Ketoconazole Topical and Midazolam: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Midazolam
No brand names on recordKetoconazole 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 midazolam exposure and potentially increased midazolam toxicity (excessive sedation and prolonged hypnotic effects)
Interaction Deep Dive
Coadministration of ketoconazole and oral midazolam is contraindicated, as concomitant use may cause midazolam toxicity (excessive sedation and prolonged hypnotic effects). Under no circumstances oral midazolam be coadministered with ketoconazole, and up to one week after discontinuation of treatment with ketoconazole. Careful monitoring is recommended when the IV midazolam is coadministered with oral ketoconazole for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and reduce IV midazolam dosage as deemed necessary. When appropriate, measure IV midazolam exposure1. Significant increases in sedative effects, AUC, peak plasma concentrations, half-life, and bioavailability of midazolam were reported in healthy volunteers when ketoconazole was coadministered with midazolam 34.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of midazolam
Literature reports
4 reports — tap to read
a) The AUC and Cmax of midazolam increased by 309% and 1490%, respectively, when ketoconazole 400 mg every day was coadministered with oral midazolam, in adult subjects 2.
b) Nine healthy individuals (six men and three women) received single doses of 2 mg intravenous and 6 mg oral midazolam (Phase I). In Phase II single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of ketoconazole 200 mg were administered. After ketoconazole therapy was initiated in Phase II, the area under the concentration-time curve (AUC) for midazolam increased five-folds and sixteen-fold after intravenous and oral administration, respectively. There was a total bioavailability increase from 25% to 80% and a decrease in intrinsic clearance by 84%. There was a greater increase in the intestinal component (2.3 fold) of midazolam bioavailability than the hepatic component (1.5 fold) 3.
c) Substantial increases in midazolam peak plasma concentration (310%), AUC (1490%), and half-life (210%) have been demonstrated to occur with concurrent oral ketoconazole compared to placebo in healthy volunteers. Significant increases in sedative effects were indicated by psychomotor tests and subjective reporting of drowsiness with the combination. Coadministration of midazolam is not recommended for patients receiving ketoconazole 4.
d) Azole antifungals, including ketoconazole are thought to inhibit the metabolism of drugs cleared by the cytochrome P450 3A subfamily of enzymes and possibly, the P450 2C subfamily 56.
Common questions
Can I take Ketoconazole Topical and Midazolam together?
Increased midazolam exposure and potentially increased midazolam toxicity (excessive sedation and prolonged hypnotic effects) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ketoconazole Topical and Midazolam 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 "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Ketoconazole Topical or Midazolam 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: midazolam hcl syrup, midazolam hcl syrup. Paddock Laboratories, Minneapolis, MN, 2004. DailyMed
- Tsunoda SM, Velez RL, von Moltke LL, et al: Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther 1999; 66:461-471. PubMed
- Olkkola KT, Backman JT, & Neuvonen PJ: Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55:481-485. DOI
- Slaughter RL & Edwards DJ: Recent advances: the cytochrome P450 enzymes. Ann Pharmacother 1995; 29:619-624. PubMed
- Shen WW: Cytochrome P450 monooxygenases and interactions of psychotropic drugs: a five-year update. Int J Psychiatry Med 1995; 25:277-290. DOI
Keep reading about Midazolam
Keep reading about Ketoconazole Topical
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