Drug & supplement interaction

Grapefruit + Estradiol, Norgestimate

Estradiol, Norgestimate brand name: Ortho-Prefest.

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

Estradiol, Norgestimate falls into 3 drug categories that Grapefruit can interact with; the most serious is rated major. Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.

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

Grapefruit and Estradiol, Norgestimate

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. Estradiol, Norgestimate 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

ESTROGENS

1 of 3

Why this applies to Estradiol, Norgestimate

Estradiol, Norgestimate falls under ESTROGENS — the group Grapefruit interacts with.

Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.
Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females.
Severity Major Likelihood Probable Evidence B

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 deal with grapefruit and your Ortho-Prefest (estradiol plus norgestimate). Grapefruit blocks an enzyme in your gut and liver called CYP3A4, which is one of the main ways your body clears out estrogen. When that enzyme is slowed down, more of the estradiol stays in your bloodstream. In fact, studies have shown grapefruit can bump up estradiol levels by roughly 20%.

Higher estrogen levels can mean more of the usual side effects, things like breast tenderness, bloating, nausea, headaches, or spotting. The research behind this is real but not huge, so don't panic. An occasional grapefruit probably isn't a big deal, but regular grapefruit or grapefruit juice is worth a quick chat with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Weber A, Jager R, Borner A, et al. Can grapefruit juice influence ethinylestradiol bioavailability? Contraception 1996;53:41-7.
  2. Schubert W, Cullberg G, Edgar B, Hedner T. Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women. Maturitas 1994;20:155-63.
  3. Monroe KR, Murphy SP, Kolonel LN, Pike MC. Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Mutliethnic Cohort Study. Br J Cancer 2007;97:440-5.
  4. Fingerova, H., Oborna, I., Petrova, P., Budikova, M., and Jezdinsky, J. [Does grapefruit juice increase the bioavailability of orally administered sex steroids?]. Ceska.Gynekol. 2003;68(2):117-121.
Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

2 of 3

Estradiol, Norgestimate 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

Here's the situation with grapefruit and your Ortho-Prefest (estradiol with norgestimate). Grapefruit can block a liver enzyme called CYP1A2, which helps break down the estrogen part of this hormone product. If that enzyme slows down, a bit more estradiol could linger in your body, which in theory might bump up estrogen-related effects like breast tenderness, bloating, nausea, or headaches.

That said, I want to keep this in perspective. This concern comes only from test-tube research, and it has not actually been seen happening in real people. So it's more of a theoretical caution than a proven problem. Occasional grapefruit is unlikely to cause trouble, but if you eat or drink it regularly, just mention it to your pharmacist or doctor so they can keep an eye on things.

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
Minor

P-GLYCOPROTEIN SUBSTRATES

3 of 3

Estradiol, Norgestimate also falls under P-GLYCOPROTEIN SUBSTRATES.

Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.
While most in vitro research shows that grapefruit products inhibit P-gp,, research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys. It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe. Grapefruit juice has been shown to reduce levels of fexofenadine, and increase levels of quinidine. However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.
Severity Minor Likelihood Possible Evidence B

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

Good question about pairing grapefruit with Ortho-Prefest (your estradiol and norgestimate hormone combo). The interaction here is rated minor and rests on the idea that grapefruit might block a transporter called P-glycoprotein in the gut. Honestly, the human evidence for this is shaky and conflicting. In people, grapefruit didn't seem to meaningfully affect this transporter in the studies we have, so any change to your hormone levels is mostly theoretical.

In plain terms, this is unlikely to cause a noticeable problem for most folks. If anything tipped, you might see slightly more estrogen-type effects like breast tenderness, bloating, or nausea, but that's far from certain. Occasional grapefruit is generally fine. If you eat it daily or have concerns, just run it by your pharmacist or doctor.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Soldner A, Christians U, Susanto M, et al. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res 1999;16:478-85. PubMed
  2. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999;48:829-38. PubMed
  3. Bailey DG, Dresser GK, Munoz C, et al. Reduction of fexofenadine bioavailability by fruit juices. Clin Pharmacol Ther 2001;69:P21.
  4. Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65:237-44. PubMed
  5. Becquemont L, Verstuyft C, Kerb R, et al. Effect of grapefruit juice on digoxin pharmacokinetics in humans. Clin Pharmacol Ther 2001;70:311-6. DOI
  6. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11-20. PubMed
  7. Parker RB, Yates CR, Soberman JE, Laizure SC. Effects of grapefruit juice on intestinal P-glycoprotein: evaluation using digoxin in humans. Pharmacotherapy 2003;23:979-87. PubMed
  8. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 2002;71:1149-60. PubMed
  9. Dresser GK, Kim RB, Bailey DG. Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides. Clin Pharmacol Ther 2005;77:170-7. PubMed
  10. Min, D. I., Ku, Y. M., Geraets, D. R., and Lee, H. Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers. J Clin Pharmacol 1996;36(5):469-476. PubMed
  11. Jia Y, Liu J, Xu J. Influence of grapefruit juice on pharmacokinetics of triptolide in rats grapefruit juice on the effects of triptolide. Xenobiotica. 2017 Apr 16:1-5. PubMed
  12. Guideline on the investigation of drug interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2. European Medicines Agency, 2015. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revision-1_en.pdf (As
  13. Piscitelli J, Nikanjam M, Capparelli EV, et al. Fexofenadine Plasma Concentrations to Estimate Systemic Exposure in Healthy Adults Using a Limited Sampling Strategy with a Population Pharmacokinetic Approach. Ther Drug Monit 2023;45(4):539-545. PubMed

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 Estradiol, Norgestimate 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. Estradiol, Norgestimate)
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 Estradiol, Norgestimate

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 Estradiol, Norgestimate, 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 Estradiol, Norgestimate

This page covers Grapefruit only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Estradiol, Norgestimate page lists 159 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), St. John's Wort (major), Adrafinil (moderate), African Wild Potato (moderate) and Aletris (moderate).

By severity: 3 major · 126 moderate · 30 minor.

From our pharmacist’s overview on the Estradiol, Norgestimate page

“Ortho-Prefest pairs estradiol with norgestimate, a hormone therapy most often prescribed for menopause symptoms, and its interaction list warrants genuine care rather than a quick skim. Of the 159 supplements and herbs on file, three carry a major rating, and all involve common products.”

Reviewed by 2 · Jul 18, 2026

Open the Estradiol, Norgestimate 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 Estradiol, Norgestimate 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 Estradiol, Norgestimate 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%

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

29 days ago today
Medication Estradiol, Norgestimate
Steady interest

#1,470 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 Estradiol, Norgestimate, 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 Estradiol, Norgestimate supplement interactions › Every supplement checked against Estradiol, Norgestimate, 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 Estradiol, Norgestimate Together: Common Questions

Can you take Grapefruit with Estradiol, Norgestimate?
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 Estradiol, Norgestimate?
Estradiol, Norgestimate 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 Estradiol, Norgestimate 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

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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.