The US 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).
Healthcare 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 currently takes 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:
- 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. (Boxed Warning, Warnings, Precautions, and Indications and Usage sections)
- 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 (Indications and Usage section).
- 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 (Contraindications section).
- Updated information on the risk of liver injury, or hepatotoxicity, with new assessment and monitoring recommendations (Boxed Warning, Warnings, and Precautions sections).
- Updated information on drug interactions (Precautions section).
- A warning regarding adrenal insufficiency with recommendations for monitoring populations at risk (Warnings section).
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 25, 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.