Ketoconazole with Midazolam Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Midazolam
- Midazolam
- Versed®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
Increased midazolam concentrations, and potentially increased midazolam toxicity (excessive sedation and prolonged hypnotic effects)
Interaction Summary
Coadministration of ketoconazole and oral midazolam is contraindicated, as concomitant use may cause midazolam toxicity (excessive sedation and prolonged hypnotic effects). 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 .
Severity
Contraindicated
Onset
Rapid
Evidence
Established
How To Manage Interaction
Coadministration of ketoconazole and oral midazolam is contraindicated because concurrent use may result in increased midazolam exposure, which may potentiate or prolong the hypnotic and sedative effects of midazolam, especially with repeated or chronic administration.
Mechanism Of Interaction
Inhibition of CYP3A4-mediated midazolam metabolism by ketoconazole
Literature Reports
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 .
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) .
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.
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 .
Ketoconazole Overview
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Ketoconazole is used to treat fungal infections when other medications are not available or cannot be tolerated. Ketoconazole should not be used to treat fungal meningitis (infection of the membranes surrounding the brain and spinal cord caused by a fungus) or fungal nail infections. Ketoconazole is in a class of antifungals called imidazoles. It works by slowing the growth of fungi that cause infection.
Midazolam Overview
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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.
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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.