Oral Ketoconazole in Dermatology: Where Are We Now?
Oral Ketoconazole in Dermatology: Where Are We Now?
Because hundreds of my patients and thousands of others treated by other dermatologists rely on ketoconazole daily to control Malassezia-mediated disease, an extensive multiauthored memo was sent to the FDA explaining the situation. The note pointed out that we in dermatology use only very small doses of this admittedly powerful medication, having learned over many years to treat it with the respect it deserves.
In preparing this submission, to gain some appreciation of the current FDA handling of and attitude toward the drug, all 24 of the FDA's 2013 Committee postings bearing on the drug were reviewed by the author (available upon request to the author at billd860@gmail.com).
In summary, the overall situation appeared to be as follows:
1. France, the EU, and the FDA acted in concert to prevent adverse effects resulting from the use of ketoconazole in the doses that have been used for years for deep fungal infections and other disorders. This is entirely wise and justified, given the risks at the original dose approved.
2. No attention was paid by regulatory authorities to the low- dose use of the medication for the management of the Malassezia-mediated disorders. There are no data in the 2013 submissions that show ketoconazole as a danger to the public in the low doses used by dermatologists.
3. Initial data, provided by the FDA under a Freedom of Information Act application, describe sobering adverse effects due to use of Nizoral® (ketoconazole) and Sporanox® (itraconazole) at approved dosage regimens (Dyson A. August 9, 2013. Personal communication). Detailed data have been requested under the Freedom of Information Act, but the FDA does not have the capacity to customize searches to stratify the adverse effects by dose.
Meanwhile, several dermatologists believe that, on the basis of 2 decades of clinical experience, restrictions on the use of low- dose ketoconazole were unjustified.
The submission to the FDA requested "an immediate reevaluation of the use of low dose ketoconazole and an immediate statement withdrawing restrictions on the use of ketoconazole for Malassezia disease pending further evaluation."
The following response was received last week from the FDA's Center for Drug Evaluation and Research (Davison L. Personal communication. August 13, 2013):
We understand your concerns for patients and appreciate your thoughtful comments on the July 26, 2013 Drug Safety Communication (DSC) "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems." As you noted in your email, your practice uses many drugs off-label, including ketoconazole, for Malassezia-related clinical conditions.
As described in the DSC, ketoconazole tablets are FDA approved for the treatment of the following fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients in whom other treatments have failed or who are intolerant to other therapies. The drug labeling for ketoconazole tablets has been updated to, among other things, limit the use of ketoconazole tablets by removing indications in which the risk outweighs the benefits and expand warnings regarding hepatotoxicity, adrenal insufficiency, and drug interactions. The use of ketoconazole tablets in Candida and dermatophyte infections is no longer indicated. The only dermatologic indication that was removed with the recent labeling change was recalcitrant cutaneous dermatophytes. In the US, ketoconazole tablets have not been approved for the use of any Malassezia-related clinical condition. With recent changes in the approved indications in product labels, the DSC has not prohibited use of oral ketoconazole for indications which are not FDA approved; these remain off-label uses for oral ketoconazole.
Agency actions are not intended to interfere with the practice of medicine, in particular with a physician's ability to prescribe approved drug products for off-label indications, when clinically appropriate. We agree that off-label use should be based on firm scientific rationale, sound medical evidence, and a consideration of risk and benefit for the patient.
FDA will continue to evaluate the safety of ketoconazole tablets and will communicate with the public again if additional information becomes available. We hope that you will reach out to us again in the future with any questions or concerns related to your patients.
Colleagues in the EU have been made aware, and efforts are under way to evaluate data held by FDA in order to clarify the safety (or otherwise) of the drug when used at a maximum of 400 mg weekly for clearance and at a maintenance dose of 400 mg once monthly. One half this dose is used in patients weighing less than 50 kg.
Updates will follow when safety is justified (or refuted) by data.
The Threat and the Response
Because hundreds of my patients and thousands of others treated by other dermatologists rely on ketoconazole daily to control Malassezia-mediated disease, an extensive multiauthored memo was sent to the FDA explaining the situation. The note pointed out that we in dermatology use only very small doses of this admittedly powerful medication, having learned over many years to treat it with the respect it deserves.
In preparing this submission, to gain some appreciation of the current FDA handling of and attitude toward the drug, all 24 of the FDA's 2013 Committee postings bearing on the drug were reviewed by the author (available upon request to the author at billd860@gmail.com).
In summary, the overall situation appeared to be as follows:
1. France, the EU, and the FDA acted in concert to prevent adverse effects resulting from the use of ketoconazole in the doses that have been used for years for deep fungal infections and other disorders. This is entirely wise and justified, given the risks at the original dose approved.
2. No attention was paid by regulatory authorities to the low- dose use of the medication for the management of the Malassezia-mediated disorders. There are no data in the 2013 submissions that show ketoconazole as a danger to the public in the low doses used by dermatologists.
3. Initial data, provided by the FDA under a Freedom of Information Act application, describe sobering adverse effects due to use of Nizoral® (ketoconazole) and Sporanox® (itraconazole) at approved dosage regimens (Dyson A. August 9, 2013. Personal communication). Detailed data have been requested under the Freedom of Information Act, but the FDA does not have the capacity to customize searches to stratify the adverse effects by dose.
Meanwhile, several dermatologists believe that, on the basis of 2 decades of clinical experience, restrictions on the use of low- dose ketoconazole were unjustified.
The submission to the FDA requested "an immediate reevaluation of the use of low dose ketoconazole and an immediate statement withdrawing restrictions on the use of ketoconazole for Malassezia disease pending further evaluation."
The FDA's Reply
The following response was received last week from the FDA's Center for Drug Evaluation and Research (Davison L. Personal communication. August 13, 2013):
We understand your concerns for patients and appreciate your thoughtful comments on the July 26, 2013 Drug Safety Communication (DSC) "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems." As you noted in your email, your practice uses many drugs off-label, including ketoconazole, for Malassezia-related clinical conditions.
As described in the DSC, ketoconazole tablets are FDA approved for the treatment of the following fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients in whom other treatments have failed or who are intolerant to other therapies. The drug labeling for ketoconazole tablets has been updated to, among other things, limit the use of ketoconazole tablets by removing indications in which the risk outweighs the benefits and expand warnings regarding hepatotoxicity, adrenal insufficiency, and drug interactions. The use of ketoconazole tablets in Candida and dermatophyte infections is no longer indicated. The only dermatologic indication that was removed with the recent labeling change was recalcitrant cutaneous dermatophytes. In the US, ketoconazole tablets have not been approved for the use of any Malassezia-related clinical condition. With recent changes in the approved indications in product labels, the DSC has not prohibited use of oral ketoconazole for indications which are not FDA approved; these remain off-label uses for oral ketoconazole.
Agency actions are not intended to interfere with the practice of medicine, in particular with a physician's ability to prescribe approved drug products for off-label indications, when clinically appropriate. We agree that off-label use should be based on firm scientific rationale, sound medical evidence, and a consideration of risk and benefit for the patient.
FDA will continue to evaluate the safety of ketoconazole tablets and will communicate with the public again if additional information becomes available. We hope that you will reach out to us again in the future with any questions or concerns related to your patients.
Colleagues in the EU have been made aware, and efforts are under way to evaluate data held by FDA in order to clarify the safety (or otherwise) of the drug when used at a maximum of 400 mg weekly for clearance and at a maintenance dose of 400 mg once monthly. One half this dose is used in patients weighing less than 50 kg.
Updates will follow when safety is justified (or refuted) by data.
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