Leucovorin and Capecitabine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Leucovorin
Capecitabine
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 capecitabine or doxifluridine or fluorouracil (prodrugs of capecitabine) or tegafur (prodrug of fluorouracil) exposure and an increased risk of capecitabine or doxifluridine or fluorouracil or tegafur toxicity
Interaction Deep Dive
Coadministration of capecitabine or doxifluridine or fluorouracil (prodrugs of capecitabine) or tegafur (prodrug of fluorouracil) with leucovorin may increase capecitabine or doxifluridine or fluorouracil or tegafur exposure and may enhance its toxicity. Instruct patients not to take folate analog products unless directed to do so1. Fluorouracil is recommended for administration either as an IV bolus or as an IV infusion. Dosage recommendations for adenocarcinoma of the colon and rectum: in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin: 400 mg/m2 for one dose, followed by 2,400 mg/m2 to 3,000 mg/m2 over 46 hours on day 1 of each 2-week cycle, until disease progression or unacceptable toxicity. In combination with leucovorin alone (bolus regimen): 500 mg/m2 on days 1, 8, 15, 22, 29 and 36 of each 8-week cycle, until disease progression or unacceptable toxicity. For pancreatic adenocarcinoma, in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin: 400 mg/m2 on day 1, followed by 2,400 mg/m2 over 46 hours every 2 weeks, until disease progression or unacceptable toxicity 2. Death from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and capecitabine or doxifluridine or fluorouracil or tegafur 1.
Why it happens (mechanism)
Formation of ternary structure with thymidylate synthase and fluorodeoxyuridine monophosphate (FdUMP) by leucovorin
Literature reports
3 reports — tap to read
a) Pharmacokinetics of fluorouracil were compared when fluorouracil was administered alone and coadministered with leucovorin. High-dose leucovorin (500 mg/m2) was infused over two hours to five patients with metastatic colorectal cancer who were receiving fluorouracil treatment. Increases were seen in the time of distribution and volume of distribution of fluorouracil when both drugs were given concurrently. However, area under the concentration-time curve (AUC), plasma clearance, and elimination of fluorouracil were unaltered by leucovorin 3.
b) 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 4.
c) Leucovorin increases the concentration of 5-fluorouracil and enhances its activity and potential toxicity 564. Death from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil 1.
Common questions
Can I take Leucovorin and Capecitabine together?
Increased capecitabine or doxifluridine or fluorouracil (prodrugs of capecitabine) or tegafur (prodrug of fluorouracil) exposure and an increased risk of capecitabine or doxifluridine or fluorouracil or tegafur toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Leucovorin and Capecitabine 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 Leucovorin or Capecitabine 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 (6)
- Product Information: XELODA(R) oral tablets, capecitabine oral tablets. Genentech USA Inc (per FDA), South San Francisco, CA, 2022. DailyMed
- Product Information: FAVLYXA™ intravenous injection, fluorouracil intravenous injection. Avyxa Pharma, LLC (per FDA), Parsippany, NJ, 2026. DailyMed
- Stein TA, Burns GP, Bailey B, et al: 5-fluorouracil pharmacokinetics in patients with metastatic colorectal carcinoma after high-dose leucovorin. Cancer Invest 1994; 12:375-378. PubMed
- 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: Teysuno oral capsules, tegafur gimeracil oteracil oral capsules. Nordic Group BV (per EMA), Hoofddorp, The Netherlands, 2012.
- Product Information: Leucovorin calcium. Immunex Corporation, Seattle, WA, 1994. DailyMed
Keep reading about Leucovorin
Keep reading about Capecitabine
These medications also interact with supplements
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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