Drug & supplement interaction

Grapefruit + Aspirin, Butalbital, Caffeine, Codeine Phosphate

Aspirin, Butalbital, Caffeine, Codeine Phosphate brand name: Fiorinal w/ Codeine.

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

Aspirin, Butalbital, Caffeine, Codeine Phosphate falls into 3 drug categories that Grapefruit can interact with; the most serious is rated major. Grapefruit juice can increase levels of drugs metabolized by CYP3A4.

Read the full interaction report
SeverityMajor
LikelihoodLikely
Interactions3
EvidenceB
What do Severity, Likelihood & Evidence mean?
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Interaction report

Grapefruit and Aspirin, Butalbital, Caffeine, Codeine Phosphate

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Grapefruit interacts with whole categories of medication. Aspirin, Butalbital, Caffeine, Codeine Phosphate falls into 3 of those categories, so it can interact with Grapefruit in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Major).

Major

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

1 of 3

Why this applies to Aspirin, Butalbital, Caffeine, Codeine Phosphate

Aspirin, Butalbital, Caffeine, Codeine Phosphate falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES — the group Grapefruit interacts with.

Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours. Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient.
Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice.
Severity Major Likelihood Likely Evidence B

Well-controlled human studies have demonstrated the likely existence of this interaction.

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

Here's the wrinkle with Fiorinal with Codeine: it's a combination product, and grapefruit doesn't treat all four pieces the same way. Grapefruit blocks an enzyme called CYP3A4, which can let some of these ingredients build up. The butalbital (a barbiturate) and caffeine can hang around longer, which may mean more drowsiness, grogginess, or feeling foggy. The codeine part is trickier because codeine is a prodrug that mainly relies on a different enzyme (CYP2D6) to turn into its active painkiller, so grapefruit's main effect there is less clear cut.

Bottom line: the evidence here is moderate, but with a sedating combo like this I'd play it safe. Please check with your pharmacist or doctor before adding regular grapefruit, especially if you're older or take other medicines.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999;66:118-27. DOI
  2. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998;64:477-83. PubMed
  3. Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002;71:21-9. PubMed
  4. Fuhr U, Muller-Peltzer H, Kern R, et al. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur J Clin Pharmacol 2002;58:45-53. PubMed
  5. Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur J Clin Pharmacol 2001;56:799-803. PubMed
  6. Charbit, B., Becquemont, L., Lepere, B., Peytavin, G., and Funck-Brentano, C. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther 2002;72(5):514-523. PubMed
  7. Tanaka S, Uchida S, Miyakawa S, Inui N, Takeuchi K, Watanabe H, Namiki N. Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4. Biol Pharm Bull. 2013;36(12):1936-41. PubMed
  8. Bailey DG. Predicting clinical relevance of grapefruit-drug interactions: a complicated process. J Clin Pharm Ther. 2017 Apr;42(2):125-27. PubMed
  9. Mouly S, Lloret-Linares C, Sellire PO, Sene D, Bergmann JF. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort? Pharmacol Res. 2017 Apr;118:82-92. PubMed
  10. Loretz C, Ho MD, Alam N, Mitchell W, Li AP. Application of cryopreserved human intestinal mucosa and cryopreserved human enterocytes in the evaluation of herb-drug interactions: evaluation of CYP3A inhibitory potential of grapefruit juice and commercial f
  11. Long Z, Ruan M, Wu W, Zeng Q, Li Q, Huang Z. The successful combination of grapefruit juice and venetoclax in an unfit acute myeloid leukemia patient with adverse risk: A case report. Front Oncol 2022;12:912696. PubMed
Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

2 of 3

Aspirin, Butalbital, Caffeine, Codeine Phosphate also falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES.

Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.
In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes. So far, this interaction has not been reported in humans.
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

This combo pill (Fiorinal with Codeine) has a lot going on, but the piece grapefruit might touch is the caffeine. Caffeine is cleared by an enzyme called CYP1A2, and lab studies suggest grapefruit could slow that enzyme a little. In theory, that might let caffeine linger longer, so you could feel more jittery, have a racing heart, or trouble sleeping. Important: this has only been seen in test tubes, not in real people, so I would not lose sleep over it.

One side note: grapefruit does not meaningfully change the codeine part here. If you enjoy grapefruit regularly, just mention it to your pharmacist so we can keep an eye on how you feel.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom 2004;1 PubMed
Moderate

CAFFEINE

3 of 3

Aspirin, Butalbital, Caffeine, Codeine Phosphate also falls under CAFFEINE.

Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.
Clinical research shows that grapefruit juice decreases caffeine clearance.
Severity Moderate Likelihood Probable Evidence D

Interaction 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..

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

Here's the thing about Fiorinal with Codeine: it's a combination pill, and the part that grapefruit can touch is the caffeine in it. Grapefruit slows down how fast your body clears caffeine, so that caffeine can linger and build up a bit. In real life that might mean more of the jittery side of caffeine, like feeling wired, a racing or pounding heart, trouble settling down to sleep, or a touch of stomach upset.

