Fluconazole for the Treatment of Onychomycosis: an Update

Review Fluconazole for the treatment of onychomycosis: an update

Aditya K. Gupta, MD, FRCP(C), Richard K. Scher, MD, FACP, and Phoebe Rich, MD

From the Division of Dermatology, Department of Medicine, Sunnybrook Health Science Center and the University of Toronto, Toronto, Canada, Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York, and Department of Dermatology, Oregon Health Sciences University, Portland, Oregon

Correspondence Aditya K. Gupta, MD, FRCP(C), Suite 6, 490 Wonderland Road South, London, Ont., N6K 1L6, Canada E-mail: [email protected]

Introduction The corresponding levels in the plasma were 0.76 Ilg! mL and 2. I 2 ug/ml., respectively. The fluconazole Onychomycosis is a common nail disorder thought to concentration in the nail plate increases with the length occur in approximately 7-9% of the North American of therapy, with the drug concentration being comparable population.v" Until quite recently, there was a paucity in both plate and plasma at the end of treatment.8 of effective and safe therapies for onychomycosis, particu Faergemann and Laufen? measured fluconazole concentra larly pedal disease. Griseofulvin was the first significant tions in fungal toenails of 36 patients treated using a oral antifungal agent to become available for the treatment regimen of 150 mg once weekly for 12 months, or of onychomycosis.v? Since then, other oral antifungal stopping therapy earlier if cured. During treatment, there agents have been reported for use in this disorder: was no statistically significant difference between healthy . ketoconazole, itraconazole, terbinafine, and fluconazole. and diseased nails." however, the concentration of In this article, the literature pertaining to fluconazole fluconazole in nails was significantly higher than that in therapy for the management of onychomycosis is serum. After I and 6 months of therapy, the mean reviewed. The advantages of fluconazole include its high concentrations of fluconazole in healthy nails were efficacy rate, low relapse rate, broad action spectrum, 3.09 Ilg!g and 8.54 ug/g, respectively.? In contrast, the weekly treatment regimen that results in high compliance, serum concentration of fluconazole remained more or and a favorable adverse effects profile. less stable at 0.45-1.36 ug/rnl, during therapy. Six Fluconazole was first approved in France and the UK months following discontinuation of the drug, fluconazole in 1988 for systemic mycoses. It is estimated that concentrations in healthy and diseased toenails were fluconazole has now been used more than 50 million 1.4 Ilg!g and 1.9 ug/g, respectively (n = 3 patients}? times worldwide (Pfizer, USA, personal communication, The data suggest that there is the potential for ongoing May 1997). improvement in onychomycosis even after discontinuation of active drug therapy. Pharmacokinetics The pharmacokinetics of fluconazole in onychomycosis have also been studied in a dose-finding, placebo The pharmacokinetics of once weekly fluconazole suggest controlled study where fluconazole (150 mg, 300 mg, that it should be effective in the management of 450 mg) or matching placebo was administered once onychomycosis. It rapidly enters the nail plate once weekly for the treatment of onychomycosis of the toes."? treatment is initiated. Hay8 measured fluconazole in the Rich et al,'? detected fluconazole in both healthy and nail plate within I day of starting the drug, 50 mg once affected nails within 2 weeks of starting therapy in weekly, for 14 consecutive days. On days I and 14 after nearly all patients (n = 151). This confirmed the earlier starting therapy, the concentrations of fluconazole in the reports of the rapid uptake of fluconazole into the nail nail plate were 1.3I ug/g and 1.80 ug/g, respectively. 8 plate by H ay8 as well as Faergemann and Laufen.? In 815

© 1998 Blackwell Science Ltd International Journal of Dermatology 1998,37,815-820 ~ '" s :II en '3 ~. til ~ g' c-n !l!. o o ~ Table 1 Efficacy of fluconazole in immunocompetent adults (;n8 years old) with dermatophyte toenail :::> ~ § o !l!. ro ~ Study Type of trial No. of patients Dose of fluconazole Duration of Efficacy Adjunctive therapy Sf ~ therapy o '<:::> ~ Clinical response Clinical cure Mycologic cure o til ::Y o 3 Coldirorr'" Open 2 100 mg alternate days 3 months Yes Yes No -c o I (1 patient) o to CIi' to .00 100 mgldayx2 weeks, 14 weeks Yes Yes, recurrence 8 Yes Nail avulsion then 100 mg alternate weeks later .-.1'" 00 daysx14 weeks (J1 I (1 patient) 00 I\) o Hochman et al.28 Open 1 (excluded: 4 with 100 mg daily 24 weeks Yes Yes Yes No fingemail onychomycosis)

