Methotrexate with Levetiracetam Interaction Details

Brand Names Associated with Methotrexate

Brand Names Associated with Levetiracetam

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 17, 2023

Interaction Effect

Increased risk of methotrexate exposure and toxicity

Interaction Summary

Concomitant use of methotrexate and levetiracetam may result in increased methotrexate exposure and toxicity, however current reports are conflicting. A patient coadministered both drugs developed increased time to methotrexate elimination from 90 hours to an average of 130 hours (range, 106 to 155 hours). In a retrospective review (N=81), there was no significant difference in the proportion of patients with delayed elimination of methotrexate at 24, 48, or 72 hours between patients that received concomitant levetiracetam and those that did not . If delayed methotrexate elimination occurs when coadministered levetiracetam, substitution of levetiracetam may be beneficial. When possible, consider temporarily switching from levetiracetam to another antiepileptic agent, especially in patients with a history of delayed methotrexate elimination with levetiracetam coadministration or in those at a greater risk for methotrexate toxicity .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of methotrexate and levetiracetam may result in an increased methotrexate exposure and toxicity. If delayed methotrexate elimination occurs when coadministered levetiracetam, substitution of levetiracetam may be beneficial. When possible, consider temporarily switching from levetiracetam to another antiepileptic agent, especially in patients with a history of delayed methotrexate elimination with levetiracetam coadministration or in those at a greater risk for methotrexate toxicity.

Mechanism Of Interaction

Delay of methotrexate elimination

Literature Reports

A) There was no significant difference in the proportion of patients with delayed elimination of methotrexate at 24, 48, or 72 hours between patients that received concomitant levetiracetam and those that did not, in a retrospective study of patients receiving methotrexate for an oncology diagnosis (N=81). Median methotrexate concentrations were significantly higher at 24 hours with those not receiving levetiracetam compared to those with concomitant levetiracetam (7.37 micromol/L vs 2.91 micromol/L); however, there were no significant differences in concentrations at 48 and 72 hours. Only baseline CrCl was found to be a predictor of delayed elimination. Patients received at least 1 dose of methotrexate 1000 mg/m(2) or greater IV over 3 to 4 hours or 800 mg/m(2) or greater IV over 22 to 24 hours with or without concomitant levetiracetam 500 to 1500 mg once or twice daily .

B) A patient treated with methotrexate (12 g/m(2)) for relapsed osteosarcoma developed increased time to methotrexate elimination from 90 hours to an average of 130 hours (range, 106 to 155 hours) when coadministered levetiracetam 2 g/day. Methotrexate elimination times decreased to 95 hours when lorazepam was substituted for levetiracetam .

Methotrexate Overview

• Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Levetiracetam Overview

• Levetiracetam is used alone and along with other medications to control partial-onset seizures (seizures that involve only one part of the brain) in adults, children, and infants 1 month of age or older. Levetiracetam is also used in combination with other medications to treat seizure in adults and children 12 years of age or older with juvenile myoclonic epilepsy. Levetiracetam is also used in combination with other medications to treat primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) in adults and children 6 years of age or older with epilepsy. Levetiracetam is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.