Levoleucovorin and Fluorouracil Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fluorouracil Injection
Levoleucovorin
No brand names on record
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 concentrations of 5-fluorouracil and fluorouracil toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting)
Interaction Deep Dive
Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with Fusilev(R) and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death may occur2. Death from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving levoleucovorin and fluorouracil 4. Capecitabine is a prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), which is converted to the active drug fluorouracil (5-FU) 3; doxifluridine and tegafur are also prodrugs of fluorouracil. If coadministration is necessary, monitor for increased 5-fluorouracil cytotoxicity and consider dose adjustments if necessary.
Why it happens (mechanism)
Formation of ternary structure with thymidylate synthase and fluorodeoxyuridine monophosphate (FdUMP) by levoleucovorin
Literature reports
1 report — tap to read
a) Thirty patients with advanced colorectal and gastric adenocarcinomas were treated with fluorouracil combined with high-dose folinic acid. The treatment used was based on biochemical and cell culture studies which have demonstrated that an excess of intracellular reduced folates is necessary to provide optimal inhibition of thymidylate synthetase and to increase the cytotoxic effect of fluorouracil. It was concluded that folinic acid at high doses (200 mg/m(2)) increases the effectiveness of fluorouracil given simultaneously 1.
Common questions
Can I take Levoleucovorin and Fluorouracil Injection together?
Increased concentrations of 5-fluorouracil and fluorouracil toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Levoleucovorin and Fluorouracil 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 "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Levoleucovorin or Fluorouracil 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 (4)
- Machover D, Schwarzenberg L, Goldschmidt E, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high dose folinic acid: a pilot study. Cancer Treat Rep 1982; 66:1803-1807.
- Product Information: KHAPZORY(TM) intravenous injection, levoleucovorin intravenous injection. Acrotech Biopharma LLC (per FDA), East Windsor, NJ, 2020. DailyMed
- Product Information: Xeloda(R), capecitabine. Roche Laboratories Inc, Nutley, NJ, 2001. DailyMed
- Product Information: levoleucovorin solution for IV injection, levoleucovorin solution for IV injection. Spectrum Pharmaceuticals,Inc, Irvine, CA, 2008. DailyMed
Keep reading about Fluorouracil Injection
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