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FDA Puts Strict Limits on Oral Ketoconazole Use

By John Gever, Deputy Managing Editor, MedPage Today

SILVER SPRING, Md. — Oral ketoconazole (Nizoral) should never be used as first-line therapy for any type of fungal infection because of the risk of liver toxicity and interactions with other drugs, the FDA said Friday.

The agency ordered a series of label changes and a new medication guide for patients that emphasize the risks, which also include adrenal insufficiency. It noted that the restrictions apply only to the oral formulation, not topical versions.

Late Thursday, the chief advisory body for the FDA’s European counterpart went further. The EU’s Committee on Medicinal Products for Human Use (CHMP) recommended that member nations pull oral ketoconazole from their markets entirely.

Both the FDA and the CHMP cited studies indicating high risks of severe, acute liver injury in patients taking the drug. Studies using the FDA’s adverse event reporting system and a similar database in the U.K. indicated that liver toxicity was more common with oral ketoconazole than with other anti-fungals in the azole class.

The FDA also said that oral ketoconazole “is one of the most potent inhibitors” of the CYP3A4 enzyme. This effect can lead to sometimes life-threatening interactions with other drugs metabolized by CYP3A4, and also to adrenal insufficiency, since the enzyme also catalyzes release of adrenal steroid hormones.

“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,” the FDA said.

The only indication for oral ketoconazole still supported by the FDA is for use in life-threatening mycoses in patients who cannot tolerate other anti-fungal medications or when such medications are unavailable.

In such instances, the FDA said, physicians should assess liver function before starting the drug. It is contraindicated in patients with pre-existing liver disease, and patients should be instructed not to drink alcohol or use other potentially hepatotoxic drugs.

Adrenal function should also be monitored in patients using the drug.

The CHMP also indicated the topical formulations of ketoconazole should stay on the market, but it found no basis for keeping the oral form available for any purpose.

“Taking into account the increased rate of liver injury and the availability of alternative anti-fungal treatments, the CHMP concluded that the benefits did not outweigh the risks,” the panel indicated in a statement.

It recommended that physicians stop prescribing oral ketoconazole and that they should review alternatives in patients currently receiving the drug. The committee also said that patients now taking oral ketoconazole “make a non-urgent appointment” with their physicians to discuss their treatment.

Acerca de Juan Antonio Chassaigne

Profesor Titular de Farmacología, Universidad Nacional Experimental "Francisco de Miranda" y Hospital "Dr. Rafael Calles Sierra", IVSS / UNEFM

3 comentarios

  1. Muy interesante esta informacion.
    Cada que uso ketokonazol oral , se que estoy corriendo un GRAN riesgo …..
    Realmente la indicacion principal para mi es la DERMATITIS SEBORREICA severa persistente y reagudizada… donde doy cursos de 20 a 30 dias….
    Como hace poco tuvimos una discusion bien interesante de este tema queria hacerle una pregunta a los Profes :

    – Les funciona igual en D. seborreica el Fluconazol que el Ketokonazol ??? y si es asi , a que dosis …. semanal o diario?

    De antemano muchas Gracias¡
    PD: FELICITACIONES A MI LINDO PAIS, QUE HOY ESTA DE DIA DE INDEPENDENCIA ….

  2. Rolando Hernández Pérez

    Angelita un cordial saludo y gracias por tu participación.
    Yo no uso ketaconasol oral , lo uso más de forma tópica (crema- ojo irrita mucho)Uso la ciclopiroxolamia en crema.
    Prefiero la terbinafina oral e el itraconazoles oral también. No me gusta el fluconazol para dermatitis seborreica, los resultados con este último son muy lentos y poco sostenidos en el tiempo.
    saludos
    Rolando Hernández Pérez

  3. fernando brenner

    TENGO ENTENDIDO QUE EN CASOS DE CANDIDIASIS MUCOCUTANEA CRONICA ,EL KETOCONAZOL ORAL ERA DE ELECCION POR SU MAYOR EFICACIA.CREO QUE SU USO ,AUN EN ESTA CONDICION, DEBERIA SER MUY CUIDADOSO ,CON CONTROL DE LABORATORIO ,Y SIEMPRE QUE LA ENFERMEDAD NO RESPONDA A OTROS ANTIMICOTICOS MENOS HEPATOTOXICOS.

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