Ketoconazole: FDA Planning to Pull It Off the Shelf?

Paul G. Auwaerter, MD


August 09, 2013

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Hello. This is Paul Auwaerter, with Medscape Infectious Diseases and Johns Hopkins University Division of Infectious Diseases. In July 2013, the US Food and Drug Administration (FDA) strengthened its warnings and withdrew FDA indications for one of the first oral antifungal drugs, ketoconazole, which was first approved in 1981.[1] You might say, "What's the big deal?"

As an infectious diseases physician, I don't think I have prescribed ketoconazole in more than 15 years. The last time was for a newspaper carrier with a limited income who came down with histoplasmosis in western Maryland, and he couldn't afford the very expensive drugs itraconazole or fluconazole. The drug [ketoconazole] is now generic. It is used overseas to some degree, especially in low-resource countries, because of its lack of expense. But for most clinicians, there has been knowledge for years that the drug had some significant toxicities among the azole class, perhaps the worst in terms of liver issues.[2] Endocrinologists have known for years that the drug can impair adrenal function, and it even has a therapeutic role at times. However, it can be catastrophic if not watched out for when treating an infectious process. There are also a host of other adverse reactions.

Some clinicians might argue that, for short courses, it is relatively safe, but accumulated data suggest that there is significant hepatotoxicity. There is also the fact that there are reasonable alternatives among the azole class for oral therapy for many dermatophyte or candidal infections, namely fluconazole or itraconazole.[3] Even the European Union has taken the stronger step of considering withdrawing the drug entirely. This doesn't apply to any of the topical indications, such as Nizoral shampoo, for example, or any of the lotions.

There has been a recent meta-analysis of over 206 studies, performed by a Chinese group.[4] Unfortunately, the journal Website does not have the current article posted but has an abstract. The authors suggest that 3.6%-4.2% of patients experience significant hepatotoxicity. In fact, the FDA uses figures of adverse drug reaction liver function test (LFT) abnormalities of 4%-20%, with severe hepatotoxicity afflicting 1 in 2000 to 1 in 15,000. Compare that with fluconazole, which might have up to 5% risk for minor LFT abnormalities. Severe hepatotoxicity is judged as a fairly rare event.

All in all, it is probably time for the FDA to look at a number of drugs. For example, mefloquine is another drug for which the warnings have been strengthened. Ketoconazole should probably be rarely used. In fact, the FDA now says that it is only for life-threatening mycoses, endemic mycoses not responding to other drugs. I can't imagine that this drug will be used to any degree in the future.

Thanks very much for listening.


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