Ketoconazole Topical and Tacrolimus: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Tacrolimus
Ketoconazole Topical
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
Increased tacrolimus exposure and an increased risk of QT interval prolongation
Interaction Deep Dive
Coadministration of ketoconazole (a strong CYP3A4 inhibitor that may prolong the QT interval) with CYP3A4 substrates that are known to prolong the QT interval, such as tacrolimus is contraindicated1 as it may cause increased tacrolimus exposure 2, increasing the risk for QT interval prolongation and result in life-threatening ventricular tachyarrhythmias such as torsade de pointes 1. If concomitant use is required, reduce the tacrolimus dose and adjust based on whole blood trough concentrations. A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose. Monitor whole blood trough concentrations early and frequently; start within 1 to 3 days and continue as necessary. In addition, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment 34.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated tacrolimus metabolism; additive QT interval prolongation
Literature reports
2 reports — tap to read
a) In 6 healthy volunteers, coadministration of ketoconazole and tacrolimus increased the bioavailability of tacrolimus; however, the clearance and volume of distribution were not significantly affected. In a crossover design, either 0.1 mg/kg orally or 0.025 mg/kg IV of tacrolimus was given on day 1 and day 7 of the study. On study day 8, ketoconazole 200 mg orally at bedtime was started. On study day 13 and day 19 either 0.04 mg/kg orally or 0.01 mg/kg IV of tacrolimus was given. When given with ketoconazole, the bioavailability of tacrolimus was 30%, compared with 14% when tacrolimus was given alone. It was proposed that the change in bioavailability was caused by inhibition of gut metabolism of tacrolimus, not an effect on hepatic metabolism, because of the lack of effect on systemic clearance of tacrolimus 5.
b) A 32-year-old female who had received a cadaveric renal transplant was immunosuppressed with tacrolimus 0.2 mg/kg daily and predniSONE. Because of a urinary tract infection caused by candida, ketoconazole 200 mg daily was initiated 20 days following transplant. At that time, her serum creatinine was 1 mg/dL and her tacrolimus blood level was 11.1 nanograms (ng)/mL. Despite a decrease in her tacrolimus dose to 0.11 mg/kg daily, her tacrolimus blood level increased to 27.9 ng/mL one day after ketoconazole was started. The tacrolimus dose was further reduced to 0.04 mg/kg daily (an 80% reduction from baseline) to maintain a blood level of 15.8 ng/mL. One week after ketoconazole was discontinued, the tacrolimus blood level had fallen to 5.8 ng/mL and the tacrolimus dose was increased to 0.11 mg/kg to achieve a blood level of 7.2 ng/mL 6.
Common questions
Can I take Ketoconazole Topical and Tacrolimus together?
Increased tacrolimus exposure and an increased risk of QT interval prolongation Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ketoconazole Topical and Tacrolimus interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
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 Ketoconazole Topical or Tacrolimus 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: Ketoconazole oral tablet, ketoconazole oral tablet. Taro Pharmaceuticals U.S.A. Inc. (per DailyMed), Hawthorne, NY, 2024. DailyMed
- Product Information: PROTOPIC(R) topical ointment, tacrolimus 0.03% topical ointment, 0.1% topical ointment. Astellas Pharma US, Inc. (per FDA), Deerfield, IL, 2011. DailyMed
- Product Information: PROGRAF(R) oral capsules, oral granules for suspension, intravenous injection, tacrolimus oral capsules, oral granules for suspension, intravenous injection. Astellas Pharma US Inc (per FDA), Northbrook, IL, 2023. DailyMed
- Product Information: ENVARSUS XR(R) oral extended-release tablets, tacrolimus oral extended-release tablets. Veloxis Pharmaceuticals Inc (per FDA), Cary, NC, 2023. DailyMed
- Floren LC, Bekersky I, Benet LZ, et al: Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 1997; 62:41-49. PubMed
- Moreno M, Latorre A, Manzanares C, et al: Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc 1999; 31:2252-2253. DOI
Keep reading about Tacrolimus
Keep reading about Ketoconazole Topical
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