Estradiol Transdermal Patch and Rifabutin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Rifabutin
Estradiol Transdermal Patch
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
Reduced hormonal contraceptive exposure, reduced efficacy of hormonal contraceptives and increased risk of breakthrough bleeding and/or contraceptive failure
Interaction Deep Dive
Avoid concomitant use of rifabutin (CYP3A4 inducer) and hormonal contraceptives1. Coadministered of rifabutin and hormonal contraceptive metabolism, resulted in reduced ethinyl estradiol AUC and Cmax by 35% and 20%, respectively and reduced norethindrone AUC by 46% 4. During an crossover study, rifabutin altered the disposition of an oral contraceptive and resulted in a higher incidence of spotting compared with controls 5. In another study, concomitant use of a CYP3A4 inducer disproportionally increased the rate of unplanned pregnancy with oral and implanted contraceptives; therefore, consider intrauterine or intravaginal routes if coadministration is required 3. Use an alternative method of contraception during coadministration and for at least 28 days after discontinuation of a CYP3A4 inducer 2.
Why it happens (mechanism)
Induction of CYP3A4-mediated metabolism of hormonal contraceptives
Literature reports
4 reports — tap to read
a) In 22 healthy women maintained on hormonal combination contraceptives (ethinyl estradiol/norethindrone), the administration of rifabutin resulted in a decrease of AUC and Cmax of both contraceptive components. Ethinyl estradiol AUC and Cmax reduced by 35% and 20%, respectively and norethindrone AUC reduced by 46% 4.
b) An open-label, randomized, three-way crossover study of healthy females (n=28) was undertaken to determine the impact of concomitant rifabutin and rifAMPin therapy on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norethindrone (Ortho-Novum 1/35(R)). Twenty-two women completed all three phases of the study. All women received the oral contraceptive for 21 days for the first cycle, which served as the control. They were then randomized to one of two sequences to receive concomitant rifAMPin or rifabutin 300 mg daily for 10 days. When evaluating the pharmacokinetics of ethinyl estradiol, women receiving rifabutin had a decreased Cmax (333.4 picograms (pg)/mL vs. 416.1 pg/mL) and a decreased AUC (2192.6 pg/hr/mL vs. 3362 pg/hr/mL) when compared with controls. Similarly, the Cmax of norethindrone was 15.37 nanograms (ng)/mL in the rifabutin group and 22.61 ng/mL in control, and the AUC of norethindrone was 86.19 ng/hr/mL during the rifabutin phase and 159.09 ng/hr/mL during control. The incidence of spotting was 3.7% during the control cycle and increased to 21.7% during rifabutin therapy. However, there was no clear evidence of ovulation in this study 5.
c) Concomitant use of a CYP3A4 inducer with oral or implantable contraceptive products containing levonorgestrel (684 events) or etonogestrel/desogestrel (864 events) was associated with a disproportionately higher rate of unintended pregnancy compared to all other event types reported to the FDA Adverse Event Reporting System (FAERS) between 1971 and 2020 [levonorgestrel (14,504 total events); etonogestrel/desogestrel (9348 total events)]. When compared between CYP3A4 inducer exposure vs no exposure, cases of unintended pregnancy made up a significantly higher proportion of total events when levonorgestrel was administered orally (32.8% vs 10.5%) or as an implant (51.9% vs 11.9%), and a similar association was identified with implanted etonogestrel products (42.5% vs 13.1%). However, when contraceptives were administered as an intrauterine device (levonorgestrel, 10.3% vs 11.5%) or intravaginal ring (etonogestrel, 10.9% vs 8.7%), no significant associations were identified. Oral desogestrel (pro-drug of etonogestrel) in combination with ethynyl estradiol also was not significantly affected (11.8% vs 17.4%). Intrauterine and vaginal ring products may be preferred in lieu of oral and implantable contraceptive products in women concomitantly receiving CYP3A4 inducers 3.
d) The effects of rifAMPin and rifabutin on an oral contraceptive were examined in a randomized, 2-period, crossover trial involving 12 females. All subjects were on a stable contraceptive regimen that contained ethinyl estradiol 35 mcg and norethindrone 1 mg (Ortho-Novum(R) 1/35). Each participant was randomized to receive 14 days of therapy with rifAMPin 600 mg daily or rifabutin 300 mg daily on days 7 through 21 of their menstrual cycle. Rifabutin decreased the mean trough ethinyl estradiol concentration (Cmin) by 50%, but the mean Cmax was not significant. Mean norethindrone Cmin values decreased by 32%, while Cmax did not significantly change. Luteinizing hormone and follicle stimulating hormone levels were not statistically altered by rifabutin. All subjects remained anovulatory after rifabutin therapy as indicated by undetectable progesterone levels 6.
Common questions
Can I take Estradiol Transdermal Patch and Rifabutin together?
Reduced hormonal contraceptive exposure, reduced efficacy of hormonal contraceptives and increased risk of breakthrough bleeding and/or contraceptive failure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Estradiol Transdermal Patch and Rifabutin interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
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 Estradiol Transdermal Patch or Rifabutin 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: FEMLYV orally disintegrating tablets, norethindrone acetate, ethinyl estradiol orally disintegrating tablets. Millicent U.S. Inc (per FDA), East Hanover, NJ, 2024. DailyMed
- Product Information: JADELLE(R) subdermal implants, levonorgestrel subdermal implants. Bayer Corp (per FDA), Pittsburgh, PA, 2016.
- Sunaga T, Cicali B, Schmidt S, et al: Comparison of contraceptive failures associated with CYP3A4-inducing drug-drug interactions by route of hormonal contraceptive in an adverse event reporting system. Contraception 2021; 103(4):222-224. PubMed
- Product Information: MYCOBUTIN(R) oral capsules, rifabutin oral capsules. Pharmacia & Upjohn Co (per FDA), New York, NY, 2024. DailyMed
- LeBel M, Masson E, Guilbert E, et al: Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol 1998; 38:1042-1050. PubMed
- Barditch-Crovo P, Trapnell CB, Ette E, et al: The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive. Clin Pharmacol Ther 1999; 65:428-438. DOI
Keep reading about Rifabutin
Keep reading about Estradiol Transdermal Patch
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