Ketoconazole with Cyclosporine Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Cyclosporine
- Cyclosporine
- Gengraf®
- Neoral®
- Sandimmune® Capsules
- Sandimmune® Oral Solution
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
An increased risk of cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias)
Interaction Summary
Administration of ketoconazole to patients receiving cycloSPORINE increases cycloSPORINE serum levels and may increase the risk of cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias, seizures, gingival hyperplasia). This interaction may be used intentionally as a cost saving measure to decrease the required therapeutic dose of cycloSPORINE . If cycloSPORINE levels are adjusted and maintained within the usual therapeutic range, there appears to be no increase in the incidence of cycloSPORINE toxicity .
Severity
Moderate
Onset
Delayed
Evidence
Established
How To Manage Interaction
Ketoconazole is often coprescribed with cycloSPORINE in order to augment the pharmacokinetic profiles of both medications. This drug interaction may be used intentionally, as a cost saving measure, to reduce the effective dose of cycloSPORINE. If this interaction is not desired, consider use of an alternate antimicrobial. Monitor cycloSPORINE levels and adjust cycloSPORINE dosage as necessary when initiating or discontinuing ketoconazole therapy; an initial dose reduction of approximately 50% will likely be necessary. Also, monitor patients for signs of cycloSPORINE toxicity (renal dysfunction, cholestasis, paresthesias); serum levels over 300 mcg/L with slowly rising serum creatinine suggest nephrotoxicity.
Mechanism Of Interaction
Altered cycloSPORINE absorption/metabolism; inhibition of cycloSPORINE hydroxylase in human liver microsomes
Literature Reports
A) Ketoconazole reduced the average dose of cycloSPORINE by 48% in children diagnosed with idiopathic steroid-dependent nephrotic syndrome in a retrospective study. All patients (n=102; mean age, 5.4+/-3.6 years; male to female ratio, 3:1, mean treatment duration, 22.9 months) initially received prednisolone 2 mg/kg/day (maximum 80 mg) during 4 to 8 weeks followed by a gradual taper. Twenty-four patients received cycloSPORINE alone (non-ketoconazole group) and 78 patients received ketoconazole 50 mg with an initial one-third reduction in the cycloSPORINE dose. CycloSPORINE levels, duration of treatment and response to cycloSPORINE withdrawal were comparable in the two study groups; however, cycloSPORINE response was 92.3% (72/78) in the ketoconazole group compared to 70.8% (17/24) in the non-ketoconazole group. The percentage of patients that were able to stop steroid therapy and remain in remission was 74.4% (58/78) in the ketoconazole group compared to 41.7% (10/24) in the non-ketoconazole group (p=0.003). Additionally, in the ketoconazole group, there was a 48% reduction in cycloSPORINE cost resulting in a net saving of 38%. Kidney function and use of ACE inhibitors were similar in both treatment groups. There were no differences in hypertension, gingival hyperplasia and hirsutism among the treatment groups .
B) Follow-up of a heart transplant patient indicated no liver or renal dysfunction after two years of combined cycloSPORINE and ketoconazole treatment . The required dose of cycloSPORINE decreased from 385 mg daily to 50 mg daily over the course of 13 months; the reduction in cost of immunosuppressive therapy was estimated at 70% to 87%. In another study, concurrent use of ketoconazole resulted in patients requiring an average of 77% less cycloSPORINE to achieve therapeutic serum levels . Following one year of combined therapy, this study observed a 53% reduction in overall cost.
C) Increased levels of cycloSPORINE caused by ketoconazole administration has been reported to result in gingival hyperplasia and impaired glucose tolerance .
D) In some studies, concomitant administration of ketoconazole has resulted in a 75% reduction in the dose of cycloSPORINE to maintain therapeutic blood levels. Some authors have suggested that this combination of drugs is beneficial, providing economic benefits as a result of the dramatically reduced dose of cycloSPORINE . In addition to cost savings, decreased rejection rates and infection have been reported . The combination of ketoconazole and cycloSPORINE should be carefully evaluated in most patients. However, if the combination is used, the dose of cycloSPORINE should be reduced by 50% initially and the levels of cycloSPORINE should be monitored carefully .
E) Three consecutive patients being treated for severe aplastic anemia with cycloSPORINE and high-dose methylprednisolone developed grand mal seizures when ketoconazole was added to therapy. Doses which induced the seizures were cycloSPORINE 400 mg daily in divided doses (one patient received 200 mg daily), methylprednisolone 60 mg daily, and ketoconazole 200 mg daily. Ketoconazole was added in order to elevate cycloSPORINE serum levels and to prevent fungal infection. In all cases, the seizures were preceded by nausea, vomiting, dizziness, headache, and hypertension. All patients were able to resume this 3-drug combination when cycloSPORINE was reduced to 100 mg daily. Ketoconazole and methylprednisolone may synergistically inhibit the metabolism of cycloSPORINE by the cytochrome P450 system .
F) Mean cycloSPORINE dose was more than 80% lower in patients receiving concurrent ketoconazole compared with those not receiving ketoconazole; mortality rate, graft loss, rejection episodes, or nephrotoxicity was not increased with the combination .
G) Ketoconazole caused a marked inhibition of cycloSPORINE hydroxylase in human liver microsomes in an in vitro study . This enzyme inhibition may be responsible for the significant reduction in cycloSPORINE metabolism seen clinically when these drugs are given in combination.
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.
Cyclosporine Overview
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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:
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.