Assaf and Open 4 with toenail disease 200 or 300 mg once Mean duration: Yes Yes Mycologic 3 of 5 patients treated Elewski29 (excluded: 2 were weekly 6 months assessment not with topical antifungals culture negative; 5 performed at end as well with fingernail disease) of therapy

Montero-Gei3o Open 72 evaluable 150 mg per week for Mean duration: 63/72 at follow-up 52/72 at follow-up 56/72 at follow-up None 3-12 months 33.1 weeks (87%) (72%) (79%)

Friki et al.33 Open At long-term follow-up: 150 mg per week 5-12 months 85/104 at 6-month 63/104 at 6-month 78/102 at 6-month Alternate patients: 104 were clinically follow-up (81.7%) follow-up (60.6%) follow-up (76.5%) pedicure with 40% assessable and 102 urea topical bandage were mycologically assessable

Scher32 See text

@ Exclusions: Aihara et al.:25 children with hyperimmunoglobulin E; Nahass and Sistor'" renal transplant patient with fingernail onychomycosis; Kuokkanen and to to Alavar'? efficacy reported according to the number of toenails and fingernails, not according to the number of patients; Smith et al.v? culture positive derrnatophytes 00 G) (IJ were not isolated. iii -§ o A jii :;: ~ ~ ::0- (f) o .~ iii til :::> :::J o Q CD r:;: Q. ~ Gupta, Scher, and Rich Fluconazole for onychomycosis Review 817

Table 2 Main drug interactions with fluconazole3s- 38

Drug Interaction

Terfenadine See text Cisapride When fluconazole coadministered with cisapride, there have been reports of cardiac events including torsades de pointes. Cisparide is contraindicated with fluconazole Astemizole Definitive interaction studies with fluconazole have not been conducted, Use of fluconazole may be associated with elevations in serum levels of astemizole. Caution should be exercised when coadministering fluconazole with astemizole. Patients should be carefully monitored Oral hypoglycemics See text Cimetidine Oral cimetidine decreases fluconazole level Warfarin Increase in prothrombin time response Phenytoin Increase in phenytoin level Cyclosporine Increase in cyclosporine levels, decrease in apparent oral clearance Theophylline Increase in theophylline levels with decreased clearance Zidovudine Increase in zidovudine levels Rifabutin Increase in rifabutin levels, may not be of clinicai significance. Rifabutin dosing may not need to be modified in patients receiving fluconazole Hydrochlorothiazide Increase in fluconazole level due to reduced renal clearance Rifampin Decrease in fluconazole with an increase in its apparent oral clearance Oral contraceptives See text

The above is only a guideline of the main interactions. In some cases, studies may not have been conducted with other medications, but such interactions may occur. Consult up-to-date product monograph and other authoritative texts before prescribing.

2 23 the three groups treated with active drug, Rich et at. 10 zole. 0- This allows for a once weekly dosing regimen reported that 8 months after starting therapy, the ratio to be used with fluconazole therapy for both onycho of fluconazole in the nails to plasma ranged from 1.3 I mycosis and other dermatomycoses. to 1.5. These results, where higher concentrations of fluconazole are present in the nail compared with plasma, Efficacy are similar to the data reported by Faergemann and Laufen.? Rich"? also found that, after fluconazole therapy Fluconazole has been shown to be effective and safe for was stopped, the concentrations of the active drug in the treatment of onychomycosis in case reports, open toenails decreased gradually with elimination half-lives and double-blind studies (Table I). 4-33 in the. 150 mg, 300 mg, and 450 mg groups of 2.5, A placebo-controlled, randomized, double-blind, dose 2·4, and 3.7 months, respectively. In fact, in most finding trial has recently been completed where once subjects, fluconazole could still be detected in the nail weekly doses of fluconazole (150 mg, 300 mg, 450 mg) plate 6 months after therapy was discontinued. were prescribed to treat distal and lateral subungual Fluconazole has several other pharmacokinetic proper onychomycosis of the toeY Scher P randomized 362 ties that are of benefit to patients being treated for patients with mycologically confirmed dermatophyte onychomycosis.II Its bioavailability when taken orally is onychomycosis to receive fluconazole, 150 mg, 300 mg, at least 90%. It is important to note that the absorption or 450 mg once weekly, for a maximum of 12 months. of orally administered fluconazole is not reduced in the To be included in the study the target toenail had to be presence of antacids,I2,I3 by the concurrent intake of a at least 25% involved and have at least 2 mm of healthy histarnine-z receptor (Hj-receptor] antagonist.Hi"! or in nail along the proximal nail foldY For those patients patients who experience frequent vomiting.I" Fluconazole who were cured, the average time to cure was 6 has a relatively low lipophilicity and distributes widely 7 months, with significant clinical improvement being to body tissues and fluids."? In healthy volunteers, it noted as early as 3 months after starting therapy. At the shows approximately 12% plasma protein binding.V end of treatment, clinical success (defined as cure or Unlike the other azoles ketoconazole and itraconazole, improvement sufficient to reduce the involved target area fluconazole is eliminated predominantly by the renal of the nail to < 25%) occurred in 86% (150 mg group, rather than hepatic route.':' Its half-life of approximately n = 79), 87% (300 mg group, n = 75), and 89% 30 h is longer than those of ketoconazole and itracona- (450 mg group, n = 80) patients, respectivelyY Clinical

