Based on reports of serious, sometimes fatal, liver injury and other health risks, FDA officials have called for strict limits(www.fda.gov) on the use of ketoconazole oral tablets (Nizoral). New drug labeling(www.accessdata.fda.gov) reflects the removal of several indications for the antifungal medication, the addition of a new contraindication for patients with acute or chronic liver disease, and other changes.
Micrograph of fungal organisms in human tissue
A new medication guide(www.fda.gov) for patients also has been developed to address these safety issues.
The FDA said oral ketoconazole should not be considered first-line therapy for any fungal infection. The drug should be used solely for a narrowly defined subset of infections -- blastomycosis, chromomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis -- and then only when other treatments have failed or are not tolerated.
Topical formulations of ketoconazole, which include creams, shampoos, foams and gels, do not share these same health risks and are not affected by the FDA's recent action.
In addition to contraindicating use of oral ketoconazole in patients with existing liver disease, new recommendations for assessing and monitoring patients who use the drug for liver toxicity have been added to the drug's package labeling.
- Based on reports of liver injury and other health risks, FDA officials have called for strict limits on the use of ketoconazole oral tablets (Nizoral).
- The agency said that oral ketoconazole should not be considered first-line therapy for any fungal infection.
- The drug should be used only for a narrowly defined subset of infections and then only when other treatments have failed or are not tolerated.
Other label revisions include updated information on possible drug interactions and a new warning about the potential for adrenal insufficiency in some patients who use the drug.
As a potent inhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4), ketoconazole decreases clearance of other medications that are metabolized by CYP3A4, which can lead to higher drug concentrations in serum and predispose patients to potentially serious adverse effects, including QT prolongation.
Ketoconazole's inhibition of the cytochrome P450 isoenzyme system also can block production of adrenal steroids, leading to endocrinologic abnormalities such as gynecomastia in men and menstrual irregularities in women.
The label changes soon may prove moot, however, if a request by the drug's manufacturer to withdraw the product is approved by the FDA.
According to Kristina Chang, director of Product Communication and Global Pharmaceuticals Communication and Public Affairs for Janssen Global Services LLC, Janssen Pharmaceuticals has submitted a request to the FDA to withdraw Nizoral tablets from the U.S. market "given advancements in treatments for fungal infections and available generic medications."
Janssen has not manufactured Nizoral tablets for the U.S. market for some time, Chang noted, and all product previously produced for the United States has since expired.
"In the interim, as the withdrawal is not completed yet, we worked with FDA on its request to update product safety information and indications," said Chang.
In related news, the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) recommended last month(www.ema.europa.eu) that marketing of oral ketoconazole-containing products should be suspended throughout the European Union. That decision was based on the committee's conclusion that the risks of liver injury outweigh the benefits of treating fungal infections.
The CHMP review of the drug was prompted, in turn, by France's National Agency for the Safety of Medicine and Health Products having earlier decided to pull the product from French pharmacy shelves.
The committee's recommendation now will be sent to the European Commission for a legally binding decision.