Fluconazole and Midazolam Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fluconazole
Midazolam Injection
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 potential midazolam toxicity (excessive sedation and prolonged hypnotic effects)
Interaction Deep Dive
Concurrent use of fluconazole and midazolam significantly increased midazolam Cmax and AUC; however, the psychomotor effects were only apparent with oral midazolam not intravenous midazolam. If concurrent use is required, consider reducing the dose of midazolam and monitor for increased midazolam toxicity (excessive sedation and prolonged hypnotic effects)41.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated midazolam metabolism by fluconazole
Literature reports
7 reports — tap to read
a) Oral fluconazole significantly increased the psychomotor effects of oral midazolam but not intravenous midazolam and increased the pharmacokinetic effects (AUC and Cmax) of IV and oral midazolam, in a randomized, cross-over study (n=12). Patients received placebo or oral fluconazole 400 milligrams (mg) on day 1 followed by 200 mg daily from day 2 to 6. Each patient received 7.5 mg midazolam orally on day 1, 0.05 mg/kilogram intravenously on day 4, and 7.5 mg orally on day 6. The clearance of IV midazolam was reduced by 51%. Fluconazole increased the AUC and Cmax by 259% and 150%, respectively, for oral midazolam (first day). Fluconazole increased the AUC and Cmax by 259% and 74%, respectively, on the 6th day 4.
b) Oral and intravenous fluconazole increased the pharmacodynamic and pharmacokinetic effects (Cmax and AUC) of oral midazolam; the pharmacokinetic effects were increased significantly more with oral vs intravenous fluconazole. In a double-dummy, placebo-controlled, cross-over study of three phases, subjects received oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and intravenous saline in each phase. Midazolam 7.5 mg was administered orally after each of the fluconazole/placebo phases. The midazolam AUC and Cmax increased by 272% and 129%, respectively, following the oral administration of fluconazole, and by 244% and 79%, respectively, after the intravenous administration of fluconazole. Fluconazole administered by the oral or intravenous route increased the pharmacodynamic effects of midazolam 4.
c) The AUC and Cmax of midazolam increased by 150% and 250%, respectively, when fluconazole 200 mg every day was coadministered with oral midazolam, in adult subjects 1.
d) In a study involving ten mechanically ventilated intensive care unit patients, intravenous fluconazole was shown to increase the concentrations of intravenous midazolam. All subjects were on a stable infusion of midazolam for at least 24 hours before beginning intravenous fluconazole 400 mg as a loading dose, followed by 200 mg daily. Three of the patients experienced a 100% to 300% increase in midazolam concentrations, and four patients showed a 20% to 30% increase. The remaining three patients only experienced minor changes in midazolam concentrations. The largest changes in midazolam concentrations occurred in patients with renal failure 5.
e) A randomized, double-blind, placebo-controlled study examined the effects of itraconazole or fluconazole on midazolam in 12 healthy volunteers over a 6-day period. Patients were assigned to a regimen of itraconazole, fluconazole, or placebo that started on day 1 and continued through day 6. Patients received 7.5 mg oral midazolam on day 1 and day 6 of the study, and 0.05 mg/kg intravenous midazolam on day 4. Itraconazole and fluconazole reduced the mean plasma clearance of intravenous midazolam by 69% and 51%, respectively. On day 1, itraconazole and fluconazole increased the mean AUC 3.5-fold and increased the Cmax 1.8-fold and 2.5-fold, respectively. Both antimycotics increased the half-life of midazolam. The effect of itraconazole was greater on day 6; oral midazolam AUC, Cmax, and half-life on day 6 were almost doubled compared to day 1 of treatment. For fluconazole, the effects on midazolam on day 1 and day 6 were similar 6.
f) A double-blind, placebo-controlled study in healthy subjects found that a single dose of oral fluconazole 150 mg given with a single dose of midazolam 10 mg increased midazolam plasma concentrations by approximately 50% 7. Objective testing showed that the combination of agents resulted in poorer performance on flicker fusion and letter cancellation tests. Subjective evaluations indicated slowness and overall feeling of impairment during combined administration of fluconazole and midazolam.
g) 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 23.
Common questions
Can I take Fluconazole and Midazolam Injection together?
Increased midazolam exposure and potential midazolam toxicity (excessive sedation and prolonged hypnotic effects) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Fluconazole and Midazolam Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Fluconazole or Midazolam Injection 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 (7)
- Product Information: midazolam hcl syrup, midazolam hcl syrup. Paddock Laboratories, Minneapolis, MN, 2004. DailyMed
- Slaughter RL & Edwards DJ: Recent advances: the cytochrome P450 enzymes. Ann Pharmacother 1995; 29:619-624. DOI
- Shen WW: Cytochrome P450 monooxygenases and interactions of psychotropic drugs: a five-year update. Int J Psychiatry Med 1995; 25:277-290. PubMed
- Product Information: DIFLUCAN(R) oral tablets, suspension, fluconazole oral tablets, suspension. Roerig (per FDA), New York, NY, 2023. DailyMed
- Ahonen J, Olkkola KT, Takala A, et al: Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol Scand 1999; 43:509-514. PubMed
- Olkkola KT, Ahonen J, & Neuvonen PJ: The effect of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996; 82:511-516. DOI
- Vanakoski J, Mattila MJ, Vainio P, et al: 150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects. Int J Clin Pharmacol Ther 1995; 33:518-523.
Keep reading about Fluconazole
Keep reading about Midazolam Injection
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