success was recorded in only 8% of the placebo group. severity, the most common being, for the fluconazole vs. At the 6-month post-treatment assessment, clinical success placebo groups, headache (6% vs. 2%), abdominal pain in the 150 mg, 300 mg, and 450 mg groups was 77%, (4% vs. 3%), respiratory disorders (4% vs. 3%), diarrhea 79%, and 86%, respectively. The corresponding value (3% vs. 2%)', eruption (3% vs. 2%), and nausea (2% for the placebo group was 3%. There was no statistical vs. 3%).32 Fluconazole was discontinued due to a significance between the three fluconazole dosage groups laboratory abnormality in the following proportions of in the rate of clinical success.P At this time point, the patients: 150 mg group (1%, AR to fluconazole: 0%), clinical relapse in the 150 mg, 300 mg, 450 mg, and 300 mg group (2%, AR: 1%), 450 mg group (1%, AR: placebo groups was 0%, 5%, 7%, and 0%, respectively.P 0%), and placebo (1%))2 The changes in the median In addition, the end-of-treatment mycologic responses laboratory values in the fluconazole and placebo groups in the 150 mg (n = 79), 300 mg (n = 75), 450 mg were similar; none of the changes in the laboratory (n = 79) and placebo (n = 78) groups were 47%, 59%, parameters in the active drug group were clinically 62 %, and 14%, respectively.P The time to mycologic significant. Five patients (four in the fluconazole group cure was 10.1 months in the 150 mg group, 8.8 months and one in the placebo group) discontinued the study in the 300 mg group, and 9.6 months in the 450 mg due to LFT abnormalities. The changes in the LFTs were group.s' At follow-up, 6 months after the completion of considered to be drug-related in the following instances: active therapy, the mycologic cure rates in the 150 mg, 150 mg group (one patient), 300 mg group (one patient), 300 mg, 450 mg, and placebo groups were 53%, 59%, and placebo group (one patient). 61%, and 16%, respectively. Other studies suggest that fluconazole may also be effective in onychomycosis Drug interactions (Table 2) 5-38 associated with Candida species29,F ,34 and nondermato phyte molds.t' and in chronic mucocutaneous can The clinical significance of fluconazole tablets coadminis didiasis.tt tered with ethinyl estradiol- and levonorgestrel-containing oral contraceptives is presently unknown. In some patients, there were decreases of up to 47% and 33 % Adverse effects in ethinyl estradiol and levonorgestrellevels. The decreases The data on the adverse effects profile of fluconazole in some individual ethinyl estradiol and levonorgestrel when used for the treatment of onychomycosis can be area under the curve (AUq values with fluconazole derived from single case reports, open and double-blind treatment are probably the result of random variation. trials.8,24-3 2 In considering the first two categories, there While fluconazole may inhibit the metabolism of ethinyl are several reports on the treatment of onychomycosis, estradiol and levonorgestrel, there is no evidence that it with a total of 143 patients on whom adverse effects is a net inducer of ethinyl estradiol or levonorgestrel data are available. While not all the protocols are metabolism. identical, they are similar enough to allow the grouping Coadministration of terfenadine is contraindicated in together of adverse effects data so that a better idea of patients receiving fluconazole at multiple doses of 400 mg the safety profile of fluconazole when used to treat or higher. Also, coadministration with cisparide is onychomycosis can be obtained. In nine published contraindicated. reports,8,24-3 I adverse effects were observed in seven Fluconazole may interact with sulfonylurea hypo (4.9%) of 143 patients. These included nausea, headaches glycemic agents (e.g. tolbutamide, glipizide, and glyburide) (two patients, one discontinued treatment), insomnia, and produce hypoglycemia. In some instances, the drug palpitations (patient discontinued therapy), pruritus, interaction may occur through the cytochrome P450 2C9 sweating, fever, and elevation of liver function tests subfamily. (LITs) (in one patient who discontinued therapy and LFTs returned to normal). In these reports, three (2.1%) Conclusions of 143 patients discontinued therapy.8,24-F . Smith et aty noted that the majority of the adverse events in Fluconazole administered once weekly has been found their patients receiving fluconazole occurred within the to be effective in onychomycosis. The drug is detectable first month. in toenails for 6 months or even longer following the It is always preferable to compare the adverse effects discontinuation of therapy (150 mg or 300 mg adminis associated with any drug with placebo. In a recent dose tered once weekly until complete clinical and mycologic finding study where once weekly fluconazole (150 mg, cure was obtained, or for a maximum period of 300 mg, 450 mg) or placebo was given for onychomycosis, 12 months). The relapse rate of onychomycosis is low. the adverse events were generally mild to moderate III The preferred once weekly dosage may be 150 mg or

