574970 research-article2015
CMSXXX10.1177/1203475415574970Journal of Cutaneous Medicine and SurgeryGupta and Lyons
Review
The Rise and Fall of Oral Ketoconazole
Journal of Cutaneous Medicine and Surgery 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1203475415574970 jcms.sagepub.com
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 Conclusion: Due to its hepatotoxic side effects, oral ketoconazole was withdrawn from the European and Australian markets in 2013.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 The development of the first broad-spectrum oral antifungal, ketoconazole (Nizoral), in 1977 by Janssen Pharmaceutica represented an exciting new advancement in the field of medical mycology.1 Ketoconazole received United States (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 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 of the risk of serious hepatic side
effects.4-6 Similarly, strict restrictions and cautionary advisements were added to oral ketoconazole labelling in the US and Canada in 2013. Today, oral ketoconazole is recommended in these countries only in the event of severe or lifethreatening systemic infections when alternatives are unavailable.7,8 1
Department of Medicine, University of Toronto, Toronto, Canada Mediprobe Research Inc., London, Ontario, Canada
2
Corresponding Author: Aditya K. Gupta, Mediprobe Research Inc, 645 Windermere Road, London, ON, N5X 2P1 Canada. Email: [email protected]
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 Development of Antifungals The first known account of successful treatment of a systemic mycosis was published in 1903 by de Beurmann and Gougerot, who effectively treated a case of sporotrichosis with potassium iodide.9,10 It was not until almost 50 years later that the first noteworthy agent with antifungal properties, nystatin, was discovered.1,10 In 1953, the polyene amphotericin B was developed and became the standard of comparison for therapies for systemic mycoses.1,11 The antimicrobial properties of the most widely used antifungals today, the azoles, were first described in 1944.12 These agents interfere with ergosterol biosynthesis, an essential component of the fungal cell wall, through inhibition of the P450-dependent enzyme lanosterol 14-α-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 antimicrobials. By 1969, developments in this field resulted in the adoption of 3 new azole antifungals, clotrimazole, miconazole, and econazole, into clinical practice.10 Despite these advancements, the field of dermatology still lacked a broadspectrum antifungal agent (Figure 1).
The Rise of Ketoconazole Ketoconazole, a broad-spectrum imidazole antifungal, was introduced in 1977 and received FDA approval in 1981.13,14 At the time of its approval, ketoconazole’s broad-spectrum activity presented clear advantages over established antimycotics in that it combined efficacy similar to miconazole with oral absorption akin to griseofulvin.15-17 Like other imidazole compounds, ketoconazole interferes with ergosterol biosynthesis through inhibition of a P450-dependent enzyme,
ultimately altering the structure and function of the cell wall.14,18 Early in vitro studies demonstrated ketoconazole’s activity against dermatophytes,13,16,19,20 yeasts,13,16,19,20 molds,19 and dimorphic fungi20 as well as some bacteria.19 Ketoconazole also demonstrated in vivo activity in animal models of oral and vaginal candidosis,19,21 cutaneous candidosis,19,20 and systemic candidosis.20 Multiple small clinical studies 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 al21). At the time, the drug appeared to be well tolerated with most adverse effects occurring in 3 times normal) or if or 30% above baseline, or if clinical signs/symptoms liver symptoms of abnormal liver disease develop function
Australia (NPS) Deregistered, discontinued
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 be prescribed solely for endemic mycoses and only when a suitable alternative is unavailable. Also, it is cautioned that current medications should be assessed for possible interactions with ketoconazole before it is prescribed.8 Within the same year, Health Canada released a risk communication 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 serious 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 mycology. 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 more evidence of hepatotoxicity, endocrine dysregulation, and drug interactions emerged. After over 30 years in clinical practice, the serious hepatotoxic risks posed by the drug6 and the availability of less toxic alternatives led to revocation of marketing authorization 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 treatment of systemic mycoses has not left a gap in medical treatment. First- and second-generation triazoles with fewer safety concerns are effective treatment options for systemic mycoses (Figure 1).48-50 Ketoconazole itself has not disappeared from use in medical practice. Topical ketoconazole does not reach the systemic circulation and is a safe and effective therapy for dermatological conditions.51 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 in treating seborrheic dermatitis and Malassezia folliculitis.52,53 Today, oral ketoconazole is now only recommended as a second line of treatment for the most severe systemic mycoses when viable alternatives are unavailable. Despite its fate, oral ketoconazole represented the beginning of a new era of research and development of antimycotic 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 author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part I. J Am Acad Dermatol. 1994;30:677-700.
