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574970

research-article2015
CMSXXX10.1177/1203475415574970Journal of Cutaneous Medicine and SurgeryGupta and Lyons

Review

Journal of Cutaneous Medicine and Surgery

The Rise and Fall of Oral Ketoconazole 1­–6


© The Author(s) 2015
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DOI: 10.1177/1203475415574970
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Aditya K. Gupta1,2 and Danika C.A. Lyons2

Abstract
Background: Ketoconazole was the first broad-spectrum oral antifungal agent available to treat systemic and superficial
mycoses. Evidence of hepatotoxicity associated with its use emerged within the first few years of its approval. Growing
evidence of serious side effects including endocrine dysregulation, several drug interactions, and death led to the review of
oral ketoconazole in 2011.
Objective: This article chronicles the use of oral ketoconazole from its introduction to its near replacement in medicine.
Conclusion: Due to its hepatotoxic side effects, oral ketoconazole was withdrawn from the European and Australian
markets in 2013. The United States imposed strict relabeling requirements and restrictions for prescription, with Canada
issuing a risk communication echoing these concerns. Today, oral ketoconazole is only indicated for endemic mycoses,
where alternatives are not available or feasible. Meanwhile, topical ketoconazole is effective, safe, and widely prescribed for
superficial mycoses, particularly as the first-line treatment for tinea versicolor.

Résumé
Contexte : Le kétoconazole a été le premier antifongique oral à large spectre servant à traiter les mycoses systémique
ou superficielles. Des preuves de son hépatoxicité ont émergé dès les premières années ayant suivi son approbation.
L’accumulation de données probantes sur ses effets secondaires graves, entre autres des troubles endocriniens, plusieurs
interactions médicamenteuses et le décès, a mené à une revue de ce médicament en 2011.
Objectif : Le présent article présente les usages du kétoconazole oral, depuis son arrivée en médecine jusqu’à son
remplacement presque total.
Conclusion : En raison de ses effets secondaires hépatotoxiques, le kétoconazole oral a été retiré du marché en Europe
et en Australie en 2013. Les États-Unis ont imposé des conditions strictes relativement au nouveau libellé des indications
approuvées et des restrictions à la prescription de ce médicament, tandis que le Canada a diffusé des communiqués sur les
risques et les préoccupations soulevées par ce médicament. À l’heure actuelle, le kétoconazole oral n’est indiqué que pour
traiter les mycoses endémiques, lorsqu’il n’existe aucune autre solution. Il reste que le kétoconazole oral est efficace, sûr et
largement utilisé pour traiter les mycoses superficielles, notamment en traitement de premier recours du pityriasis versicolor.

Keywords
ketoconazole, azole antifungal, history, hepatotoxic, indication

Introduction effects.4-6 Similarly, strict restrictions and cautionary advise-


ments were added to oral ketoconazole labelling in the US
The development of the first broad-spectrum oral antifungal, and Canada in 2013. Today, oral ketoconazole is recom-
ketoconazole (Nizoral), in 1977 by Janssen Pharmaceutica mended in these countries only in the event of severe or life-
represented an exciting new advancement in the field of threatening systemic infections when alternatives are
medical mycology.1 Ketoconazole received United States unavailable.7,8
(US) Food and Drug Administration (FDA) clearance for use
in systemic fungal infections in July 1981.2,3 It remained the
only oral antifungal available for the treatment of systemic 1
Department of Medicine, University of Toronto, Toronto, Canada
fungal infections for nearly a decade thereafter.3 Until 2
Mediprobe Research Inc., London, Ontario, Canada
recently, oral ketoconazole has been a mainstay of treatment
Corresponding Author:
for a plethora of superficial and systemic fungal infections. Aditya K. Gupta, Mediprobe Research Inc, 645 Windermere Road,
However, the drug was taken off the market in Europe and London, ON, N5X 2P1 Canada.
Australia in 2013 as a result of the risk of serious hepatic side Email: agupta@execulink.com
2 Journal of Cutaneous Medicine and Surgery 

Figure 1.  Timeline of major advancements in treating superficial and systemic mycoses.

