Fluconazole with Sirolimus Interaction Details
Brand Names Associated with Fluconazole
- Diflucan®
- Fluconazole
Brand Names Associated with Sirolimus
- Rapamune®
- Rapamycin
- Sirolimus
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 27, 2023
Interaction Effect
Increased sirolimus/temsirolimus exposure and an increased risk of sirolimus/temsirolimus toxicity (anemia, leukopenia, thrombocytopenia, hypokalemia, diarrhea)
Interaction Summary
Temsirolimus and sirolimus are extensively metabolized by CYP3A4, and sirolimus is a substrate of the P-gp transporter system. Fluconazole is a moderate CYP3A4 inhibitor and modulator of P-gp. Using fluconazole together with temsirolimus or sirolimus may increase sirolimus exposure and risk for toxicity . If concomitant use is required, dose adjustments of fluconazole and/or sirolimus or temsirolimus may be necessary . Guide sirolimus dosage adjustments based on sirolimus concentrations and effect. Due to its long half-life, the enzyme inhibitory effect of fluconazole may persist for 4 to 5 days following discontinuation .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Caution is advised when using fluconazole (a moderate CYP3A4 inhibitor and P-glycoprotein [P-gp] modulator) together with sirolimus or temsirolimus (CYP3A4 and P-gp substrates) as concomitant use may increase sirolimus exposure and risk for toxicity . If concomitant use is required, dose adjustments of fluconazole and/or sirolimus or temsirolimus may be necessary . Guide sirolimus dosage adjustments based on sirolimus concentrations and effect. Due to its long half-life, the enzyme inhibitory effect of fluconazole may persist for 4 to 5 days following discontinuation .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated sirolimus/temsirolimus metabolism by fluconazole; inhibition of P-gp-mediated efflux transport of sirolimus/temsirolimus by fluconazole
Literature Reports
A) A study of the administration of two 5 mg doses of sirolimus, the first alone, the second with concomitant oral ketoconazole 200 mg daily for 10 days at steady-state, resulted in a significant increase sirolimus whole blood concentrations. The study included 23 healthy volunteers, 8 women and 15 men. The maximum concentration (Cmax), time to Cmax (Tmax) increased 4.4-fold and 1.4-fold, respectively. Area under the concentration-time curve (AUC (0-144 hours)) increased 11-fold (297 +/- 93 vs. 3319 +/- 1048 nanograms x hr/mL). The terminal half-life of sirolimus was not changed. Single doses of sirolimus had no effect on the steady-state 12-hour plasma concentrations of ketoconazole . Fluconazole, an azole antifungal similar to ketoconazole, although less potent of a CYP3A4 and P-gp inhibitor than ketoconazole, would also be expected to increase sirolimus plasma concentrations when used concurrently.
B) A case study of a 49 year-old Aboriginal male who had undergone a primary cadaveric renal transplant describes the effect of fluconazole on sirolimus plasma concentrations. On day 5 after transplantation sirolimus replaced cyclosporine in the immunosuppression therapy to mitigate cycloSPORINE nephrotoxicity. Sirolimus trough concentrations were stabilized at 10 mcg/L between days 20 and 25. On day 18 the patient complained of a sore throat. Consequent diagnosis on day 23 revealed esophageal candidiasis and oral fluconazole 200 mg each evening was added to his regimen on day 25. In anticipation of a drug interaction between fluconazole and sirolimus, the sirolimus dose was decreased from 4 mg to 3 mg each morning beginning day 26. Sirolimus trough levels increased to 19 mcg/L and 22.8 mcg/L on days 28 and 29, respectively. The sirolimus dose again was decreased to 2 mg daily. Trough concentrations reached a peak of 35.5 mcg/L on day 32. Other possible causes for the increased sirolimus concentrations include concurrent sepsis, multi-organ failure, and decreased hepatic function. However, the strong temporal relationship with the addition of fluconazole to the patient's therapy and the increasing trough concentrations suggests the likelihood that a drug interaction caused the significant increase in sirolimus plasma concentrations .
Fluconazole Overview
-
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.
Sirolimus Overview
-
Sirolimus is used in combination with other medications to prevent rejection of kidney transplants. Sirolimus is in a class of medications called immunosuppressants. It works by suppressing the body's immune system.
Return To Our Drug Interaction Homepage
Feedback, Question Or Comment About This Information?
Ask Dr. Brian Staiger, PharmD, our medical editor, directly! He's always more than happy to assist.
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.