Ketoconazole with Tolterodine Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Tolterodine
- Detrol®
- Detrol® LA
- Tolterodine
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
Enhanced tolterodine bioavailability in individuals with deficient CYP2D6 activity; increased risk for QT interval prolongation
Interaction Summary
Tolterodine is metabolized via hydroxylation catalyzed by CYP2D6 and via N-dealkylation catalyzed by CYP3A4. The high CYP2D6 specificity of tolterodine suggests that extensive metabolizers are not likely to be affected by the coadministration of a CYP3A4 inhibitor. However, in subjects deficient in CYP2D6, the oral clearance of tolterodine decreased by 60% when ketoconazole, a potent CYP3A4 inhibitor, was coadministered. In addition, both ketoconazole and tolterodine have been shown to cause QT interval prolongation . Concomitant use may result in additive effects on the QT, increasing the risk for serious ventricular arrhythmias including torsades de pointes. A dose adjustment of tolterodine is warranted in patients taking concomitant ketoconazole or other potent CYP3A4 inhibitors. The recommended dose of tolterodine is 1 mg twice a day , and the recommended dose of the long-acting formulation is 2 mg per day .
Severity
Major
Onset
Rapid
Evidence
Probable
How To Manage Interaction
Caution is advised when using ketoconazole together with tolterodine, as both drugs are known to prolong the QT interval and concomitant use may increase the risk for QT interval prolongation and serious ventricular arrhythmias including torsades de pointes. In addition, concomitant use may result in enhanced tolterodine bioavailability in individuals with deficient CYP2D6 activity. If concomitant use is required, it is recommended that the dose of tolterodine be decreased to 1 mg twice daily or 2 mg once a day (long-acting formulation) .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated tolterodine metabolism; additive effects on the QT interval
Literature Reports
A) Eight healthy volunteers, all deficient in CYP2D6 activity, received single and multiple doses of tolterodine in the presence and absence of ketoconazole during an open, non-randomized, crossover study. During the single-dose study, subjects were given ketoconazole 200 mg once daily for four days, with a 2 mg dose of tolterodine being coadministered on day 2. Tolterodine was given as 1 mg twice daily for 4.5 days during the multiple-dose study. The pharmacokinetic values obtained after the multiple-dose study were similar to those seen after the single-dose study during the ketoconazole phase. The Cmax of tolterodine increased approximately 2-fold in the presence of ketoconazole, with no effect on the time to Cmax. The apparent oral clearance of tolterodine decreased by 60% during ketoconazole coadministration, with a subsequent 2.5-fold increase in the area under the concentration-time curve (AUC). This study demonstrated that CYP3A4 catalyzed the N-dealkylation of tolterodine in poor metabolizers of CYP2D6 .
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.
Tolterodine Overview
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Tolterodine is used treat overactive bladder (a condition in which the bladder muscles contract uncontrollably and cause frequent urination, urgent need to urinate, and inability to control urination). Tolterodine is in a class of medications called antimuscarinics. It works by relaxing the bladder muscles preventing bladder contraction.
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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.