Fluconazole with Cyclosporine Interaction Details

Brand Names Associated with Fluconazole

Brand Names Associated with Cyclosporine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 27, 2023

Interaction Effect

Increased cycloSPORINE exposure and an increased risk of cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias)

Interaction Summary

Concomitant use of cycloSPORINE and fluconazole significantly increases cycloSPORINE exposure in renal transplant recipients with or without renal impairment. If concomitant use is required, dose reduction of cycloSPORINE and careful monitoring of cycloSPORINE concentrations and serum creatinine is recommended. Following the administration of fluconazole 200 mg orally once daily for 14 days in 8 transplant recipients receiving a stable regimen of cycloSPORINE, AUC values for cyclosporine increased by 92%, the Cmax increased by 60% and the Cmin increased by 157%. The apparent oral clearance decreased by 45%. Dose reduction of cycloSPORINE by 50% was used in patients treated with fluconazole; however, a large interindividual variability in the degree of drug interaction exists . Several other studies have demonstrated the interaction , with a clinical manifestation of increased serum creatinine levels in some cases . Another report found no significant interaction between the two drugs in bone marrow transplant recipients .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of cycloSPORINE and fluconazole significantly increases cycloSPORINE exposure in renal transplant recipients with or without renal impairment. If concomitant use is required, dose reduction of cycloSPORINE and careful monitoring of cycloSPORINE concentrations and serum creatinine is recommended. The metabolism of cycloSPORINE appears to be maximally inhibited around day 4 of concomitant administration with fluconazole. A cycloSPORINE dose reduction of 50% was used in patients who received fluconazole, although a large interindividual variability in the degree of drug interaction exists .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated cycloSPORINE metabolism by fluconazole

Literature Reports

A) Concomitant use of cycloSPORINE and fluconazole significantly increased cycloSPORINE exposure in renal transplant recipients with or without renal impairment. Following the administration of fluconazole 200 mg orally once daily for 14 days in 8 transplant recipients receiving a stable regimen of cycloSPORINE, AUC values for cyclosporine increased by 92% (+/- 43%; range, 18% to 147%), the Cmax increased by 60% (+/- 48%; range, -5% to 113%) and the Cmin increased by 157% (+/- 96%; range, 33% to 360%). The apparent oral clearance decreased 45% (+/- 15%; range, -15% to -60%) .

B) An increase in the trough cycloSPORINE concentration was reported with increase in serum creatine after addition of fluconazole in a 43-year-old female with double renal-pancreatic transplantation . She was on triple immunosuppressive regimen of azaTHIOprine 2.5 mg/kg daily, predniSONE 2 mg daily, and cycloSPORINE 10 mg/kg daily after transplantation. She became febrile and was initiated on fluconazole 100 mg daily with gentamicin and imipenem after obtaining culture. Positive culture for C. albicans persisted with treatment; thus, fluconazole was increased to 300 mg daily with discontinuation of gentamicin and imipenem. Three days after the increase in dose, the trough cycloSPORINE concentration increased dramatically and continued to increase; furthermore, the serum creatine also increased. Decreasing fluconazole to 100 mg daily caused a sharp decrease in the trough cycloSPORINE concentration to almost the pretreatment level.

C) A 46-year-old female with diabetes was on immunosuppressive therapy of predniSONE, azaTHIOprine, and cycloSPORINE for the renal transplantation . However, after initiation of fluconazole 100 mg daily, with a loading dose of 200 mg, the cycloSPORINE concentration doubled after just six days of therapy.

D) Concurrent cycloSPORINE and fluconazole in a 54-year-old patient with diabetes (two years post-renal-transplantation) produced a precipitous rise in creatinine levels. After reducing the cycloSPORINE and halving the dose of fluconazole, levels slowly returned to normal and he was successfully treated. The authors stated that measurement of the patient's serum cycloSPORINE had not been clinically useful (many fluctuations were recorded) and they also noted other reports of neurotoxicity that had occurred despite normal blood levels of cycloSPORINE and fluconazole .

E) A randomized, double-blind, placebo-controlled study of 16 renal transplant patients was done in which comparisons were made of cycloSPORINE levels in those receiving concurrent fluconazole versus those receiving placebo with cycloSPORINE . The patients coadministered cycloSPORINE and fluconazole had significant increases in cycloSPORINE area under the concentration-time curve (AUC) and significant decreases in cycloSPORINE clearance. Neither group experienced increases in serum creatinine.

F) Six renal transplant recipients receiving immunosuppressive therapy with cycloSPORINE participated in a prospective, unblinded, crossover trial to determine the effects of fluconazole coadministration. All patients had evidence of systemic candidiasis and were receiving the microemulsion preparation of cycloSPORINE. Following a week of monitoring the cycloSPORINE area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to Cmax (Tmax), clearance, and serum creatinine, fluconazole 200 mg daily was added to therapy for seven days. Patients were instructed to decrease their dose of cycloSPORINE by 50% when fluconazole was initiated. Baseline values included AUC 2887.8 nanogram x hr/mL, Cmax 701.8 ng/mL, and serum creatinine 139.0 mcgmol/L. Both the AUC and Cmax of cycloSPORINE peaked at day 4 of the study (4750.5 nanogram x hr/mL and 941.5 nanogram x hr /mL, respectively) and had decreased by day 7 (4052.0 nanogram x hr/mL and 768.0 nanogram x hr/mL, respectively), raising the possibility of cytochrome P450 system autoinduction. All cycloSPORINE pharmacokinetic parameters were again evaluated at day 14. With the reduction of the cycloSPORINE dose by 50% at day 7, the AUC and Cmax decreased to 2230.8 nanogram x hr/mL and 498.0 nanogram x hr/mL, respectively, by day 14, and the serum creatinine was 147.8 mcgmol/L. However, because of large interindividual variability in the sensitivity of cycloSPORINE metabolism to inhibition by fluconazole, firm recommendations on empirical cycloSPORINE dose reductions can not be made .

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.

Cyclosporine Overview

• Cyclosporine and cyclosporine (modified) are used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system of the person who received the organ) in people who have received kidney, liver, and heart transplants. Cyclosporine (modified) is also used alone or with methotrexate (Rheumatrex) to treat the symptoms of rheumatoid arthritis (arthritis caused by swelling of the lining of the joints) in patients whose symptoms were not relieved by methotrexate alone. Cyclosporine (modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some areas of the body) in certain patients who have not been helped by other treatments. Cyclosporine and cyclosporine (modified) are in a class of medications called immunosuppressants. They work by decreasing the activity of the immune system.

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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:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

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.