300 mg for the treatment of pedal onychomycosis. fluconazole and ketoconazole. Ann Intern Med 1991; Fluconazole has a favorable adverse effects profile with 114: 755-757· 15 Lim SG, Sawyerr AM, Hudson M, et al. Short report: a high compliance to the treatment regimen. The drug the absorption of fluconazole and itraconazole under is an important addition to the armamentarium of oral conditions of 'low intragastric acidity. Aliment agents available to treat onychomycosis. Pharmacol Ther 1993; 7: 317-321. 16 Schafer-Korting M. Pharmacokinetic optimization of oral antifungal therapy. Clin Pharmacokinet 1993; 25: References 329-341. I Gupta AK, Jain HC, Lynde CW, et al. Prevalence of 17 Debruyne 0, Ryckelynck J-P. Clinical pharmacokinetics unsuspected onychomycosis in patients visiting of fluconazole. Clin Pharmacokinet 1993; 24: 10-27. dermatologists' offices in Ontario, Canada-a 18 Humphrey MJ, Jevons S, Tarbit MH. Pharmacokinetic multicenter survey of 2001 patients. Int ] Dermatol evaluation of UK-49, 858, a metabolically stable 1997; 36: 783-787. triazole antifungal drug, in animals and humans. 2 Charif MA, Elewski BE. The prevalence of Antimicrob Agents Chemother 1985; 028: 648-653. onychomycosis in Northeastern Ohio. Arch Dermatol 19 Lazar JD, Hilligoss OM. The clinical pharmacology of 1997; 133: II72-II73· fluconazole. Semin Oncol 1990; 3 (Suppl, 6): 14-18. 3 Gupta AK, Scher RK. Management of onychomycosis: 20 Ripa S, Ferrante L, Prenna M. Pharmacokinetics of a North American perspective. Dermatologic Ther fluconazole in normal volunteers. Chemotherapy 1993; 1997; 3: 58-65' 39: 6-12. 4 Gupta AK, Scher RK, De Doncker P. Current 21 Hardin TC, Graybill JR, Fetchick R, et al. management of onychomycosis: an overview. Derm Pharmacokinetics of itraconazole following oral Clinics 1997; IS: 121-135· administration to normal volunteers. Antimicrob 5 Gupta AK, Sauder ON, Shear NH. Antifungal agents: Agents Chemother 1988; 32: 1310-1313. an overview. Part 1. ] Am Acad Dermatol 1994; 30 : 22 Heel RC, Bragden RN, Carmine A, et al. 677-69 8. Ketoconazole: a review of its therapeutic efficacy in 6 Gupta AK, Sauder ON, Shear NH. Antifungal agents: superficial and systemic fungal infections. Drugs 1982; an overview. Part II. ] Am Acad Dermatol 1994; 30: 23: 1-3 6. 9 II-933· 23 Van Cauteren H, Heykants J, De Coster R, 7 Gupta AK, Scher RK. Oral antifungal agents for Cauwenbergh G. Itraconazole: pharmacologic studies onychomycosis. Lancet 1998; 351: 541-542. in animals and humans. Rev Infect Dis 1987; 9 8 Hay RJ. Pharmacokinetic evaluation of fluconazole in (Supp!.): 43-46. skin and nails. lnt ] Dermatol 1992; 3I (Supp!. 2): 24 Coldiron B. Recalcitrant onychomycosis of the toenails 6-7· successfully treated with fluconazole. Arch Dermatol 9 Faergemann J, Laufen H. Levels of fluconazole in 1992; 28: 9°9-910. diseased and normal nails during and after treatment 25 Aihara Y, Mori M, Yokota S. Successful treatment of of onychomycosis in toe-nails with fluconazole 150 mg onychomycosis with fluconazole in two patients with once weekly. Acta Dermatol Venereol (Stockh) 1996; hyperimmunoglobulin E syndrome. Pediat Dermatol 76: 219-221. 199 6; 13: 493-495· 10 Rich P. Pharmacokinetics of three doses of once 26 Nahass GT, Sisto M. Onychomycosis: successful weekly fluconazole (150, 300, and 450 mg) in the treatment with once-weekly fluconazole. Dermatology management of distal subungual onychomycosis of the 1993; 186: 59-61. toenai!. ] Am Acad Dermatol 1998; 38: SI03-S109. 27 Kuokkanen K, Alava S. Fluconazole in the treatment II Goa KL, Barradell LB. Fluconazole. An update of its of onychomycosis caused by dermatophytes. pharmacodynamic and pharmacokinetic properties and J Dermatol Treat 199 2; 3: II5-II7· therapeutic use in major superficial and systemic 28 Hochman LG, Scher RK, Meyerson MS, et al. The mycoses in immunocompromised patients. Drugs 1995; safety and efficacy of oral fluconazole in the treatment 50: 657-690. of onychomycosis. ] Geriat Dermatol 1993; I: 12 De Muria 0, Forrest A, Rich J, et al. 169-172 . Pharmacokinetics and bioavailability of fluconazole in 29 Assaf RR, Elewski BE. Intermittent fluconazole dosing patients with AIDS. Antimicrob Agents Chemother in patients with onychomycosis: results of a pilot 1993; 37: 2187-2192. study. ] Am Acad Dermatol 1996; 35: 216-219. 13 Thorpe JE, Baker N, Bromet-Petit M. Effect of oral 30 Montero-Gei F. Fluconazole in the treatment of severe antacid administration on the pharmacokinetics of oral onychomycosis. lnt ] Dermatol 1996; 35: 587-588. fluconazole. Antimicrob Agents Chemother 1990; 34: 3I Smith SW, Sealy DP, Schneider E, Lackland D. An 2°32-2°33. evaluation of the safety and efficacy of fluconazole in 14 Blum RA, D'Andrea DT, Florentio BM, et al. the treatment of onychomycosis. South Med ] 1995; Increased gastric pH and the bioavailability of 88: 1217-1220.

