Journal of cutaneous medicine and surgery(lM)
`v. J9, no. 4 (Jul-Aug 2015)
`General Collection
`W1 .JO612M
`2015-08-17
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`The Journal of Cutaneous Medicine and Surgery (JCMS) aims to refleet the state of the art in cutaneous biology and dermatology
`by providing original scientific writings, as well as a complete critical review of the dermatology literature for clinicians, trainees, and
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`provide theoretical framework for practitioners to make sound practical decisions. The evolving field of dermatology is highlighted through
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`Volume 19 Number 4
`
`July/August 2015
`
`Contents
`
`Editorial
`
`Journal of Cutaneous
`
`Medicine and Surgery
`
`A Team Effort: Working With Non—Dermatologists to Deliver Better Patient Care / Un effort
`d'équipe — Collaborer avec des non—dermatologues pour fournir de meilleurs soins aux patients
`Jason K. Rivers
`
`Letters to the Editors
`
`Oral Squamous Cell Carcinoma Mimicking Cewico-Facial Actinomycosis: A Rare
`Presentation and Review of Literature
`
`K. A. Prithvi Raj, Keshavarnurthy Vinay, Uma N. Saikia, and Muthu Senclhil Kumaran
`
`Verrucous Carcinoma on the Dorsal Aspect of the Hand
`Dulc Hee Lee and Jung Il Lee
`
`Reviews
`
`The Rise and Fall of Oral Ketoconazole
`
`Aditya K. Gupta and Danika C.A. Lyons
`
`Steroid—Induced Osteonecrosis in Dermatology: A Review
`Dominik Alex Nowak and Jensen Yeung
`
`Basic/ Clinical Science
`
`Reasons for Treatment Changes in Patients With Moderate to Severe Psoriasis
`Kathryn L. Anderson and Steven R. Feldman
`
`Psoriatic Nail Changes Are Associated With Clinical Outcomes in Psoriatic Arthritis
`Matthew K. Sandre, Sherry Rohekar, and Lyn Guenther
`
`Trends in Ambulatory Health Care Usage for Adult Acne
`Scott A. Davis, Karen E. Huang, Steven R. Feldman, Alan B. Fleischer, Jr., and William W. Huang
`
`Development and Validation of a Clinical Scale for the Evaluation of Forearm Skin Photoaging
`C.O.Z. Guirnaraes, E. Bagatin, L.R.S. Guadanhim, F. Sternberg, F.R. Picosse, G. Nunes, C. Milanez,
`and H.A. Miot
`
`Contact Cryoprobe Sterilization Practices: A Patient Quality and Safety Issue for Dermatologists
`Genevieve Gavigan, Alana McEvoy, and Jennifer Beecker
`
`Quality of Life of Patients With Pyoderma Gangrenosum and Hidradenitis Suppurativa
`Arielle J. Gerard, Steven R. Feldman, and Lindsay Strowd
`
`Case Reports
`
`Blistering Distal Dactylitis in an Adult
`Ramya Kollipara, Christopher Downing, Michael Lee, Jacqueline Guidry,
`Samantha Robare—St0ut, and Stephen Tyring
`
`Recovery of Transplanted Eyebrow Prom Radiation-Induced Anagen Effluvium
`Ekpemi Irune, Florian Bast, Gregory Williams, and Niall Kirkpatrick
`
`342
`
`346
`
`349
`
`352
`
`358
`
`361
`
`367
`
`377
`
`380
`
`388
`
`391
`
`397
`
`400
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`Systemic Sarcoidosis Revealed by Axillary Electrolysis
`Meggie Morand, Solcmge Beauregard, and Steve Mathieu
`
`Primary Cutaneous Carcinosarcoma of the Basal Cell Subtype Should Be Treated as a High—Risk
`Basal Cell Carcinoma
`
`Emilie Bourgeault, Jimmy Alain, and Eric Gagne’
`
`Chronic Larva Currens Following Tourist Travel to the Gambia and Southeast Asia Over 20 Years Ago
`Kristy E. Bailey, Alexis Dcmylo, and Andrea K. Boggild
`
`Deleterious Effect of Radiation Therapy on Epidermodysplasia Verruciformis Patients
`Wczlmar Roncalli de Oliveira, Lana Luiza da Cruz Silva, Cyro Festa Neto, and Stephen Tyring
`
`Erratum
`
`Erratum
`
`404
`
`407
`
`412
`
`416
`
`422
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`This material may be protected by Copyright law (Title 17 U 5 Code)
`
`The Rise and Fall of Oral Ketoconazole
`
`Aditya K. Gupta” and Danika C.A. Lyonsz
`
`Journal of Cutaneous Medicine and Surgery
`20|5, Vol. l9(4) 352-357
`© The Author(s) 20 I S
`Reprints and permissions:
`sagepub.com/journalsPermissions.nav
`DOI: l0.l l77/l2034754| 5574970
`jcms.sagepub.com
`
`fiifly
`Association
`Canadian
`Dermatology W (D canadiennede
`Association
`dermatologie
`Army;
`
`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 l<etoconazo|e in 20| l.
