FDA Restricts, EMA Moves to Ban Ketoconazole Tablets

Note: This article and the Food and Drug Administration’s restrictions apply to the tablet form of ketoconazole only and not to ketoconazole creams, shampoos, foams and gels applied to the skin, which can continue to be used as indicated for fungal skin infections because very little of the drug is absorbed into the body.

On July 26, 2013, the Food and Drug Administration (FDA) issued a safety communication restricting the approved uses of the antifungal tablet ketoconazole (NIZORAL) due to the drug’s severe risks of liver injury, adrenal gland dysfunction and numerous medication interactions.[1] The FDA also mandated that a Medication Guide be distributed with the drug, informing patients of these risks and restricted uses.

On the same day, the Committee on Medicinal Products for Human Use (CHMP), a key committee of the European Medicines Agency (EMA, the FDA’s European equivalent) recommended that ketoconazole tablets be removed from the European market, concluding that the drug’s risks outweighed its benefits and that safer alternatives existed for the fungal infections for which the FDA allowed the drug to remain on the U.S. market.[2] (The CHMP did allow individual member countries to permit the continued, “controlled” off-label use of ketoconazole for Cushing’s syndrome, a rare hormonal disorder.[3])

The two moves represent the latest instance in which the FDA has opted for a weaker, less public-health-oriented response than the EMA to a serious drug safety concern.

Ketoconazole’s risks evident since approval

Ketoconazole was approved in 1981 for the treatment of several fungal infections. There are currently six generic versions and one brand name version on the market in tablet form.[4] Before 2013, ketoconazole was indicated to treat several systemic and nonsystemic fungal infections.[5] In addition to these approved indications, ketoconazole is commonly used off-label to treat hormonal disorders, such as Cushing’s syndrome[6] and androgen-dependent prostate cancer,[7] because of its ability to suppress steroid production in the adrenal glands.

Ketoconazole’s liver toxicity was apparent soon after its approval. In 1983, the FDA required that a boxed warning about fatal liver injury be added to the label.[8] Since then, more evidence has accumulated shedding light on the scale and severity of ketoconazole’s effects on the liver.

According to the FDA, liver injury caused by ketoconazole tablets has been estimated to occur in 1 of 500 patients with no prior history of liver disease.[9] Liver damage can be severe, leading to liver transplant or death in some patients, including in those without a prior history of liver disease. Although other antifungal medications in the same class, such as itraconazole and fluconazole, can cause liver damage, the FDA stated that the risk appears higher with ketoconazole.[10]

Ketoconazole tablets also can cause adrenal insufficiency, affecting the body’s balance of water, as well as salts and minerals (electrolytes), and can interact with numerous drugs, leading to potentially fatal heart rhythm disturbances.[11] In fact, ketoconazole is such a potent inhibitor of a critical enzyme responsible for metabolizing many drugs that it was previously used in drug interaction studies conducted in the pre-approval clinical testing stage of new drugs.[12] However, on Oct. 16, 2013, the FDA recommended that drug companies and researchers avoid using ketoconazole in drug interaction studies to prevent the exposure of otherwise healthy subjects to its serious side effects.[13]

Use in decline

The unique dangers of ketoconazole have long been known to physicians and have resulted in a dramatic decline in its use over time for the fungal infections for which it is approved. In response to the FDA’s July announcement restricting the drug, Paul G. Auwaerter, M.D., an infectious disease specialist and clinical director of the Division of Infectious Diseases at the Johns Hopkins University School of Medicine, shed some light on why ketoconazole has fallen out of favor — in some cases out of use entirely — with physicians treating serious fungal infections.[14]

“As an infectious diseases physician, I don’t think I have prescribed ketoconazole in more than 15 years,” he stated, saying that the last time he used it was for a patient with a rare fungal infection, histoplasmosis, who could not afford the safer alternatives fluconazole or itraconazole.[15]

In 2012, approximately 609,000 prescriptions were dispensed for the ketoconazole tablet formulation.[16] According to the FDA, in recent years, the most common diagnoses for which the tablets were prescribed in outpatient clinics included non-life-threatening superficial skin and nail fungal infections that are now no longer approved uses.[17] Commenting on the newly limited indications for the drug, Auwaerter concluded, “I can’t imagine that this drug will be used to any degree in the future.”[18]

