Fluorouracil Drug Interactions: What to Avoid and What to Tell Your Doctor

Fluorouracil (5-FU) is a chemotherapy drug with a complex pharmacology. It interacts with several other medications in ways that can significantly change its effectiveness or safety. Before starting fluorouracil — either as an IV chemotherapy infusion or as a topical cream — make sure your oncologist, dermatologist, and pharmacist have a complete list of everything you take.

This guide covers the most important interactions to know, organized by severity.

Critical Interaction: Brivudine (and Sorivudine)

The most dangerous interaction with fluorouracil involves antiviral drugs called brivudine and sorivudine. These drugs powerfully inhibit the DPD enzyme — the same enzyme that normally breaks down more than 80% of fluorouracil. If fluorouracil is given to a patient who has recently taken brivudine, fluorouracil blood levels can reach life-threatening concentrations.

Brivudine is not currently approved in the United States (it is used in parts of Europe for herpes zoster). However, if you have ever taken it or are considering it, this interaction is potentially fatal and must be discussed with your oncologist. The DPD inhibition from brivudine can persist for weeks after the last dose.

Major Interaction: Warfarin (and Other Anticoagulants)

Fluorouracil significantly increases the anticoagulant effect of warfarin. This means your INR (international normalized ratio) can rise unpredictably, greatly increasing the risk of bleeding. If you take warfarin (Coumadin, Jantoven) and start fluorouracil, your INR must be monitored much more frequently — at minimum weekly, and potentially more often when starting or ending a fluorouracil cycle.

This interaction is particularly important with capecitabine (the oral prodrug of 5-FU) because of its intermittent dosing schedule, which creates cyclical peaks and troughs of drug concentration. If your oncologist is considering switching you from fluorouracil to capecitabine and you take warfarin, this must be explicitly discussed.

Major Interaction: Metronidazole (Flagyl)

Metronidazole, a common antibiotic and antiparasitic drug, inhibits the metabolism of fluorouracil, leading to increased 5-FU blood levels and heightened toxicity. If you develop an infection while on fluorouracil chemotherapy and your doctor prescribes metronidazole (often used for bacterial vaginosis, C. diff, or dental infections), make sure your oncologist is aware so they can monitor for increased 5-FU toxicity or consider alternative antibiotics.

Therapeutic Combination: Leucovorin (Not an Interaction to Avoid)

Leucovorin (folinic acid) is intentionally given with fluorouracil in most standard chemotherapy regimens (FOLFOX, FOLFIRI, etc.) because it enhances 5-FU's effectiveness. Leucovorin stabilizes the binding of fluorouracil's active metabolite to the thymidylate synthase enzyme, making it more potent. While this is not an interaction to avoid, it does increase fluorouracil toxicity, which is why dose monitoring is important.

Important Interaction: Cimetidine (Tagamet)

Cimetidine, an H2 blocker antacid sometimes used for heartburn, can increase fluorouracil blood levels. If you take cimetidine regularly and are starting fluorouracil, discuss alternatives like famotidine (Pepcid) or proton pump inhibitors with your care team.

Interaction: Allopurinol

Allopurinol (used for gout or to prevent tumor lysis syndrome) may reduce the effectiveness of fluorouracil by interfering with one of the pathways that converts it to its active form. This interaction is complex and context-dependent. Your oncologist should be aware if you are taking allopurinol.

Interaction: Other Myelosuppressive Drugs

Fluorouracil suppresses bone marrow (reduces blood cell production). Combining it with other drugs that have the same effect — including other chemotherapy agents, immunosuppressants, and some antibiotics — can dangerously worsen myelosuppression, leading to severe neutropenia, anemia, or bleeding risk. This is managed carefully by your oncology team, but make sure all prescribers know your complete medication list.

Alcohol and Fluorouracil

Alcohol use during fluorouracil treatment is generally discouraged. Alcohol can increase nausea and gastrointestinal side effects, contribute to dehydration, and may affect liver metabolism. There is one documented alcohol/food interaction listed for fluorouracil — discuss alcohol use with your oncologist before and during treatment.

What to Tell Your Doctor Before Starting Fluorouracil

Give your oncologist and pharmacist a complete medication list including:

All prescription medications, including anticoagulants, antifungals, antibiotics, and antiseizure drugs.

Over-the-counter drugs including antacids (especially cimetidine/Tagamet), NSAIDs, and vitamins.

Herbal supplements — some can affect drug metabolism enzymes.

Any history of unusual reactions to fluorouracil or related drugs (capecitabine, tegafur).

For more on what to expect from fluorouracil treatment, see our fluorouracil side effects guide. If you're having difficulty finding fluorouracil in stock, medfinder can help you locate it at a pharmacy near you.