Gupta and Lyons 2. Food and Drug Administration. Label and approval history. http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index .cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Accessed February 12, 2015. 3. Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2004;10(suppl 1):1-10. 4. European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. Eur Med Agency. 2013;1-3. 5. Administration AGD of HTG. Oral ketoconazole (Nizoral) 200 mg tablets. http://www.tga.gov.au/safety/alerts-medicine-oral-ketoconazole-131010.htm#.U0gmjfldWCk. Accessed April 11, 2014. 6. Gupta AK, Daigle D, Foley KA. Drug safety assessment of oral formulations of ketoconazole. Expert Opin Drug Saf. 2014;1-10. 7. Health Canada. Health Canada endorsed important safety information on ketoconazole. http://healthycanadians.gc.ca/ recall-alert-rappel-avis/hc-sc/2013/34173a-eng.php. Published 2013. Accessed May 30, 2014. 8. Food and Drug Administration. 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. http://www.fda.gov/drugs/drugsafety/ucm362415. htm. Published July 26, 2013. Accessed February 12, 2015. 9. Utz JP. Chemotherapy for the systemic mycoses: the prelude to ketoconazole. Rev Infect Dis. 1980;2:625-632. 10. Fromtling RA. Overview of medically important antifungal azole derivatives. Clin Microbiol Rev. 1988;1:187-217. 11. Dutcher JD. The discovery and development of amphotericin B. Dis Chest. 1968;54(suppl 1):296-298. 12. Woolley DW. Some biological effects produced by benzimidazole and their reversal by purines. J Biol Chem. 1944;152:225-232. 13. Dixon D, Shadomy S, Shadomy HJ, Espinel-Ingroff A, Kerkering TM. Comparison of the in vitro antifungal activities of miconazole and a new imidazole, R41,400. J Infect Dis. 1978;138:245-248. 14. Van den Bossche H, Willemsens G, Cools W, Cornelissen F, Lauwers WF, van Cutsem JM. In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrob Agents Chemother. 1980;17:922-928. 15. Botter AA, Dethier F, Mertens RL, Morias J, Peremans W. Skin and nail mycoses: treatment with ketoconazole, a new oral antimycotic agent. Mykosen. 1979;22:274-278. 16. Odds FC, Milne LJ, Gentles JC, Ball EH. The activity in vitro and in vivo of a new imidazole antifungal, ketoconazole. J Antimicrob Chemother. 1980;6:97-104. 17. Graybill JR, Drutz DJ, Murphy AL. Ketoconazole: a major innovation for treatment of fungal disease. Ann Intern Med. 1980;93:921-923. 18. Drugs@FDA: FDA approved drug products. http://www .accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= Search.Label_ApprovalHistory. Accessed April 28, 2014. 19. Heeres J, Backx LJ, Mostmans JH, Van Cutsem J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J Med Chem. 1979;22:1003-1005. 20. Thienpont D, Van Cutsem J, Van Gerven F, Heeres J, Janssen PA. Ketoconazole—a new broad spectrum orally active antimycotic. Experientia. 1979;35:606-607. 21. Heel RC, Brogden RN, Carmine A, Morley PA, Speight TM, Avery GS. Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs. 1982;23:1-36.