FDA falls behind

In its July announcement, the FDA allowed continued marketing of ketoconazole to treat five rare systemic fungal infections — blastomycosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis and chromomycosis — as a last resort if other antifungals fail or are not tolerated, and only in those without pre-existing liver disease.[19]

However, the EMA’s CHMP concluded that the unique, often fatal risks of ketoconazole outweighed its benefits for all of its approved uses.[20] That committee stated that there were “inadequate data to support the efficacy of ketoconazole when other treatments have failed or are not tolerated, or resistance has been detected” and that proposals (similar to the FDA’s) to mitigate the drug’s risks would not be “sufficient to reduce the risk of hepatotoxicity to an acceptable level” in light of the drug’s uncertain benefits.[21]

For at least three (blastomycosis, histoplasmosis and coccidiodomycosis) of the remaining five fungal infections for which ketoconazole is still indicated in the U.S., the Infectious Diseases Society of America has recommended a number of other safer therapies and, in the case of blastomycosis and histoplasmosis, emphasizes that ketoconazole is “seldom used” because of its more dangerous side effect profile compared with other drugs, such as itraconazole.[22]

Because of the presence of safer alternatives and given the gravity of the drug’s risks, we agree with the conclusion of the EMA’s CHMP that ketoconazole should be completely banned for use in fungal infections rather than merely restricted. Its apparently rare use by infectious disease specialists for serious fungal infections means that a ban would have at most a minimal impact on the treatment of serious fungal infections.

Regarding the off-label uses of ketoconazole for Cushing’s syndrome (which even the EMA’s CHMP recommended leaving up to the discretion of individual European country authorities[23]) and certain types of prostate cancer, the drug has yet to be declared safe and effective for these indications by the FDA. FDA-approved therapies for these serious conditions exist (e.g., mifepristone [KORLYM] for Cushing’s syndrome[24] and abiraterone [ZYTIGA] for androgen-dependent prostate cancer[25]) that, unlike ketoconazole, have undergone extensive review by the agency for these uses.

What You Should Do

Do not use ketoconazole tablets under any circumstances. If you are currently taking ketoconazole, see your doctor immediately to consider switching to another therapy. Never stop a medicine before seeing your doctor.

References

[1] 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. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[2] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed October 11, 2013.

[3] Ibid.

[4] Brand name version is Nizoral, approved by NDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed November 6, 2013.

[5] 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. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[6] Schteingart DE. Drugs in the medical treatment of Cushing's syndrome. Expert Opin Emerg Drugs. 2009 Dec;14(4):661-71.

[7] Keizman D, et al. Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer: clinical factors associated with PSA response and disease progression. Prostate. 2012 Mar;72(4):461-7.

[8] Boxed warning added to ketoconazole labeling. FDA Drug Bull. 1983 Aug;13(2):15-6.

[9] Ibid.

[10] Ibid.

[11] Ibid.

[12] FDA. FDA advises against using oral ketoconazole in drug interaction studies due to serious potential side effects. October 16, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm371017.htm. Accessed November 4, 2013.

[13] Ibid.

[14] Auwaerter P. Ketoconazole: FDA Planning to Pull It Off the Shelf? Medscape. August 9, 2013. http://www.medscape.com/viewarticle/809089. Accessed November 5, 2013.

[15] Ibid.

[16] 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. July 26, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed October 11, 2013.

[17] Ibid.

[18] Ibid.

[19] Food and Drug Administration. Nizoral tablets label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018533s040lbl.pdf. Accessed December 18, 2013.

[20] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed October 11, 2013.

[21] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. Accessed on July 29, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1

[22] Blastomycosis: Chapman SW, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008 Jun 15;46(12):1801-12. Histoplasmosis:Wheat LJ, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007 Oct 1;45(7):807-25. Coccidiodomycosis: Galgiani JN, et al. Coccidioidomycosis. Clin Infect Dis. 2005 Nov 1;41(9):1217-23.

[23] European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. July 26, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp&mid=WC0b01ac058004d5c1. Accessed October 11, 2013.

[24] Food and Drug Administration. FDA-approved label. Korlym (mifepristone). http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202107s000lbl.pdf. Accessed November 6, 2013.

[25] Food and Drug Administration. FDA-approved label. Zytiga (abiraterone). http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202379s007lbl.pdf. Accessed November 6, 2013.