DO NOT USE KETOCONAZOLE TABLETS*

October 14, 2013

On July 26, 2013, a key committee of the European Medicines Agency (EMA, the European equivalent of the U.S. Food and Drug Administration [FDA]) recommended that ketoconazole (brand name: Nizoral) tablets, an antifungal treatment, be removed from the European market because the drug’s severe risks — including liver injury, adrenal gland dysfunction and numerous medication interactions — outweigh its benefits.[1]

The same day, the FDA announced that despite these serious risks, the agency would keep ketoconazole tablets on the market but would add language to the drug’s label significantly restricting its recommended uses.[2] The FDA also mandated that a Medication Guide be distributed with the drug to inform patients of these risks and restricted uses.

Ketoconazole is approved to treat fungal infections and is often used off-label to treat hormonal problems, such as Cushing’s syndrome.[3] In 2012, approximately 5.2 million ketoconazole prescriptions were dispensed, of which 609,000 (12%) were for the tablet formulation.[4]

Liver injury caused by ketoconazole tablets has been estimated to occur in 1 of 500 patients with no prior history of liver disease. Liver damage can be severe, leading to liver transplant or death in some patients, including in those without a prior history of liver disease. Although other antifungal medications in the same class also can cause liver damage, the risk is considerably higher with ketoconazole.[5]

Ketoconazole tablets also can cause problems with the adrenal glands, affecting the body’s balance of water and salts and minerals (electrolytes) and can interact with numerous drugs, leading to potentially fatal heart rhythm disturbances.[6]

These risks prompted the EMA’s move to ban the drug, but the FDA allowed the tablets to continue to be available for five fungal infections (blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis and paracoccidioidomycosis) as a last resort if other antifungals fail or are not tolerated, and only in those without preexisting liver disease.

We agree with the EMA’s conclusions that there are “inadequate data to support the efficacy of ketoconazole when other treatments have failed or are not tolerated, or resistance has been detected” and that proposals (similar to the FDA’s) to mitigate the drug’s risks, especially that of potentially fatal liver injury, would be insufficient to make the risks acceptable in light of the drug’s uncertain benefits.[7]

Do not use ketoconazole tablets under any circumstances. If you are currently taking ketoconazole, see your doctor immediately to consider switching to another therapy. Never stop taking a medicine before consulting your doctor.

To read the EMA’s announcement, visit: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1

To read the FDA’s announcement, visit: http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm

* Note: This e-alert applies to the tablet form only and does not apply to ketoconazole creams, shampoos, foams and gels applied to the skin, which can continue to be used as indicated for fungal skin infections since very little of the drug is absorbed into the body.

References

[1] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed October 11, 2013.

[2] FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[3] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed October 11, 2013.

[4] FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[5] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed on July 29, 2013.

[6] FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[7] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed on July 29, 2013.