5 22. Janssen Pharmaceutica NV. Business information, profile, and history. http://companies.jrank.org/pages/2250/JanssenPharmaceutica-N-V.html. Accessed May 26, 2014. 23. Janssen PA, Symoens JE. Hepatic reactions during ketoconazole treatment. Am J Med. 1983;74:80-85. 24. DeFelice R, Johnson DG, Galgiani JN. Gynecomastia with ketoconazole. Antimicrob Agents Chemother. 1981;19:10731074. 25. Sugar AM, Alsip SG, Galgiani JN, et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother. 1987;31:1874-1878. 26. Craven PC. Interaction of ketoconazole with rifampin and isoniazid. N Engl J Med. 1985;312:1061. 27. D’Mello AP, D’Souza MJ, Bates TR. Pharmacokinetics of ketoconazole-antipyrine interaction. Lancet. 1985;2:209210. 28. Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol. 2014;54:1321-1329. 29. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology. 1984;86:503-513. 30. Stricker BH, Blok AP, Bronkhorst FB, Van Parys GE, Desmet VJ. Ketoconazole-associated hepatic injury. A clinicopathological study of 55 cases. J Hepatol. 1986;3:399-406. 31. García Rodríguez LA, Duque A, Castellsague J, Pérez Gutthann S, Stricker BH. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999;48:847-852. 32. Johnson & Johnson unit agrees to stiffen nizoral label warnings. Wall Street Journal. http://search.proquest.com.proxy1. lib.uwo.ca/docview/134874933/abstract/E1F9C9D5D6D14C B7PQ/5?accountid=15115. Accessed May 21, 2014. 33. Chien RN, Yang LJ, Lin PY, Liaw YF. Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatol Baltim Md. 1997;25:103-107. 34. Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole in the United Kingdom. Br Med J Clin Res Ed. 1987;294:419-422. 35. Bernuau J, Durand F, Pessayre D. Ketoconazole-induced hepatotoxicity. Hepatol Baltim Md. 1997;26:802. 36. Yan JY, Nie XL, Tao QM, Zhan SY, Zhang YD. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci BES. 2013;26:605-610. 37. Stevens DA, Stiller RL, Williams PL, Sugar AM. Experience with ketoconazole in three major manifestations of progressive coccidioidomycosis. Am J Med. 1983;74:58-63. 38. Pont A, Williams PL, Loose DS, et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med. 1982;97:370-372. 39. Rajfer J, Sikka SC, Rivera F, Handelsman DJ. Mechanism of inhibition of human testicular steroidogenesis by oral ketoconazole. J Clin Endocrinol Metab. 1986;63:1193-1198. 40. Santen RJ, Van den Bossche H, Symoens J, Brugmans J, DeCoster R. Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab. 1983;57:732-736. 41. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D. Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest. 1983;71:1495-1499. 42. Boxenbaum H. Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated
6 with high clearance drugs in general. J Pharm Pharm Sci Publ Can Soc Pharm Sci Société Can Sci Pharm. 1999;2:47-52. 43. Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther. 1999;66:374379. 44. Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet. 1988;14:13-34. 45. Chin TW, Loeb M, Fong IW. Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole. Antimicrob Agents Chemother. 1995;39:1671-1675. 46. Hoeschele JD, Roy AK, Pecoraro VL, Carver PL. In vitro analysis of the interaction between sucralfate and ketoconazole. Antimicrob Agents Chemother. 1994;38:319-325. 47. Ford N, Lee J, Andrieux-Meyer I, Calmy A. Safety, efficacy, and pharmacokinetics of rilpivirine: systematic review with an emphasis on resource-limited settings. HIVAIDS Auckl NZ. 2011;3:35-44.
Journal of Cutaneous Medicine and Surgery 48. Fera MT, La Camera E, De Sarro A. New triazoles and echinocandins: mode of action, in vitro activity and mechanisms of resistance. Expert Rev Anti Infect Ther. 2009;7:981-998. 49. Marques SA. Paracoccidioidomycosis: epidemiological, clinical, diagnostic and treatment up-dating. An Bras Dermatol. 2013;88: 700-711. 50. Welsh O, Vera-Cabrera L, Rendon A, Gonzalez G, Bonifaz A. Coccidioidomycosis. Clin Dermatol. 2012;30:573-591. 51. Janssen Pharmaceutica. Nizoral (ketoconazole) 2% shampoo. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/ 019927s032lbl.pdf. Accessed November 11, 2014. 52. Gupta AK, Lyons DCA. Pityriasis versicolor: an update on pharmacological treatment options. Expert Opin Pharmacother. 2014;15:1707-1713. 53. Hald M, Arendrup MC, Svejgaard EL, Lindskov R, Foged EK, Saunte DML. Evidence-based Danish guidelines for the treatment of malassezia-related skin diseases. Acta Derm Venereol. 2014;95:12-19.