`
`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 20l3. The United States imposed strict relabeling requirements and restrictions for prescription, with Canada
`issuing a risk communication echoing these concerns. Today, oral
`|<etoconazole 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 '21 large spectre servant a traiter les mycoses systémique
`ou superficielles. Des preuves de son hépatoxicité ont émergé des les premieres années ayant suivi son approbation.
`L’accumu|ation de données probantes sur ses effets secondaires graves, entre autres des troubles endocriniens, plusieurs
`interactions médicamenteuses et le décés, a mené a une revue de ce médicament en 20| l.
`Objectif: Le présent article présente les usages du kétoconazole oral, depuis son arrivée en médecine jusqu’a son
`remplacement presque total.
`Conclusion : En raison de ses effets secondaires hépatotoxiques, le |<étoconazo|e oral a été retiré du marché en Europe
`et en Australie en 20l3. Les Etats-Unis ont imposé des conditions strictes relativement au nouveau libellé des indications
`approuvées et des restrictions a la prescription de ce médicament, tandis que le Canada a diffuse des communiqués sur les
`risques et les préoccupations soulevées par ce médicament. A l’heure actuelle,
`le kétoconazole oral n’est indiqué que pour
`traiter les mycoses endémiques, lorsqu’il n’existe aucune autre solution. ll reste que le kétoconazole oral est eflicace, sur et
`largement utilisé pour traiter les mycoses superficielles, notamment en traitement de premier recours du pityriasis versicolor.
`
`Keywords
`l<etoconazo|e, azole antifungal, history, hepatotoxic, indication
`
`Introduction
`
`The development of the first broad—spectru1n oral antifungal,
`ketoconazole (Nizoral), in l977 by Janssen Pharmaceutica
`represented an exciting new advancement
`in the field of
`medical mycology.' Ketoconazole received United States
`(US) Food and Drug Administration (FDA) clearance for use
`in systemic fungal infections in July 1981.25 It remained the
`only oral antifungal available for the treatment of systemic
`fungal
`infections for nearly a decade thereafter.3 Until
`recently, oral ketoconazole has been a mainstay of treatment
`for a plethora of superficial and systemic fungal infections.
`However, the drug was taken off the market in Europe and
`Australia in 2013 as a result ofthe risk ofserious hepatic side
`
`effects.” Similarly, strict restrictions and cautionary advise-
`ments were added to oral ketoconazole labelling in the US
`and Canada in 2013. Today, oral ketoconazole is recom-
`mended in these countries only in the event of severe or life-
`threatening systemic
`infections when alternatives
`are
`unavailable.7’8
`
`‘Department of Medicine, University of Toronto, Toronto. Canada
`2Mediprobe Research |nc., London, Ontario, Canada
`
`Corresponding Author:
`Aditya K. Gupta, Mediprobe Research Inc. 645 Windermere Road,
`London, ON, NSX 2Pl Canada.
`Email: agupta@execu|ink.com
`
`
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`Gupta and Lyons
`
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`O)03
`071-41
`
`2006
`205
`2002
`201
`* Not approved in Canada and U.S.
`** Not approved in Canada
`
`2014
`
`1903
`
`1944
`
`1951
`
`1953
`
`1958
`
`1969
`
`1974
`
`1977
`
`
`
`990
`
`1993
`
`1996
`
`I1
`
`Figure I. Timeline of major advancements in treating superficial and systemic mycoses.
