Fluconazole with Tacrolimus Interaction Details
Brand Names Associated with Fluconazole
- Diflucan®
- Fluconazole
Brand Names Associated with Tacrolimus
- Astagraf XL®
- Envarsus XR®
- FK 506
- Prograf®
- Tacrolimus
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 27, 2023
Interaction Effect
Increased tacrolimus exposure and toxicity and an increased risk of QT interval prolongation
Interaction Summary
Concomitant use of fluconazole with drugs that are known to prolong the QT interval and are CYP3A4 substrates, such as tacrolimus, is contraindicated. When used concomitantly, serum concentrations of oral tacrolimus were increased up to 5-fold; however no significant changes were observed when tacrolimus was administered intravenously. Increased tacrolimus exposure has been associated with nephrotoxicity. If concomitant use is required, frequently monitor for QT-interval prolongation and tacrolimus-related adverse reactions and evaluate whole blood tacrolimus concentrations and make appropriate dosage adjustments. In addition, consider obtaining electrocardiograms and monitor electrolytes (magnesium, potassium calcium) periodically during treatment . Use topical tacrolimus and fluconazole cautiously in patients with widespread and/or erythrodermic disease . Fluconazole-mediated CYP3A4 inhibition continues for 4 to 5 days after discontinuation because of the long half-life .
Severity
Contraindicated
Onset
Unspecified
Evidence
Established
How To Manage Interaction
Concomitant use of fluconazole with drugs that are known to prolong the QT interval and are CYP3A4 substrates, such as tacrolimus, is contraindicated. When used concomitantly, serum concentrations of oral tacrolimus were increased up to 5-fold; however no significant changes were observed when tacrolimus was administered intravenously. Increased tacrolimus exposure has been associated with nephrotoxicity. If concomitant use is required, frequently monitor for QT-interval prolongation and tacrolimus-related adverse reactions and evaluate whole blood tacrolimus concentrations and make appropriate dosage adjustments. In addition, consider obtaining electrocardiograms and monitor electrolytes (magnesium, potassium calcium) periodically during treatment . Use topical tacrolimus and fluconazole cautiously in patients with widespread and/or erythrodermic disease . Fluconazole-mediated CYP3A4 inhibition continues for 4 to 5 days after discontinuation because of the long half-life .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated tacrolimus metabolism by fluconazole; additive QT interval prolongation
Literature Reports
A) Concomitant use of tacrolimus and fluconazole significantly increased mean trough concentration/dose ratio of tacrolimus in adult transplant patients (N=11) compared with tacrolimus use alone (4.5 vs 1.9) in a prospective study. The mean trough concentration of tacrolimus significantly increased (15.7 vs 9.1 nanograms/mL), despite a significantly lower mean daily dose (5.3 vs 6.4 mg). In addition, 2 adverse drug events were reported: 1 instance each of hypertension and hyperglycemia occurring 5 and 9 days, respectively, after concomitant use. Monitoring of therapeutic immunosuppressant concentrations and dosage reduction should be considered with concomitant use .
B) Twenty organ transplant patients received concurrent therapy with tacrolimus and fluconazole. Tacrolimus was given IV at 0.1 mg/kg/day until conversion to oral therapy of 0.15 mg/kg every 12 hours. Fluconazole was used at a dose of 200 mg per day in 8 patients and 100 mg per day in 12 patients. On day 1, the median plasma trough concentration of tacrolimus increased 1.4-fold and 3.1-fold in patients receiving 100 mg per day and 200 mg per day of fluconazole, respectively. A median dose reduction of 56% was required in order to maintain tacrolimus concentrations below 2 ng/mL (2.5 nanomol/L). The authors recommend that fluconazole doses of up to 200 mg per day can be safely and effectively used in transplant patients if the tacrolimus dose is decreased by 50%. If higher doses of fluconazole are required, trough tacrolimus concentrations should be monitored and appropriate reductions in tacrolimus should be made .
C) A case report describes the transient occurrence of Pelger-Huet cells possibly related to an increase in tacrolimus serum levels due to coadministration of fluconazole. A 38-year-old Japanese woman, 44 days post-bone marrow transplant, was treated with tacrolimus and methylprednisolone following acute graft-versus-host-disease (GVHD). Fluconazole 200 mg was administered 112 days posttransplant to treat oral candidiasis. One month later, the patient complained of headache and thirst. Her blood pressure was within normal limits. A stained blood smear revealed mono-lobed or bi-lobed nuclei consistent with Pelger-Huet anomaly. The patient was anemic, hyperglycemic, had glucosuria, and increased serum creatinine levels, indicative of tacrolimus toxicity despite a trough concentration of 15.1 nanogram/mL (18.78 nanomol/L). Tacrolimus was discontinued on day 163, and symptoms and laboratory data quickly improved. As the blood concentration of tacrolimus decreased, so did the presence of Pelger-Huet cells .
D) There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus .
Fluconazole Overview
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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.
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.