Ketoconazole with Nirmatrelvir Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
Increased ketoconazole and/or ritonavir serum concentrations and increased risk for QT-interval prolongation
Interaction Summary
Caution is advised when using nirmatrelvir/ritonavir, a potent CYP3A4 inhibitor and substrate, together with ketoconazole, also a potent CYP3A4 inhibitor and substrate, as concomitant use may result in increased plasma concentrations of either drug and potentially cause additive effects on the QT interval resulting in ventricular tachyarrhythmias, torsades de pointes, or potentially fatal arrhythmias . If concomitant use is required, do not exceed ketoconazole doses of 200 mg/day . In pharmacokinetic studies, coadministered ritonavir (alone or in combination with saquinavir) has led to significant increases in ketoconazole serum concentrations .
Severity
Major
Onset
Delayed
Evidence
Established
How To Manage Interaction
Caution is advised when using nirmatrelvir/ritonavir, a potent CYP3A4 inhibitor and substrate, together with ketoconazole, also a potent CYP3A4 inhibitor and substrate, as concomitant use may result in increased plasma concentrations of either drug and potentially cause additive effects on the QT interval resulting in ventricular tachyarrhythmias, torsades de pointes, or potentially fatal arrhythmias . If concomitant use is required, do not exceed ketoconazole doses of 200 mg/day .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated metabolism of ketoconazole by ritonavir and inhibition of CYP3A4-mediated metabolism of ritonavir by ketoconazole; additive QT-interval prolongation
Literature Reports
A) Ketoconazole exposure and plasma concentrations were greatly increased following 14 days of coadministration with ritonavir-boosted saquinavir in an open-label, randomized, two-arm, crossover study. In arm one, 20 healthy subjects were given saquinavir 1000 mg/ritonavir 100 mg twice daily alone for 14 days, then coadministered with ketoconazole 200 mg once daily for another 14 days. In arm two, 12 healthy subjects were given ketoconazole 200 mg once daily for 6 days followed in combination with saquinavir 1000 mg/ritonavir 100 mg twice daily for 14 days. At day 28, saquinavir and ritonavir pharmacokinetic exposures were not significantly affected by coadministration with ketoconazole in arm 1 (90% CI for mean AUC and Cmax values of saquinavir and ritonavir, 86% to 126%). In study arm 2, ketoconazole AUC was increased by 45% (90% CI, 32% to 59%), Cmax was increased by 168% (90% CI, 146% to 193%), and the median elimination half-life more than doubled (4.3 vs 10.7 hours) after coadministration with saquinavir/ritonavir, although increases were not associated with unacceptable safety or tolerability .
B) The coadministration of ketoconazole 200 mg daily for 7 days and ritonavir 500 mg twice daily for 10 days to 12 subjects resulted in an 18% increase in the ritonavir AUC and a 10% increase in the ritonavir Cmax. At the same time, the ketoconazole AUC increased 3.4-fold and the Cmax increased 55%. Doses of ketoconazole greater than 200 mg daily are not recommended .
C) A pharmacokinetic study involving 12 HIV-positive patients treated with ritonavir, saquinavir, and ketoconazole determined that ketoconazole may inhibit the efflux of ritonavir from the cerebrospinal fluid (CSF) as well as the systemic clearance of ritonavir. The patients were receiving 400 mg each of ritonavir and saquinavir twice daily when ketoconazole 200 mg or 400 mg once a day for 10 days was added to their medication treatment. Blood and CSF samples were taken before and after the addition of ketoconazole. The area under the plasma concentration-time curve (AUC), the plasma concentration 12 hours after the dose and half-life of ritonavir were significantly increased (29%, 62%, and 31%, respectively) by concomitant ketoconazole administration. Ritonavir CSF concentration was also significantly increased by 178% (from 2.4 to 6.6 nanograms(ng)/mL) without a change in the paired unbound plasma level of 26 ng/mL. The investigators concluded that the administration of ketoconazole increases plasma and CSF concentrations of ritonavir by a concurrent inhibition of CYP3A metabolism and of the active transport system responsible for transferring ritonavir from the CSF to the plasma .
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.
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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.