`
`A Brief Historical Overview of the
`
`Development of Antifungals
`
`The first known account of successful treatment of a sys-
`
`temic mycosis was published in 1903 by de Beurmann and
`Gougerot, who effectively treated a case of sporotrichosis
`with potassium iodide.9‘l° It was not until almost 50 years
`later that the first noteworthy agent with antifungal proper-
`ties, nystatin, was discovered.l’l° In 1953,
`the polyene
`amphotericin B was developed and became the standard of
`comparison for therapies for systemic mycoses.l’”
`The antimicrobial properties of the most widely used anti-
`fungals today,
`the azoles, were first described in 1944.12
`These agents interfere with ergosterol biosynthesis, an essen-
`tial component of the fungal cell wall, through inhibition of
`the P450—dependent enzyme lanosterol 14-or-demethylase.3
`In 1958, chlormidazole was the first compound specifically
`developed and marketed as an antifungal. Chlormidazole’s
`development renewed research interest in the field of antimi-
`crobials. By 1969, developments in this field resulted in the
`adoption of 3 new azole antifungals, clotrimazole, micon—
`azolc, and econazole, into clinical practice.” Despite these
`advancements, the field of dermatology still lacked a broad-
`spectrtun antifungal agent (Figure 1).
`
`The Rise of Ketoconazole
`
`Ketoconazole, a broad—spectrum imidazole antifungal, was
`introduced in 1977 and received FDA approval in 198l.'3‘l4
`At the time of its approval, ketoconazole’s broad-spectrum
`activity presented clear advantages over established anti1ny-
`cotics in that it combined efficacy similar to miconazole with
`oral absorption akin to griseofulvin.l5‘l7 Like other imidazole
`compounds, ketoconazole interferes with ergosterol biosyn-
`thesis through inhibition of a P450—dependent enzyme,
`
`ultimately altering the structure and function of the cell
`wall.”’l8 Early in vitro studies de11ip3111st1rz1ted ketoconazole’s
`activit
`arainst
`dermato h tes,
`’ ” °“°
`casts l3‘”"'°‘2°
`molds,ll9 anld dimorphic ftttllgigol as well as soine bzicteria.l9
`Ketoconazole also demonstrated in vivo activity in animal
`models of oral and vaginal candidosis,l9‘2' cutaneous candi-
`-
`1920
`-
`-
`-
`20
`dosts,
`’
`and systemic candidosts.
`Multiple small clinical stttdies demonstrated the efficacy
`of oral ketoconazole as treatment for both systemic and
`
`superficial mycoses caused by yeasts and fungi, including
`dermatophytes (reviewed in Heel et alzl). At the time, the
`drug appeared to be well tolerated with most adverse effects
`occurring in <l% of stttdy participants. Nausea and vomiting
`(3%), pruritus (1.7%), and abdominal pain (1.3%) were the
`most frequently reported adverse side effects.“ The versatil-
`ity of oral ketoconazole led to its recognition as the most
`effective and most extensively prescribed oral azole antifun-
`gal of its time} It was also included in the World Health
`Organizations (WHO) Model List of Essential Medicines for
`many years.” However, concern over much more serious
`adverse reactions to oral ketoconazole soon catne to the
`forefront.“
`
`The Descent of Oral Ketoconazole
`
`The descent of oral ketoconazole began with the acknowl-
`edgment of symptomatic and asymptomatic hepatotoxicity
`associated with its use.” Evidence soon followed that sug-
`gested that ketoconazole may not only cause liver injury bttt
`also interfere with endocrine regulation.24’25 Finally,
`the
`potential for drug-drug interactions became apparent, as oral
`ketoconazole was found to alter the metabolism of concomi-
`tant medications via its effect on CYP3A enzy1nes.2(”28
`By the early 1980s, it was apparent that oral ketoconazole
`was associated with hepatic injury. In 1983, Janssen and
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`354
`
`journal of Cutaneous Medicine and Surgery I9(4)
`
`Symoenszs conducted an analysis of the incidence of sy1np—
`tomatic and asymptomatic (elevated liver enzymes with no
`clinical signs or symptoms) hepatic reactions to ketocon-
`azole reported worldwide from March 1981 to March 1982.
`The report suggested that hepatic abnormalities manifested
`most often as asymptomatic increases in liver enzyme levels.
`These abnormalities were transient, normalizing throughout
`the duration of treatment or following cessation of treatment.
