharged without treatment.

All patients should be discharged with advice to monitor for signs of toxicity (fever, sore throat, mouth ulcers, bruising, vomiting and diarrhoea) over the next 5 -10 days, and to return for assessment if they occur.

1. Cairns R, Brown JA, Buckley NA. A decade of Australian MTX dosing errors. Med J Aust 2016;205(10):486. PDF
2. Chan BS, Dawson AH, Buckley NA. What can clinicians learn from therapeutic studies about the treatment of acute oral MTX poisoning? Clin Toxicol (Phila) 2017;55(2):88–96. PDF
3. Chan BS, Dawson AH, Buckley NA. Response to the letter regarding “Is it really safe to withhold folinic acid when less than 1000 mg/m2 MTX is ingested?”. Clin Toxicol (Phila) 2017;55(9):1020. PDF
4. Hays H, Beuhler MC, Spiller HA, Weber J, Mowry JB, Ryan ML, et al. Evaluation of toxicity after acute accidental MTX ingestions in children under 6 years old: a 16-year multi-center review. Clin Toxicol (Phila) 2018;56(2):120–5. PDF