Nitrofurantoin and Methotrexate Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate Injection
Nitrofurantoin
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, an increased risk of methotrexate-related severe adverse reactions
Interaction Deep Dive
Coadministration of methotrexate with oral antibiotics which are also hepatotoxic agents increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with oral antibiotics which are also hepatotoxic agents may also subsequently reduce active metabolite formation, which may reduce the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions1. Additionally, alternative therapies which may be less harmful to the lungs (eg, hydroxychloroquine) should be considered in patients requiring long-term nitrofurantoin therapy who are also taking methotrexate to decrease risk of pulmonary toxicity 2.
Why it happens (mechanism)
Reduced methotrexate absorption, additive hepatotoxicity
Literature reports
1 report — tap to read
a) A 94-year-old woman with long-standing rheumatoid arthritis was treated with methotrexate for over a decade and was also taking hydroxychloroquine as part of her disease-modifying therapy. In addition, she had been taking nitrofurantoin 50 mg/day for several years for urinary tract infection suppression. She presented with shortness of breath and a nonproductive cough for a duration of approximately 2 weeks. She was treated with antibiotics for pneumonia 6 weeks earlier. On admission, her physical exam was significant for a pulse oximetry of 98% on supplemental oxygen (2L nasal cannula) and bilateral rhonchi. Laboratory findings were significant for a WBC of 9100 cells/microliter with elevated neutrophils (76.9%) and monocytes (10.9%), mild hyponatremia (130 mmol/dL), and elevated troponin of 0.08 nanograms/mL. Chest x-ray showed bilateral mid- and lower-lung airspace disease, and CT showed a moderate honeycombing pattern consistent with pulmonary fibrosis. Despite treatment for pneumonia with ceftriaxone and azithromycin, she continued to have difficulty breathing and elevated neutrophils and lymphocytes. Given her irreversible pulmonary fibrosis and clinical decline, she refused further treatment, transitioned to hospice care, and died a few days later 2.
Common questions
Can I take Nitrofurantoin and Methotrexate Injection together?
Increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions Always confirm with your pharmacist or prescriber before making any change.
How serious is the Nitrofurantoin and Methotrexate Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Nitrofurantoin or Methotrexate Injection 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 (2)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Kochhar S, Bommu VJL, Kocur M, et al: A unique interaction of methotrexate and nitrofurantoin resulting in irreversible pulmonary fibrosis. Cureus 2022; 14(1):e20892. PubMed
Keep reading about Methotrexate Injection
Keep reading about Nitrofurantoin
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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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