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[7-26-2013] The U.S. Food and Drug Administration (FDA) is taking several actions related to Nizoral (ketoconazole) oral tablets, including limiting the drug’s use, warning that it can cause severe liver injuries and adrenal gland problems and advising that it can lead to harmful drug interactions with other medications. FDA has approved label changes and added a new Medication Guide to address these safety issues. As a result, Nizoral oral tablets should not be a first-line treatment for any fungal infection. Nizoral should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.
The topical formulations of Nizoral have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.
Liver Injury (Hepatotoxicity)
Nizoral tablets can cause liver injury, which may potentially result in liver transplantation or death. FDA has revised the Boxed Warning, added a strong recommendation against its use (contraindication) in patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxicity (see Additional Information sections).
Serious liver damage has occurred in patients receiving high doses of Nizoral for short periods of time as well as those receiving low doses for long periods. Some of these patients had no obvious risk factors for liver disease. The liver injury is sometimes reversible upon stopping the drug, but that is not always possible.
Adrenal Gland Problems (Adrenal Insufficiency)
Nizoral tablets may cause adrenal insufficiency by decreasing the body’s production of hormones called corticosteroids. Corticosteroids are produced by the adrenal glands, which are small glands located on top of each kidney. Corticosteroids affect the body’s balance of water and salts and minerals (electrolytes). Health care professionals should monitor adrenal function in patients taking Nizoral tablets who have existing adrenal problems or in patients who are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital.
Nizoral tablets may interact with other drugs a patient is taking and can result in serious and potentially life-threatening outcomes, such as heart rhythm problems. All medications that a patient is currently taking should be assessed for possible interactions with Nizoral tablets .
In summary, the drug label for Nizoral tablets has been updated to include the following information:
FDA has also approved a new patient Medication Guide containing information on the potential risks associated with Nizoral tablets, which must be dispensed with every prescription for the drug.
On July 26, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) announced their negative risk-benefit assessment for oral ketoconazole-containing medicines used to treat infections caused by dermatophytes and yeasts and recommended suspensions of these medicines throughout the European Union (EU). The EMA public announcement of the recommendation to suspend the marketing authorizations of ketoconazole for oral use as antifungal treatment is available at http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146613.pdf .
In addition to the indications for treatment of infections caused by dermatophytes and Candida, the previous US drug label also included indications for the following serious fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. In the revised US drug label, indications for dermatophyte and Candida infections have been removed and the indications for treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis have been retained only for patients in whom other antifungal treatments have failed or are not tolerated.
FDA will continue to evaluate the safety of Nizoral tablets and will communicate with the public again if additional information becomes available.
Facts about Nizoral (ketoconazole) tablets
Additional Information for Patients
Additional Information for Health Care Professionals
FDA conducted a comprehensive benefit-risk assessment of the safety and efficacy of Nizoral (ketoconazole) tablets in the context of the drug’s labeled indications for the treatment of superficial and systemic fungal infections, which resulted in the changes to the drug’s label.
Serious hepatic injury was identified as the major toxicity for Nizoral tablets and was noted to be unrelated to dose, duration, or indication for treatment. In conducting the benefit-risk assessment, spontaneous adverse event reports of ketoconazole-induced liver injury, including fatalities and liver transplantations, retrieved from the FDA Adverse Event Reporting System (AERS) were assessed independently by a hepatology expert in FDA. The overall risk for ketoconazole-induced serious liver injury appeared higher than that associated with other azole antifungal drugs as assessed from pharmacoepidemiologic studies.
One published study in the U.K. General Practice Research Database suggested a risk of acute liver injury (defined as patients presenting with symptoms of liver disorder: nausea, vomiting, abdominal pain and/or jaundice requiring referral to a specialist or hospitalization and free of history of liver disease and other chronic illnesses in the past 5 years) of approximately 1 in 500 patients, and analysis of liver transplantation data indicates that hepatotoxicity from ketoconazole accounted for proportionately more liver transplants than hepatotoxicity from other antifungal drugs3. However, in view of various methodological limitations, there was uncertainty in quantifying precise estimates of the risk of acute liver injury for Nizoral tablets compared to other marketed oral azole antifungals.
Through its inhibition of the cytochrome P450 isoenzyme system, ketoconazole can block production of adrenal steroids. This accounts for clinically important endocrinologic abnormalities observed in some patients (particularly when the drug is administered at high dosages), including gynecomastia in men and menstrual irregularities in women.
Ketoconazole is one of the most potent inhibitors of the cytochrome P450 3A4 isoenzyme (CYP3A4). The clearance of other co-administered drugs that are metabolized by CYP3A4 is decreased by ketoconazole and can result in increased drug concentrations in plasma, which can predispose patients to potentially serious adverse reactions including QT prolongation. Thus, the co-administration of ketoconazole with some other drugs is restricted or contraindicated in the drug labels .
In conclusion, ketoconazole should not be a first-line treatment for any fungal infection. Ketoconazole is not recommended for the treatment of any form of candidiasis or any superficial fungal infection. Ketoconazole may be considered in the treatment of certain life-threatening systemic mycoses in patients for whom alternate antifungal drugs are not available or cannot be tolerated.