A Brief Historical Overview of the ultimately altering the structure and function of the cell
Development of Antifungals wall.14,18 Early in vitro studies demonstrated ketoconazole’s
activity against dermatophytes,13,16,19,20 yeasts,13,16,19,20
The first known account of successful treatment of a sys- molds,19 and dimorphic fungi20 as well as some bacteria.19
temic mycosis was published in 1903 by de Beurmann and Ketoconazole also demonstrated in vivo activity in animal
Gougerot, who effectively treated a case of sporotrichosis models of oral and vaginal candidosis,19,21 cutaneous candi-
with potassium iodide.9,10 It was not until almost 50 years dosis,19,20 and systemic candidosis.20
later that the first noteworthy agent with antifungal proper- Multiple small clinical studies demonstrated the efficacy
ties, nystatin, was discovered.1,10 In 1953, the polyene of oral ketoconazole as treatment for both systemic and
amphotericin B was developed and became the standard of superficial mycoses caused by yeasts and fungi, including
comparison for therapies for systemic mycoses.1,11 dermatophytes (reviewed in Heel et al21). At the time, the
The antimicrobial properties of the most widely used anti- drug appeared to be well tolerated with most adverse effects
fungals today, the azoles, were first described in 1944.12 occurring in <1% of study participants. Nausea and vomiting
These agents interfere with ergosterol biosynthesis, an essen- (3%), pruritus (1.7%), and abdominal pain (1.3%) were the
tial component of the fungal cell wall, through inhibition of most frequently reported adverse side effects.21 The versatil-
the P450-dependent enzyme lanosterol 14-α-demethylase.3 ity of oral ketoconazole led to its recognition as the most
In 1958, chlormidazole was the first compound specifically effective and most extensively prescribed oral azole antifun-
developed and marketed as an antifungal. Chlormidazole’s gal of its time.3 It was also included in the World Health
development renewed research interest in the field of antimi- Organizations (WHO) Model List of Essential Medicines for
crobials. By 1969, developments in this field resulted in the many years.22 However, concern over much more serious
adoption of 3 new azole antifungals, clotrimazole, micon- adverse reactions to oral ketoconazole soon came to the
azole, and econazole, into clinical practice.10 Despite these forefront.6
advancements, the field of dermatology still lacked a broad-
spectrum antifungal agent (Figure 1).
The Descent of Oral Ketoconazole
The descent of oral ketoconazole began with the acknowl-
The Rise of Ketoconazole edgment of symptomatic and asymptomatic hepatotoxicity
Ketoconazole, a broad-spectrum imidazole antifungal, was associated with its use.23 Evidence soon followed that sug-
introduced in 1977 and received FDA approval in 1981.13,14 gested that ketoconazole may not only cause liver injury but
At the time of its approval, ketoconazole’s broad-spectrum also interfere with endocrine regulation.24,25 Finally, the
activity presented clear advantages over established antimy- potential for drug-drug interactions became apparent, as oral
cotics in that it combined efficacy similar to miconazole with ketoconazole was found to alter the metabolism of concomi-
oral absorption akin to griseofulvin.15-17 Like other imidazole tant medications via its effect on CYP3A enzymes.26-28
compounds, ketoconazole interferes with ergosterol biosyn- By the early 1980s, it was apparent that oral ketoconazole
thesis through inhibition of a P450-dependent enzyme, was associated with hepatic injury. In 1983, Janssen and
Gupta and Lyons 3

