Ketoconazole with Tacrolimus Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Tacrolimus
- Astagraf XL®
- Envarsus XR®
- FK 506
- Prograf®
- Tacrolimus
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
Increased tacrolimus exposure and an increased risk of QT interval prolongation
Interaction Summary
Concomitant use of tacrolimus with a strong CYP3A inhibitor that also has additive effects on the QT interval, such as ketoconazole, may increase tacrolimus whole blood trough concentrations and the risk of serious toxicity, including enhanced QT-interval prolongation. If concomitant use is required, decrease the tacrolimus dose and adjust based on whole blood trough concentrations. A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose. Monitor whole blood trough concentrations early and frequently; start within 1 to 3 days and continue as necessary. In addition, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. Use caution when coadministering topical tacrolimus, a CYP3A4 substrate, and a strong CYP3A4 inhibitor, such as ketoconazole, in patients with widespread or erythrodermic disease as this may result in elevated plasma concentrations of tacrolimus .
Severity
Major
Onset
Rapid
Evidence
Probable
How To Manage Interaction
Concomitant use of tacrolimus with a strong CYP3A inhibitor that also has additive effects on the QT interval, such as ketoconazole, may increase tacrolimus whole blood trough concentrations and the risk of serious toxicity, including enhanced QT-interval prolongation. If concomitant use is required, decrease the tacrolimus dose and adjust based on whole blood trough concentrations. A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose. Monitor whole blood trough concentrations early and frequently; start within 1 to 3 days and continue as necessary. In addition, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. Coadministration of topical tacrolimus, a CYP3A4 substrate, and a strong CYP3A4 inhibitor, such as ketoconazole, should be undertaken with caution in patients with widespread and/or erythrodermic disease as this may result in elevated plasma concentrations of tacrolimus .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated tacrolimus metabolism; additive QT interval prolongation
Literature Reports
A) In 6 healthy volunteers, coadministration of ketoconazole and tacrolimus increased the bioavailability of tacrolimus; however, the clearance and volume of distribution were not significantly affected. In a crossover design, either 0.1 mg/kg orally or 0.025 mg/kg IV of tacrolimus was given on day 1 and day 7 of the study. On study day 8, ketoconazole 200 mg orally at bedtime was started. On study day 13 and day 19 either 0.04 mg/kg orally or 0.01 mg/kg IV of tacrolimus was given. When given with ketoconazole, the bioavailability of tacrolimus was 30%, compared with 14% when tacrolimus was given alone. It was proposed that the change in bioavailability was caused by inhibition of gut metabolism of tacrolimus, not an effect on hepatic metabolism, because of the lack of effect on systemic clearance of tacrolimus .
B) A 32-year-old female who had received a cadaveric renal transplant was immunosuppressed with tacrolimus 0.2 mg/kg daily and prednisone. Because of a urinary tract infection caused by candida, ketoconazole 200 mg daily was initiated 20 days following transplant. At that time, her serum creatinine was 1 mg/dL and her tacrolimus blood level was 11.1 nanograms (ng)/mL. Despite a decrease in her tacrolimus dose to 0.11 mg/kg daily, her tacrolimus blood level increased to 27.9 ng/mL one day after ketoconazole was started. The tacrolimus dose was further reduced to 0.04 mg/kg daily (an 80% reduction from baseline) to maintain a blood level of 15.8 ng/mL. One week after ketoconazole was discontinued, the tacrolimus blood level had fallen to 5.8 ng/mL and the tacrolimus dose was increased to 0.11 mg/kg to achieve a blood level of 7.2 ng/mL .
Ketoconazole Overview
-
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.
Tacrolimus Overview
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Tacrolimus (Astagraf XL, Envarsus XR, Prograf) is used along with other medications to prevent rejection (attack of a transplanted organ by the immune system of a person receiving the organ) in people who have received a kidney transplant. Tacrolimus (Prograf) is also used along with other medications to prevent rejection in people who have received a liver, lung, or heart transplant. Tacrolimus is in a class of medications called immunosupressants. It works by decreasing the activity of the immune system to prevent it from attacking the transplanted organ.
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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.