Regulators suspend marketing of oral ketoconazole in Europe

On Friday last week, US regulators recommended that oral ketoconazole should no longer be used as a first-line treatment for fungal infections whereas European regulators recommended a complete suspension of marketing for all oral ketoconazole-containing drugs. The full impact of these two recommendations on the use of oral ketoconazole as a treatment for men with metastatic or non-metastatic castration-resistant prostate cancer (CRPC) is a little unclear at this point in time.

A detailed report on these recommendations is available on the FirstWord pharmaceutical news web site. The specific announcements by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency’s Committee on Medicinal Products for Human Use (CHMP) are available if you click here and here.

It has long been known that the use of oral ketoconazole was associated with relatively high risk for serious side effects, including things like severe liver injury, adrenal gland malfunction and drug-drug interactions. It also has to be noted that the approval of abiraterone acetate as a treatment for men with metastatic CRPC has significantly reduced the need for (and the potential clinical value of) ketoconazole in the treatment of advanced prostate cancer. On the other hand, by comparison with abiraterone acetate, oral ketoconazole is an old, generic, low-cost drug that specialists in the treatment of advanced prostate cancer are very familiar with and know how to use with care.

In the USA, this drug will still be available for clinical use in the treatment of advanced forms of prostate cancer. In European nations it appears that (at least for the time being) oral forms of ketoconazole will not be available at all if marketing authorization has been suspended. The implications for the availability and use of this drug in other countries around the world is not known at this time.

In making their recommendations, CHMP took note of a decision to suspension marketing of ketoconazole by French regulatory authorities. The French regulators had concluded that ketoconazole had a negative benefit-risk balance because of its link with liver injury and the availability of safer alternatives. CHMP then concluded that use of ketoconazole was associated with a greater risk of liver injury than other antifungals and that it was not possible to identify measures to directly mitigate the risks of the drug.

The U.S. FDA, by comparison, has simply added new information to the warning statements in the prescribing information for ketoconazole to state very clearly that this drug should not be used as a first-line treatment for any fungal infection. From the perspective of men with advanced prostate cancer and their physicians, this would certainly appear to be the more rational approach. The European decision to suspend marketing altogether appears to ignore the well-established, off-label use of ketoconazole in the treatment of advanced forms of prostate cancer.

One Response

  1. Thank goodness the US regulators took a sensible approach.

    Those of us who have become familiar with ketoconazole as an actual or potential second line of defense in hormonal therapy for prostate cancer are aware that it needs to be carefully administered (by us) and managed, especially regarding drug interactions and both liver and adrenal issues.

    Regarding new, probably equally or more effective functional replacements, such as abiraterone acetate and enzalutamide, that’s great, but those drugs also cost a bundle, and it strikes me that ketoconazole should continue to play an important role considering the balance of benefits, risks, and cost. Of course, as Sitemaster’s review mentioned, ketoconazole (with hydrocortisone for the adrenal issues as is routine) has a long track record.

    Regarding liver damage, I’m wondering if ursodiol and similar liver protection drugs are able to fully protect against liver damage from ketoconazole. (I have never taken ketoconazole, but I am taking ursodiol during my fourth round, 14th year, of intermittent triple ADT for protection against potential damage from flutamide. I switched from bicalutamide due to evidence of a possible ARM, which appeared at the beginning of my third “off-therapy” vacation. I’m doing fine with ADT3 support of the TomoTherapy radiation I had in March/April.)

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