Drug & supplement interaction

Folic Acid + Fluorouracil

Fluorouracil brand names: Efudex, Tolak.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Folic Acid has a moderate interaction with Fluorouracil. Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.

Read the full interaction report
SeverityModerate
LikelihoodPossible
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Folic Acid and Fluorouracil

Here is the interaction we found between these two, with the evidence behind it.

Moderate

5-FLUOROURACIL

Why this applies to Fluorouracil

Fluorouracil falls under 5-FLUOROURACIL — the group Folic Acid interacts with.

Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.
Increases in gastrointestinal side effects of 5-fluorouracil, such as stomatitis and diarrhea, have been described in two clinical studies when leucovorin, a form of folic acid, was administered with 5-fluorouracil.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist with fluorouracil (often called 5-FU): this chemo drug works by latching onto an enzyme inside cancer cells. Folate actually helps lock that grip in place, which is why a folate-like medicine called leucovorin is sometimes given on purpose alongside 5-FU to make it work harder. The flip side is that more activity can also mean more side effects.

So in theory, taking high-dose folic acid supplements on your own could nudge up 5-FU's typical rough spots, like mouth sores, diarrhea, and irritated skin where it's applied. Keep in mind this is based on pharmacology and a couple of studies with leucovorin, not strong proof folic acid pills do the same. Normal food and a standard multivitamin are unlikely to matter. Please don't add or stop any folic acid without checking with your oncology team first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Bedford Laboratories. Leucovorin calcium [package insert]. Bedford, OH. September 2008. Available at: http://www.bedfordlabs.com/BedfordLabsWeb/products/inserts/LCV-P02.pdf.

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Folic Acid Also Interacts With Other Medications

Folic Acid has 39 moderate known drug interactions in our database — the Fluorouracil one above is one of them. If you take anything else, check it against the full list below.

Moderate 39 No known interaction 2,791 (incl. Fluorouracil)
Taking anything else?

Check Another of Your Medications Against Folic Acid

Covers the 2,830 medications we’ve checked against Folic Acid. Pick one to open its full report.

From our Q&A

Questions About Folic Acid or Fluorouracil

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Folic Acid or Fluorouracil, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Fluorouracil

This page covers Folic Acid only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Fluorouracil page lists 26 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Alfalfa (moderate), Angelica Archangelica (moderate), Arrach (moderate), Bergamot (moderate) and Bishop's Weed (moderate).

By severity: 23 moderate · 3 minor.

From our pharmacist’s overview on the Fluorouracil page

“If you are using fluorouracil cream (Efudex, Tolak) on sun-damaged skin, your skin is already primed to react to sunlight, and that is where most of its supplement interactions sit. Of the 26 ingredients on file, 20 can make skin more sun-sensitive on their own, chlorophyll, chlorella, and bergamot oil among them, so pairing one with t…”

Reviewed by 2 · Jul 18, 2026

Open the Fluorouracil interaction page

One more smart check

Taking Folic Acid as Part of a Dietary Supplement Product? Check It for Interactions

We hold 92 real supplement products containing Folic Acid, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Folic Acid. Your product may carry other ingredients that interact with Fluorouracil too, on top of Folic Acid — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Folic Acid and Fluorouracil Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Folic Acid
Top 25%

#198 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Fluorouracil
Steady interest

#2,128 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Folic Acid

What is Folic Acid?

  • Preventing neural tube birth defects
  • Treating or preventing folate deficiency
  • Supporting pregnancy health
  • Certain types of anemia
  • Heart and blood vessel health

Folic acid is the man-made form of vitamin B9 and is one of the most well-studied supplements, especially for preventing serious birth defects when taken before and during early pregnancy. It is widely available, inexpensive, and generally safe at recommended doses, but you should still check with your pharmacist or doctor about the right amount for you.

Read the full Folic Acid monograph & all interactions
Medication

About Fluorouracil Injection

What Is Fluorouracil Injection Used For?

Brand names: Efudex, Tolak

Fluorouracil Injection is used to treat four types of adenocarcinoma (a common form of cancer that begins in glandular cells): cancer of the colon and rectum, breast cancer, stomach (gastric) cancer, and pancreatic cancer.

It is nearly always given as part of a combination chemotherapy regimen alongside other cancer medicines, and the specific drugs paired with it depend on which cancer is being treated.

See full Fluorouracil Injection drug information
Keep checking

Other Drugs & Folic Acid

Browse every other medication we’ve checked against Folic Acid — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
39Moderate
0Minor
2,790No known interaction
39 Moderate 2,790 No interaction
Moderate

39 interactions

No interaction 2,790 drugs checked — show the list

We also checked Folic Acid against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 2,790 medications checked with no known interaction — see the full Folic Acid list.

See the full Folic Acid interactions page
See every supplement checked against Fluorouracil, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Folic Acid monograph › Uses, safety, and every drug interaction in one place Fluorouracil supplement interactions › Every supplement checked against Fluorouracil, ranked by severity Fluorouracil Injection drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Folic Acid and Fluorouracil Together: Common Questions

Can you take Folic Acid with Fluorouracil?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
How serious is the Folic Acid and Fluorouracil interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Fluorouracil and Folic Acid?

Our pharmacists answer your medication & supplement questions — free.

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.