`The report described 31 incidences of symptomatic hepatic
`reactions to oral ketoconazole. All symptomatic patients made
`a full recovery with the exception of 1 patient who died of
`hepatic necrosis.” A subsequent addendum to the publication
`described an additional 46 cases of symptomatic hepatic reac-
`tions to oral ketoconazole and an additional death by September
`1982.“ The authors estimated that 0.008% (1:12 000) of
`patients administered oral ketoconazole may suffer symp-
`tomatic hepatic side effects. Subsequent estimations of the
`incidence rate of symptomatic ketoconazole-induced liver
`injury ranged from 0.007% (1 :15 000)” to as high as 0.05%
`(1:2000)3° and 0.2% (1:500).“
`The recognition of ketoconazole-associated hepatotoxic-
`ity among scientists, physicians, and the general public led to
`debate regarding the proper prescription of oral ketoconazole
`and indications for the timing of treatment termination. For
`instance, in 1983, the Wall Street Journal described the out-
`rage and discontent of a local consumer advocacy organiza-
`tion, the Public Citizen’s Health Research Group (PCHRG),
`regarding ketoconazole.” The PCHRG was petitioning the
`FDA for additional warnings of hepatotoxicity on ketocon-
`azole packaging and cautioning physicians against off-label
`prescription of the drug for superficial mycoses. The group
`accused the FDA of failing to acknowledge the extent of the
`liver damage that ketoconazole had caused.” A representa-
`tive of the FDA assured the public that the package labelling
`of ketoconazole would be revised to include mention that 1
`
`in every 10 000 patients may suffer often reversible, but
`sometimes fatal, liver damage.”
`In the scientific community, some argued that asymptom-
`atic increases in liver enzyme levels were fleeting and did not
`warrant drug cessation unless clinical signs of liver injury
`developed.” Others argued that elevated liver enzyme levels
`were extremely serious and warranted treatment cessation once
`levels 3 times the upper limit of normal were reached, regard-
`less of whether or not patients were symptomatic.34’35 Bernuau
`et a135 noted that 3 incidences ofsudden hepatic failure occurred
`after treatment termination was delayed in spite of elevated
`liver enzymes. Furthermore, the incidence of acute liver injury
`associated with oral ketoconazole use was determined to be
`higher than any of the other oral antifungal medications.“ A
`meta—analysis of studies from 1979 to 2012 calculated the inci-
`dence of oral ketoconazole-associated hepatotoxicity to range
`from 3.6% (95% CI, 3.2-4.2) to 4.2% (95% CI, 3.7-4.9) and to
`be unrelated to dose and duration of treatment.“
`
`Endocrine dysregulation as a result of oral ketoconazole
`administration can lead to decreased testosterone production,
`
`decreased libido, gynecomastia, and oligospermia. By 1982,
`6 incidences of gynecomastia following ketoconazole treat-
`ment were documented.24’37 Subsequent in vitro investiga-
`tions
`revealed that ketoconazole
`inhibits
`testosterone
`synt11esis38‘3° and adrenal steroidogenesis.” Ketoconazole
`was thought to achieve its effects on testosterone synthesis
`and adrenal steroidogenesis through interference with P450-
`dependent enzy1nes.4°’41 It became clear that the activity of
`ketoconazole is not specific to P450-dependent
`fungal
`enzymes;
`rather,
`it may affect any mammalian P450-
`dependent enzyme, potentially leading to unforeseen inci-
`dences of adverse reaction or toxicity.
`Oral ketoconazole was also found to increase the risk of
`
`drug interactions as it is a potent inhibitor of the CYP3A4
`enzyme.'8 Therefore, co-administration with any agent that
`inhibits CYP3A4 may increase the bioavailability of keto-
`conazole and thereby increase the therapeutic and/or adverse
`effects of the drug.” Similarly, co-administration of ketocon-
`azole with any other drug metabolized by CYP3A4 may
`increase the blood plasma levels of that agent and prolong its
`effects.42’43 Conversely, agents that decrease gastric acidity
`or induce CYP3A4 may decrease the bioavailability and
`therapeutic effect of ketoconazole.44'47 As a result, many
`medications are contraindicated with ketoconazole, while
`others are simply not recommended or advised to be used
`with caution.”
`
`Ketoconazole Under Review:
`
`New Restrictions and Regulations
`Worldwide
`
`The use of oral ketoconazole was suspended in France in
`July 2011 after a review performed by the National Agency
`for the Safety of Medicine and Health Products (ANSM)
`deemed that its risks outweighed its therapeutic benef1ts.4
`This suspension triggered an EU-wide evaluation. Two years
`later,
`the European Medicines Agency (EMA) released a
`statement announcing the Committee on Medicinal Products
`for Human Use’s (CHMP) recommendation that oral keto-
`conazole’s marketing
`authorizations
`be
`suspended.4
`Additionally, the Australian government announced that oral
`ketoconazole would be dcregistered and discontinued as of
`December 1, 2013.5 Again, the risks of serious hepatotoxic-
`ity associated with oral ketoconazole use were believed to be
`higher than the benefits of its therapeutic effects.
