Fluconazole with Midazolam Interaction Details
Brand Names Associated with Fluconazole
- Diflucan®
- Fluconazole
Brand Names Associated with Midazolam
- Midazolam
- Versed®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 27, 2023
Interaction Effect
Increased midazolam exposure and potential midazolam toxicity (excessive sedation and prolonged hypnotic effects)
Interaction Summary
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).
Severity
Major
Onset
Rapid
Evidence
Established
How To Manage Interaction
Concurrent use of fluconazole and short-acting benzodiazepines such as midazolam increases midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concurrent use is required, consider reducing the dose of midazolam, and monitor for increased midazolam toxicity (excessive sedation and prolonged hypnotic effects).
Mechanism Of Interaction
Inhibition of CYP3A4-mediated midazolam metabolism by fluconazole
Literature Reports
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 .
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 .
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 .
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 .
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 .
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% . 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 .
Fluconazole Overview
-
Fluconazole is used to treat fungal infections, including yeast infections of the vagina, mouth, throat, esophagus (tube leading from the mouth to the stomach), abdomen (area between the chest and waist), lungs, blood, and other organs. Fluconazole is also used to treat meningitis (infection of the membranes covering the brain and spine) caused by fungus. Fluconazole is also used to prevent yeast infections in patients who are likely to become infected because they are being treated with chemotherapy or radiation therapy before a bone marrow transplant (replacement of unhealthy spongy tissue inside the bones with healthy tissue). Fluconazole is in a class of antifungals called triazoles. It works by slowing the growth of fungi that cause infection.
Midazolam Overview
-
Midazolam is given to children before medical procedures or before anesthesia for surgery to cause drowsiness, relieve anxiety, and prevent any memory of the event. Midazolam is in a class of medications called benzodiazepines. It works by slowing activity in the brain to allow relaxation and sleep.
Return To Our Drug Interaction Homepage
Feedback, Question Or Comment About This Information?
Ask Dr. Brian Staiger, PharmD, our medical editor, directly! He's always more than happy to assist.
Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.