From the Guidelines
Treatment of methotrexate toxicity primarily involves leucovorin (folinic acid) rescue therapy, which should be initiated as soon as possible after methotrexate overdose is recognized, with oral leucovorin (10 mg) administered twice daily, beginning on the day of treatment and continuing for 3 days, to mitigate systemic toxicity 1.
Key Considerations
- Accidental overdoses of MTX can be treated with carboxypeptidase G2, which highlights the importance of having this agent available for emergency use 1.
- The treatment approach should also consider the patient's overall clinical context, including renal function, presence of third space fluid collections, and abnormal CSF flow, as these factors can influence the risk and severity of MTX toxicity 1.
- Leucovorin does not appear to cross the blood-brain barrier in amounts sufficient to interfere with the effect of MTX in the CSF, making it a safe choice for mitigating systemic toxicity without compromising the therapeutic effect of MTX in the central nervous system 1.
Management Strategies
- Oral leucovorin administration is a practical approach for managing MTX toxicity, given its ease of use and the fact that it can be started promptly in outpatient settings or continued after discharge 1.
- Monitoring for potential complications such as myelosuppression, particularly in patients with poor bone marrow reserve, and managing these complications appropriately, is crucial for optimizing patient outcomes 1.
- The potential for drug interactions that could increase MTX toxicity, such as displacement from serum albumin by certain drugs (aspirin, phenytoin, sulfonamides, and tetracycline), should be considered and managed through careful medication review and adjustment as needed 1.
From the FDA Drug Label
OVERDOSAGE: Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function
The treatment for Methotrexate (MTX) toxicity includes:
- Leucovorin administration as soon as possible to counteract the effects of methotrexate overdose
- Hydration and urinary alkalinization in cases of massive overdosage to prevent precipitation of methotrexate in the renal tubules
- Glucarpidase for patients with delayed methotrexate clearance due to impaired renal function 2
From the Research
Treatment for Methotrexate (MTX) Toxicity
The treatment for MTX toxicity has several goals, including clearance of MTX from the bloodstream, folinic acid therapy, and organ treatment 3. The preferred antidote for MTX poisoning is folinic acid, which is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after high-dose MTX therapy 3.
Treatment Options
- Clearance of MTX from the bloodstream: This can be achieved through hydration and urinary alkalinization 4.
- Folinic acid therapy: High-dose leucovorin can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity 5.
- Organ treatment: Treatment of organ toxicity, such as acute kidney injury (AKI), is crucial to prevent further toxicity and facilitate renal recovery 4.
- Glucarpidase: This enzyme has been licensed for the treatment of high plasma MTX levels of >1 μmol/L in patients with compromised renal function who have delayed MTX elimination 3, 6.
Prevention of Toxicity
Prevention of MTX toxicity is essential, and measures include:
- Monitoring of serum creatinine, urine output, and serum methotrexate concentration to assess renal clearance 4.
- Concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity 4.
- Avoidance of drug interactions that may increase the risk of MTX toxicity 7, 4.
- Implementation of safety-practical measures to prevent administration errors 7.