`In July 2013, the US FDA announced their amendments to
`oral ketoconazole product labelling and warned against the
`use of oral ketoconazole as a first line of treatment. The new
`
`product monographs included a strong recommendation
`against the use of ketoconazole in patients with liver disease
`and introduced new recommendations for assessing and 1non—
`itoring liver function. Recommended testing prior to treat-
`ment
`includes baseline alanine aminotransferase (ALT),
`aspartate aminotransferase (AST),
`total bilirubin, alkaline
`phosphatase, prothrombin time, and international normalized
`
`
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`Gupta and Lyons
`
`355
`
`
`Table I. Summary of Worldwide Oral Ketoconazole Guidelines.“
`
`Canada (Health Canada)
`
`USA (FDA)
`
`EU (EMA)
`
`Australia (NPS)
`
`lndications
`
`Monitoring
`
`Serious or life-threatening
`systemic fungal infections
`when other options not
`available or tolerated
`
`Liver function tests before
`treatment, at weeks 2 and 4,
`monthly thereafter.
`
`Serious or life-threatening
`systemic fungal infections
`when other options not
`available or tolerated (not for
`skin or nails)
`Liver function tests before
`treatment, serum ALT
`monitored weekly, adrenal
`function monitored in select
`
`No longer prescribed
`
`Deregistered,
`discontinued
`
`Criteria to interrupt use
`
`patients.
`ALT at upper limit of normal
`Elevated liver parameters
`or 30% above baseline, or if
`(>3 times normal) or if
`symptoms of abnormal liver
`clinical signs/symptoms liver
`function
`disease develop
`
`“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 (1NR).8 The FDA recommended that oral ketoconazole
`be prescribed solely for endemic iriycoses and only when a
`suitable alternative is unavailable. Also, it is cautioned that
`current medications should be assessed for possible interac-
`tions with ketoconazole before it is prescribed.8
`Within the same year, Health Canada released a risk com-
`munication endorsing amendments to oral ketoconazole’s
`product monograph.7 The label now emphasizes the risk of
`hepatotoxicity and the need for liver function monitoring
`even when prescribed at
`the recommended dose and in
`patients with no preexisting liver abnormalities or serious
`medical conditions.7 As in the US, indications were revised
`such that oral ketoconazole is to be prescribed only for seri-
`ous or life-threatening systemic fungal infections and never
`prescribed to individuals with existing liver disease. The new
`restrictions and recommendations for North America and
`
`Europe are summarized in Table 1.
`
`Conclusion
`
`In 1977, the introduction of ketoconazole represented an
`exciting new advancement in the field of medical iriycology.
`Few effective therapeutic options to treat systemic mycoses
`were available at the time, and the development of new
`agents was at a near standstill. The therapeutic efficacy of
`ketoconazole against a wide range of fungi, dimorphic fungi,
`and yeasts led to widespread use in patients with superficial
`and systemic mycoses. Ketoconazole was heralded for many
`years as the only drug of its kind. Oral ketoconazole use
`would eventually wane as iriore evidence of hepatotoxicity,
`endocrine dysregulation, and drug interactions emerged.
`After over 30 years in clinical practice, the serious liepato—
`toxic risks posed by the drug(’ and the availability of less
`toxic alternatives led to revocation of marketing authoriza-
`tion in Europe and Australia,4’5 the imposition of strict
`
`prescription regulations in the US,8 and endorsement of this
`new safety information by Health Canada.7
`The decrease in popularity of oral ketoconazole for treat-
`ment of systemic mycoses has not left a gap in medical treat-
`mcnt. First- and second-generation triazoles with fewer
`safety concerns are effective treatment options for systemic
`mycoses (Figure l).48'5° Ketoconazole itself has not disap-
`peared from use in iriedical practice. Topical ketoconazole
`does not reach the systemic circulation and is a safe and
`effective therapy for dermatological C011(lltlO1lS.5l Topical
`formulations of ketoconazole cream, shampoo, and foam are
`particularly effective in treating superficial mycoses caused
`by Malassezia species. Topical ketoconazole serves as the
`first-line treatment for tinea versicolor and is also used
`
`treating
`in
`fol1iculitis.52’53
`
`seborrheic
`
`dermatitis
`
`and Malassezia
`
`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,
`oral ketoconazole represented the beginning of a new era of
`research and development of antiiriycotic agents, without
`which, the treatment options for superficial and systemic
`mycoses that we have today would not exist (Figure 1).
`
`Declaration of Conflicting Interests
`
`The autlior(s) declared no potential conflicts of interest with respect
`to the research, authorship, and/or publication of this article.
`
`Funding
`
`The authoi‘(s) received no financial support for the research, author-
`ship, and/or publication of this article.
`
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