Keep in mind this one is mostly theoretical, based on how the chemistry works, and the caffeine dose in this pill is fairly small. An occasional grapefruit probably won't cause trouble, but if you drink grapefruit juice often, it's worth a quick chat with your pharmacist or doctor to be sure it's a good fit for you.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Fuhr U. Drug Interactions with Grapefruit Juice. Drug Saf 1998;18:251-72. DOI

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

Grapefruit Also Interacts With Other Medications

Grapefruit has 775 major, 151 moderate, 63 minor known drug interactions in our database — the Aspirin, Butalbital, Caffeine, Codeine Phosphate one above is among them. If you take anything else, check it against the full list below.

Major 775 Moderate 151 Minor 63 No known interaction 1,841 (incl. Aspirin, Butalbital, Caffeine, Codeine Phosphate)
Taking anything else?

Check Another of Your Medications Against Grapefruit

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

From our Q&A

Questions About Grapefruit or Aspirin, Butalbital, Caffeine, Codeine Phosphate

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Grapefruit or Aspirin, Butalbital, Caffeine, Codeine Phosphate, 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 Aspirin, Butalbital, Caffeine, Codeine Phosphate

This page covers Grapefruit only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Butalbital, Caffeine, Codeine Phosphate page lists 398 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Asarabacca (major), Beer (major) and Danshen (major).

By severity: 17 major · 334 moderate · 47 minor.

From our pharmacist’s overview on the Aspirin, Butalbital, Caffeine, Codeine Phosphate page

“Fiorinal with Codeine packs four active drugs into one capsule, and I would treat its supplement list with genuine wariness rather than a quick skim. The aspirin component is why roughly half of the 398 ingredients on file raise bleeding risk, while the codeine and butalbital explain a second large cluster that deepens sedation, someti…”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Butalbital, Caffeine, Codeine Phosphate interaction page

One more smart check

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

We hold 1,144 real supplement products containing Grapefruit, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Grapefruit. Your product may carry other ingredients that interact with Aspirin, Butalbital, Caffeine, Codeine Phosphate too, on top of Grapefruit — 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 Grapefruit and Aspirin, Butalbital, Caffeine, Codeine Phosphate 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 Grapefruit
Top 10%

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

29 days ago today
Medication Aspirin, Butalbital, Caffeine, Codeine Phosphate
Steady interest

#1,938 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 Grapefruit

What is Grapefruit?

Grapefruit
  • Source of vitamin C
  • Digestive complaints
  • Antimicrobial (seed extract)
  • Weight management
  • Skin and cosmetic uses

Grapefruit is a nutritious citrus fruit rich in vitamin C and other nutrients, and it is generally safe to eat. However, grapefruit is famous for serious interactions with many prescription medicines, so anyone taking medication should check with a pharmacist or doctor before consuming it regularly.

Read the full Grapefruit monograph & all interactions
Keep checking

Other Drugs & Grapefruit

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

775Major
151Moderate
63Minor
1,840No known interaction
775 Major 151 Moderate 63 Minor 1,840 No interaction
Major

775 interactions

Showing 60 of 775 major interactions — see all 775 on the Grapefruit page.

Moderate

151 interactions

Showing 60 of 151 moderate interactions — see all 151 on the Grapefruit page.

Minor

63 interactions

Showing 60 of 63 minor interactions — see all 63 on the Grapefruit page.

No interaction 1,840 drugs checked — show the list

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

Showing the 60 most looked-up of 1,840 medications checked with no known interaction — see the full Grapefruit list.

See the full Grapefruit interactions page
See every supplement checked against Aspirin, Butalbital, Caffeine, Codeine Phosphate, 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
Grapefruit monograph › Uses, safety, and every drug interaction in one place Aspirin, Butalbital, Caffeine, Codeine Phosphate supplement interactions › Every supplement checked against Aspirin, Butalbital, Caffeine, Codeine Phosphate, ranked by severity 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 Grapefruit and Aspirin, Butalbital, Caffeine, Codeine Phosphate Together: Common Questions

Can you take Grapefruit with Aspirin, Butalbital, Caffeine, Codeine Phosphate?
This is rated a major interaction, so the combination is best avoided unless your doctor or pharmacist has specifically told you otherwise. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 3 interactions listed for Grapefruit and Aspirin, Butalbital, Caffeine, Codeine Phosphate?
Aspirin, Butalbital, Caffeine, Codeine Phosphate belongs to more than one drug category, and Grapefruit interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Grapefruit and Aspirin, Butalbital, Caffeine, Codeine Phosphate interaction?
We rate it Major. This is a clinically significant combination that is generally best avoided, or used only under the direct supervision of your physician or pharmacist.

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

Still Have a Question About Aspirin, Butalbital, Caffeine, Codeine Phosphate and Grapefruit?

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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.