By: Hayeon Na, Co-Copy Editor [Content-Focused]
The Food and Drug Administration (FDA) announced on July 26th that oral dosage forms of ketoconazole (Nizoral®) should no longer be prescribed as first-line therapy for any fungal infections.1 The label and indication for oral ketoconazole were updated, and a new medication guide was added. Other dosage forms of the drug (creams, ointments, and shampoos) were not included in this change due to their limited systemic absorption.1
These recent changes were fairly drastic. The FDA withdrew the indication for Candida and dermatophyte infections. Oral ketoconazole is now only indicated as second-line therapy for life-threatening fungal infections called endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis), when first-line treatments have failed, alternatives cannot be found, or the patient cannot tolerate others. 2 The FDA also revised the Black Box Warning, added a contraindication for patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxicity while taking oral ketoconazole.2 These seemingly abrupt changes were triggered by the recent recommendation for the withdrawal of ketoconazole from the EU national markets by the European Union (EU) drug regulators.3
In a news release on July 25, 2013, the European Medicine Agency (EMA) stated that the “benefit of oral ketoconazole does not outweigh risk of liver injury in fungal infections” in early stages of treatment at recommended doses (200mg – 400mg/day in a single dose),4 and that other antifungals have a lower incidence of liver injury. The reported cases of hepatotoxicity in ketoconazole use include hepatitis, cirrhosis, and liver failure that may require transplantation or may even result in death.3
In July of 2011, the French National Agency of Medicine and Health Products Safety (ANSM) suspended the marketing authorization of ketoconazole due to the unfavorable risk-to-benefit ratio. All oral dosage forms were withdrawn from the market except for those in hospitals. In cases such as Cushing’s syndrome in an in-patient setting, individual patients were to be granted temporary authorization for use (ATU) by the French Drug regulatory body (AFSSAPS) after assessments of risk-to-benefit ratios.5 ANSM requested that an EU-wide review be conducted according to the European legislation, which requires that “there is a coordinated European approach when a Member State takes a regulatory action in relation to a medicine authorized in more than one country.”3 While the EU conducted a review of the medication, ANSM noted that alternatives should be used in lieu of the high-risk medication.5
At the end of the review, the Committee on Medicinal Products for Human Use (CHMP) of EMA stated that data on the efficacy of ketoconazole’s are “limited and do not meet current standards.”3 This conclusion was made by consulting available data from preclinical, clinical, and post-marketing studies, as well as case reports, epidemiological studies, expert opinions, and current scientific literature. According to the recommendation by CHMP, patients currently on the medication should make appointments with doctors who will review the patients’ state and either stop therapy or find alternatives, because other measures to reduce the risks associated with ketoconazole cannot be identified.3 The EMA website states that the CHMP opinion will now be sent to the European Commission for a legally binding decision.
Ketoconazole (Nizoral®) is an antifungal medicine once used to treat infections caused by dermatophytes and yeasts.3 Dermatophytes are the most common fungal infections in humans, invading the keratinized areas of the body (hair, nails, and skin).7 Ketoconazole prevents the growth of several types of fungi by disrupting the production of fungal cell membranes. The FDA approved ketoconazole in June 1981,8 after the EU authorized it in 1980.3 Later, topical formulations such as creams, ointments, and shampoos became available.3
Ketoconazole tablets may decrease the body’s production of corticosteroids—an electrolyte balancing hormone—produced by the adrenal glands on top of each kidney.6 Adrenal function should be monitored in patients who have existing adrenal problems or who are under prolonged stress, such as receiving major surgery or being under intensive care at a hospital.2
Administration of oral ketoconazole with other medications may result in serious drug interactions such as arrhythmia. Patient medication history should be reviewed before administration of the antifungal to predict possible adverse drug interactions.3
Clinicians should not prescribe oral ketoconazole to anyone who has an underlying liver disease.6 The FDA recommends that health care professionals assess liver status with values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, prothrombin time (PTT), and international normalized ratio (INR), in patients with and without liver problems before starting the medication. Patients who are on ketoconazole should be monitored weekly for ALT values to detect liver damage. If the patient develops symptoms of abnormal liver function, if the ALT level increases more than 30% from baseline, or if the ALT level reaches above the upper limit of normal level, the treatment should be discontinued and a full set of liver tests should be performed and repeated to ensure normalization.2
Although keeping up with the FDA updates on medications can be difficult and time-consuming, it is necessary for practitioners to be aware of changes. Because various professionals work together in patient care, there are numerous opportunities for error prevention. Pharmacists who encounter prescriptions for oral ketoconazole should consult the prescriber about the new recommendations before dispensing the medication to make sure that the patient is receiving optimal care.
- Lowes R. “FDA, EMA Come Down Hard on Oral Ketoconazole.” Medscape. http://www.medscape.com/viewarticle/808484?nlid=32316_745&src=wnl_edit_medp_phar&uac=199191MR&spon=30. July 26, 2013. Accessed August 7, 2013.
- FDA Drug Safety Podcast: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. U.S. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm362820.htm. July 26, 2013. Accessed August 7, 2013.
- Benstetter M. “European Medicines Agency recommends suspension of marketing authorizations for oral ketoconazole.” European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. July 26, 2013. Accessed August 7, 2013.
- Lexi-Comp OnlineTM, Lexi-Drugs Online TM, Hudson, Ohio: Lexi-Comp, Inc.; August 7, 2013.
- Reminder Specialty Nizoral 200mg tablet. Agence nationale de sécurité du médicament et des produits de santé. http://www.ansm.sante.fr/S-informer/Informations-de-securite-Retraits-de-lots-et-de-produits/Rappel-de-la-specialite-NIZORAL-200-mg-comprime/. July 11, 2011. Accessed August 7, 2013.
- 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. U.S. Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. July 26, 2013. Accessed August 7, 2013.
- Lexi-Comp OnlineTM, Infectious Diseases Online TM, Hudson, Ohio: Lexi-Comp, Inc.; August 7, 2013.
- Ogbru O. “Ketoconazole, Nizoral, Extina, Xolegel, Kuric” MedicineNet.com. http://www.medicinenet.com/ketoconazole/article.htm. Accessed August 7, 2013.