Symoens23 conducted an analysis of the incidence of symp- decreased libido, gynecomastia, and oligospermia. By 1982,
tomatic and asymptomatic (elevated liver enzymes with no 6 incidences of gynecomastia following ketoconazole treat-
clinical signs or symptoms) hepatic reactions to ketocon- ment were documented.24,37 Subsequent in vitro investiga-
azole reported worldwide from March 1981 to March 1982. tions revealed that ketoconazole inhibits testosterone
The report suggested that hepatic abnormalities manifested synthesis38,39 and adrenal steroidogenesis.38 Ketoconazole
most often as asymptomatic increases in liver enzyme levels. was thought to achieve its effects on testosterone synthesis
These abnormalities were transient, normalizing throughout and adrenal steroidogenesis through interference with P450-
the duration of treatment or following cessation of treatment. dependent enzymes.40,41 It became clear that the activity of
The report described 31 incidences of symptomatic hepatic ketoconazole is not specific to P450-dependent fungal
reactions to oral ketoconazole. All symptomatic patients made enzymes; rather, it may affect any mammalian P450-
a full recovery with the exception of 1 patient who died of dependent enzyme, potentially leading to unforeseen inci-
hepatic necrosis.23 A subsequent addendum to the publication dences of adverse reaction or toxicity.
described an additional 46 cases of symptomatic hepatic reac- Oral ketoconazole was also found to increase the risk of
tions to oral ketoconazole and an additional death by September drug interactions as it is a potent inhibitor of the CYP3A4
1982.23 The authors estimated that 0.008% (1:12 000) of enzyme.18 Therefore, co-administration with any agent that
patients administered oral ketoconazole may suffer symp- inhibits CYP3A4 may increase the bioavailability of keto-
tomatic hepatic side effects. Subsequent estimations of the conazole and thereby increase the therapeutic and/or adverse
incidence rate of symptomatic ketoconazole-induced liver effects of the drug.18 Similarly, co-administration of ketocon-
injury ranged from 0.007% (1:15 000)29 to as high as 0.05% azole with any other drug metabolized by CYP3A4 may
(1:2000)30 and 0.2% (1:500).31 increase the blood plasma levels of that agent and prolong its
The recognition of ketoconazole-associated hepatotoxic- effects.42,43 Conversely, agents that decrease gastric acidity
ity among scientists, physicians, and the general public led to or induce CYP3A4 may decrease the bioavailability and
debate regarding the proper prescription of oral ketoconazole therapeutic effect of ketoconazole.44-47 As a result, many
and indications for the timing of treatment termination. For medications are contraindicated with ketoconazole, while
instance, in 1983, the Wall Street Journal described the out- others are simply not recommended or advised to be used
rage and discontent of a local consumer advocacy organiza- with caution.18
tion, the Public Citizen’s Health Research Group (PCHRG),
regarding ketoconazole.32 The PCHRG was petitioning the Ketoconazole Under Review:
FDA for additional warnings of hepatotoxicity on ketocon- New Restrictions and Regulations
azole packaging and cautioning physicians against off-label
prescription of the drug for superficial mycoses. The group
Worldwide
accused the FDA of failing to acknowledge the extent of the The use of oral ketoconazole was suspended in France in
liver damage that ketoconazole had caused.32 A representa- July 2011 after a review performed by the National Agency
tive of the FDA assured the public that the package labelling for the Safety of Medicine and Health Products (ANSM)
of ketoconazole would be revised to include mention that 1 deemed that its risks outweighed its therapeutic benefits.4
in every 10 000 patients may suffer often reversible, but This suspension triggered an EU-wide evaluation. Two years
sometimes fatal, liver damage.32 later, the European Medicines Agency (EMA) released a
In the scientific community, some argued that asymptom- statement announcing the Committee on Medicinal Products
atic increases in liver enzyme levels were fleeting and did not for Human Use’s (CHMP) recommendation that oral keto-
warrant drug cessation unless clinical signs of liver injury conazole’s marketing authorizations be suspended.4
developed.33 Others argued that elevated liver enzyme levels Additionally, the Australian government announced that oral
were extremely serious and warranted treatment cessation once ketoconazole would be deregistered and discontinued as of
levels 3 times the upper limit of normal were reached, regard- December 1, 2013.5 Again, the risks of serious hepatotoxic-
less of whether or not patients were symptomatic.34,35 Bernuau ity associated with oral ketoconazole use were believed to be
et al35 noted that 3 incidences of sudden hepatic failure occurred higher than the benefits of its therapeutic effects.
after treatment termination was delayed in spite of elevated In July 2013, the US FDA announced their amendments to
liver enzymes. Furthermore, the incidence of acute liver injury oral ketoconazole product labelling and warned against the
associated with oral ketoconazole use was determined to be use of oral ketoconazole as a first line of treatment. The new
higher than any of the other oral antifungal medications.31 A product monographs included a strong recommendation
meta-analysis of studies from 1979 to 2012 calculated the inci- against the use of ketoconazole in patients with liver disease
dence of oral ketoconazole-associated hepatotoxicity to range and introduced new recommendations for assessing and mon-
from 3.6% (95% CI, 3.2-4.2) to 4.2% (95% CI, 3.7-4.9) and to itoring liver function. Recommended testing prior to treat-
be unrelated to dose and duration of treatment.36 ment includes baseline alanine aminotransferase (ALT),
Endocrine dysregulation as a result of oral ketoconazole aspartate aminotransferase (AST), total bilirubin, alkaline
administration can lead to decreased testosterone production, phosphatase, prothrombin time, and international normalized
4 Journal of Cutaneous Medicine and Surgery 