CMSXXX10.1177/1203475415574970Journal of Cutaneous Medicine and SurgeryGupta and Lyons
Review
The Rise and Fall of Oral Ketoconazole
Journal of Cutaneous Medicine and Surgery 1–6 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1203475415574970 jcms.sagepub.com
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 The development of the first broad-spectrum oral antifungal, ketoconazole (Nizoral), in 1977 by Janssen Pharmaceutica represented an exciting new advancement in the field of medical mycology.1 Ketoconazole received United States (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 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 of the risk of serious hepatic side
effects.4-6 Similarly, strict restrictions and cautionary advisements were added to oral ketoconazole labelling in the US and Canada in 2013. Today, oral ketoconazole is recommended in these countries only in the event of severe or lifethreatening systemic infections when alternatives are unavailable.7,8 1
Department of Medicine, University of Toronto, Toronto, Canada Mediprobe Research Inc., London, Ontario, Canada
2
Corresponding Author: Aditya K. Gupta, Mediprobe Research Inc, 645 Windermere Road, London, ON, N5X 2P1 Canada. Email: [email protected]
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 Development of Antifungals The first known account of successful treatment of a systemic mycosis was published in 1903 by de Beurmann and Gougerot, who effectively treated a case of sporotrichosis with potassium iodide.9,10 It was not until almost 50 years later that the first noteworthy agent with antifungal properties, nystatin, was discovered.1,10 In 1953, the polyene amphotericin B was developed and became the standard of comparison for therapies for systemic mycoses.1,11 The antimicrobial properties of the most widely used antifungals today, the azoles, were first described in 1944.12 These agents interfere with ergosterol biosynthesis, an essential component of the fungal cell wall, through inhibition of the P450-dependent enzyme lanosterol 14-α-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 antimicrobials. By 1969, developments in this field resulted in the adoption of 3 new azole antifungals, clotrimazole, miconazole, and econazole, into clinical practice.10 Despite these advancements, the field of dermatology still lacked a broadspectrum antifungal agent (Figure 1).
The Rise of Ketoconazole Ketoconazole, a broad-spectrum imidazole antifungal, was introduced in 1977 and received FDA approval in 1981.13,14 At the time of its approval, ketoconazole’s broad-spectrum activity presented clear advantages over established antimycotics in that it combined efficacy similar to miconazole with oral absorption akin to griseofulvin.15-17 Like other imidazole compounds, ketoconazole interferes with ergosterol biosynthesis through inhibition of a P450-dependent enzyme,
ultimately altering the structure and function of the cell wall.14,18 Early in vitro studies demonstrated ketoconazole’s activity against dermatophytes,13,16,19,20 yeasts,13,16,19,20 molds,19 and dimorphic fungi20 as well as some bacteria.19 Ketoconazole also demonstrated in vivo activity in animal models of oral and vaginal candidosis,19,21 cutaneous candidosis,19,20 and systemic candidosis.20 Multiple small clinical studies 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 al21). At the time, the drug appeared to be well tolerated with most adverse effects occurring in 3 times normal) or if or 30% above baseline, or if clinical signs/symptoms liver symptoms of abnormal liver disease develop function
Australia (NPS) Deregistered, discontinued
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 be prescribed solely for endemic mycoses and only when a suitable alternative is unavailable. Also, it is cautioned that current medications should be assessed for possible interactions with ketoconazole before it is prescribed.8 Within the same year, Health Canada released a risk communication 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 serious 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 mycology. 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 more evidence of hepatotoxicity, endocrine dysregulation, and drug interactions emerged. After over 30 years in clinical practice, the serious hepatotoxic risks posed by the drug6 and the availability of less toxic alternatives led to revocation of marketing authorization 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 treatment of systemic mycoses has not left a gap in medical treatment. First- and second-generation triazoles with fewer safety concerns are effective treatment options for systemic mycoses (Figure 1).48-50 Ketoconazole itself has not disappeared from use in medical practice. Topical ketoconazole does not reach the systemic circulation and is a safe and effective therapy for dermatological conditions.51 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 in treating seborrheic dermatitis and Malassezia folliculitis.52,53 Today, oral ketoconazole is now only recommended as a second line of treatment for the most severe systemic mycoses when viable alternatives are unavailable. Despite its fate, oral ketoconazole represented the beginning of a new era of research and development of antimycotic 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 author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part I. J Am Acad Dermatol. 1994;30:677-700.
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