Cyclosporine and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Cyclosporine
Methotrexate
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased methotrexate exposure, potentiation of methotrexate efficacy, methotrexate toxicity or methotrexate-related severe adverse reactions, possibly reduced active metabolite formation and reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with hepatotoxic agents like cycloSPORINE may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with cycloSPORINE may also subsequently reduce active metabolite formation, which may reduced the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic products1. In a study involving patients with rheumatoid arthritis, cycloSPORINE potentiated methotrexate efficacy 4. Concomitant use of methotrexate and cycloSPORINE may interfere with the elimination of both drugs. This interference may result in increased blood concentrations of both drugs, increased toxicity, and increased potential for renal dysfunction 23.
Why it happens (mechanism)
CycloSPORINE blocks oxidation of methotrexate to its inactive metabolite, 7-OH-methotrexate; additive hepatotoxicity; reduced methotrexate absorption
Literature reports
1 report — tap to read
a) CycloSPORINE may potentiate methotrexate efficacy when the combination is used. Thirty rheumatoid arthritis patients were entered into the study. Each patient received a stable weekly dose of methotrexate for 2 months prior to being enrolled. The use of certain NSAIDs were allowed in the study. On day 8, daily doses of cycloSPORINE were initiated and continued and on day 23 each patient received their weekly methotrexate dose with cycloSPORINE. CycloSPORINE led to a 26% increase in the mean peak plasma methotrexate concentration (Cmax, p less than 0.01), a 60% increase in the time to peak plasma concentration (Tmax, p less than 0.01), and an 18% increase in mean plasma methotrexate concentration area under the curve (AUC, p less than 0.01). CycloSPORINE with methotrexate lowered the mean plasma 7-OH-methotrexate concentration AUC by 80% (p less than 0.01). The plasma Cmax for 7-OH-methotrexate was also reduced to 26% (p less than 0.01) of that observed with methotrexate alone. In a subset of 13 patients receiving methotrexate 10 mg, cycloSPORINE reduced urinary 7-OH-methotrexate excretion by 87% (p less than 0.01) without altering methotrexate excretion. Methotrexate did not change the pharmacokinetics of cycloSPORINE or its metabolites. The ability of cycloSPORINE to potentiate methotrexate efficacy may mean that a lower methotrexate dose be used when this combination therapy is initiated 4.
Common questions
Can I take Cyclosporine and Methotrexate together?
Increased methotrexate exposure, potentiation of methotrexate efficacy, methotrexate toxicity or methotrexate-related severe adverse reactions, possibly reduced active metabolite formation and reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Cyclosporine and Methotrexate interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Cyclosporine or Methotrexate need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (4)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Product Information: NEORAL(R) oral soft gelatin capsules oral solution, cyclosporine modified oral soft gelatin capsules oral solution. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2023. DailyMed
- Korstanje MJ, van Breda Vriesman CJP, & van de Staak WJBM: Cyclosporine and methotrexate: a dangerous combination. Am Acad Dermatol 1990; 23:320-321. PubMed
- Fox R, Morgan S, Smith H, et al: Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone. Rheumatology 2003; 42:989-994. DOI
Keep reading about Cyclosporine
Keep reading about Methotrexate
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Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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