The 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. The 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.
Nizoral (ketoconazole) tablets are an antifungal drug indicated for the treatment of the following fungal infections when alternatives are not available or not tolerated: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Nizoral tablets should not be used for fungal meningitis because it penetrates poorly into the cerebrospinal fluid.
During 2012, approximately 5.2 million ketoconazole prescriptions were dispensed, of which 609,000 (12%) were for the tablet formulation. The most common diagnoses associated with the use of oral ketoconazole tablets in outpatient settings over recent years have included superficial skin and nail fungal infections as reported by office-based physicians.
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.
The 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.
Nizoral tablets can cause liver injury, which may potentially result in liver transplantation or death. The FDA has revised the Boxed Warning, added a strong recommendation against its use in patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxicity.
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.
The FDA assessment identified serious hepatic injury as the major toxicity for Nizoral tablets. Serious hepatic injury was noted to be unrelated to dose, duration, or indication for treatment. 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 five years) of approximately one 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 drugs.
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. 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.
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.
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.
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 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. In summary, the drug label for Nizoral tablets has been updated to include the following information:
- Limitation of the usage of Nizoral tablets by removing indications in which the risk outweighs the benefits. The use of ketoconazole tablets in Candida and dermatophyte infections is no longer indicated. Nizoral tablets should be used only when other antifungal drugs are not available or tolerated by the patient.
- Nizoral tablets are indicated only for the treatment of the following fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients in whom other treatments have failed or who are intolerant to other therapies.
- Nizoral tablets are not indicated for the treatment of fungal infections of the skin or nails.
- A new contraindication that Nizoral tablets should not be used in patients with acute or chronic liver disease.
- Updated information on the risk of liver injury, or hepatotoxicity, with new assessment and monitoring recommendations.
- Updated information on drug interactions.
- A warning regarding adrenal insufficiency with recommendations for monitoring populations at risk.
The 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).
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.
See the FDA Announcement
See the EMA Announcement
See also, Medical Law Perspectives May 2013 Report: Drugs, Dosage, and Damage: Physician Liability for Prescribing or Administering Medication