Methotrexate with Leflunomide Interaction Details
Brand Names Associated with Methotrexate
- Amethopterin
- Methotrexate
- MTX
- Rheumatrex®
- Trexall®
Brand Names Associated with Leflunomide
- Arava®
- Leflunomide
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 17, 2023
Interaction Effect
Increased exposure of methotrexate and increased risk of hepatotoxicity and bone marrow toxicity
Interaction Summary
The active metabolite of leflunomide is teriflunomide, which is an organic anion transporter 3 (OAT3) inhibitor. Concomitant administration of leflunomide or teriflunomide with methotrexate (an OAT3 substrate) may increase the plasma concentration of methotrexate via inhibition of OAT-mediated transport system. Consider reducing the dose of methotrexate when coadministered with teriflunomide. The starting and maximum dosage of leflunomide is 20 mg once a day without a loading dose when coadministered with methotrexate. Monitor blood counts monthly during concurrent treatment. If evidence of bone marrow suppression occurs, stop leflunomide or teriflunomide and reduce the plasma concentration of the active metabolite with cholestyramine or charcoal. If leflunomide and methotrexate are given concomitantly, American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity must be followed, with ALT, AST, and serum albumin testing monthly .
Severity
Major
Onset
Delayed
Evidence
Established
How To Manage Interaction
Concomitant administration of leflunomide or teriflunomide (active metabolite) with methotrexate (an OAT3 substrate) may increase the plasma concentration and subsequently increase the side effects of methotrexate. Consider reducing the dose of methotrexate when given with teriflunomide. The starting and maximum dosage of leflunomide is 20 mg once a day without a loading dose when coadministered with methotrexate. Monitor the blood counts monthly during concurrent treatment. If evidence of bone marrow suppression occurs, stop leflunomide or teriflunomide and reduce the plasma concentration of the active metabolite with cholestyramine or charcoal. If leflunomide and methotrexate are given concomitantly, American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity must be followed, with ALT, AST, and serum albumin testing monthly .
Mechanism Of Interaction
Inhibition of OAT-mediated transport of methotrexate by leflunomide or its active metabolite, teriflunomide
Literature Reports
A) In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients. These effects were generally reversible. Pancytopenia, agranulocytosis, and thrombocytopenia have also been reported more frequently when leflunomide was given concomitantly with methotrexate .
B) The combination of leflunomide and methotrexate has been associated with increased risk of pancytopenia in 18 cases of leflunomide-associated pancytopenia in elderly patients. Of the 18 patients, 14 were receiving the combination of leflunomide and methotrexate. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in 9 cases. Eleven of the 14 patients were over 60 years old and 4 of these patients died. Time to onset of pancytopenia ranged from 11 days to 4 years. Acute renal failure associated with dehydration and nonsteroidal antiinflammatory drugs may have led to the decreased clearance of leflunomide and precipitated the onset of pancytopenia in 1 fatal case. This patient was treated with leflunomide 20 mg/day for 4 years and methotrexate 10 mg/week for 10 years. Her regimen had been stable for 6 months prior to admission. A cohort study of 3325 patients treated with leflunomide over 33 months had 5 cases of leukopenia but no cases of pancytopenia .
Methotrexate Overview
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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.
Leflunomide Overview
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Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function). Leflunomide is in a class of medications called disease-modifying antirheumatic drugs (DMARDs). It works by decreasing inflammation and slowing the progress of the condition, which can help improve the physical activity of people with rheumatoid arthritis.
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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:
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.