Table 1.  Summary of Worldwide Oral Ketoconazole Guidelines.a

Canada (Health Canada) USA (FDA) EU (EMA) Australia (NPS)


Indications Serious or life-threatening Serious or life-threatening No longer prescribed Deregistered,
systemic fungal infections systemic fungal infections discontinued
when other options not when other options not
available or tolerated available or tolerated (not for
skin or nails)
Monitoring Liver function tests before Liver function tests before  
treatment, at weeks 2 and 4, treatment, serum ALT
monthly thereafter. monitored weekly, adrenal
function monitored in select
patients.
Criteria to interrupt use Elevated liver parameters ALT at upper limit of normal  
(>3 times normal) or if or 30% above baseline, or if
clinical signs/symptoms liver symptoms of abnormal liver
disease develop function
a
Symptoms of liver dysfunction include anorexia, nausea, vomiting, jaundice, abdominal pain, dark urine, or pale stool. ALT, alanine aminotransferase;
EMA, European Medicines Agency; FDA, Food and Drug Administration; NPS, National Prescribing Service

ratio (INR).8 The FDA recommended that oral ketoconazole prescription regulations in the US,8 and endorsement of this
be prescribed solely for endemic mycoses and only when a new safety information by Health Canada.7
suitable alternative is unavailable. Also, it is cautioned that The decrease in popularity of oral ketoconazole for treat-
current medications should be assessed for possible interac- ment of systemic mycoses has not left a gap in medical treat-
tions with ketoconazole before it is prescribed.8 ment. First- and second-generation triazoles with fewer
Within the same year, Health Canada released a risk com- safety concerns are effective treatment options for systemic
munication endorsing amendments to oral ketoconazole’s mycoses (Figure 1).48-50 Ketoconazole itself has not disap-
product monograph.7 The label now emphasizes the risk of peared from use in medical practice. Topical ketoconazole
hepatotoxicity and the need for liver function monitoring does not reach the systemic circulation and is a safe and
even when prescribed at the recommended dose and in effective therapy for dermatological conditions.51 Topical
patients with no preexisting liver abnormalities or serious formulations of ketoconazole cream, shampoo, and foam are
medical conditions.7 As in the US, indications were revised particularly effective in treating superficial mycoses caused
such that oral ketoconazole is to be prescribed only for seri- by Malassezia species. Topical ketoconazole serves as the
ous or life-threatening systemic fungal infections and never first-line treatment for tinea versicolor and is also used
prescribed to individuals with existing liver disease. The new in treating seborrheic dermatitis and Malassezia
restrictions and recommendations for North America and folliculitis.52,53
Europe are summarized in Table 1. Today, oral ketoconazole is now only recommended as a
second line of treatment for the most severe systemic myco-
ses when viable alternatives are unavailable. Despite its fate,
Conclusion oral ketoconazole represented the beginning of a new era of
In 1977, the introduction of ketoconazole represented an research and development of antimycotic agents, without
exciting new advancement in the field of medical mycology. which, the treatment options for superficial and systemic
Few effective therapeutic options to treat systemic mycoses mycoses that we have today would not exist (Figure 1).
were available at the time, and the development of new
agents was at a near standstill. The therapeutic efficacy of Declaration of Conflicting Interests
ketoconazole against a wide range of fungi, dimorphic fungi, The author(s) declared no potential conflicts of interest with respect
and yeasts led to widespread use in patients with superficial to the research, authorship, and/or publication of this article.
and systemic mycoses. Ketoconazole was heralded for many
years as the only drug of its kind. Oral ketoconazole use Funding
would eventually wane as more evidence of hepatotoxicity, The author(s) received no financial support for the research, author-
endocrine dysregulation, and drug interactions emerged. ship, and/or publication of this article.
After over 30 years in clinical practice, the serious hepato-
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