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London Medicine 1888 London is a vast beehive, numbering amongst its workers some four thousand medical men, some of whom are called doctors, some surgeons, some apothecaries. The surgeons are grieved if you call them "doctor;" "mister" is their title. The doctors are of course, called "doctor." This stickling for titles is somewhat confusing and a source of embarrassment at times. Our way of calling all "doctors," is more convenient. The proper form of address in writing is "John Smith Esq." for the surgeons; "Tom Brown Esq., M.D." for the doctors. But here again we run against a snag, for some of the doctors are only bachelors of medicine, and such must be addressed as "Robt, Jones Esq., M.B." Use accustoms one to all things, and perhaps to one who has acquired a knowledge of the distinctions between Earls, Dukes, Marquises, Lords, Barons, and so on infinitum from earliest infancy, such nice points come easier than to one of us. Now, some of the dermatologists here are surgeons, and some physicians, and hence these remarks. This shows that our beloved specialty has not yet attained to its settled place, but occupies a position similar to that of syphilis, which is claimed by both the venerealist and the dermatologist. However, these little niceties of language are but trifles, and the London medical men are like their fellows everywhere, a very pleasant set of men. Of course an introduction to a few of them will be useful to anyone coming here, but I am quite sure that any decent fellow will be pleasantly received by them, if he simply presents his card and says that he is from America. London is as great in its charities as in its fashion, and has many hospitals, among which are four, I believe, which are specially for skin diseases. Skin patients are received in nearly all, if not all, of the general hospitals, and most of them have dermatologists in attendance. Thus we find Mister Wm. Anderson at St. Thomas Hospital; Dr. Cavafy at St. George's; Mr. Cripps, at Bartholomew's; Dr. Duffin, at King's College; Dr. T. Colcott Fox, at Westminster; Dr. Mackenzie, at the London; Mr. Morris, at St. Mary's; Dr Perry, at Guy's; Dr. Pringle, at Middlesex and Dr. Sangster, at Charing cross.

From Jackson GT. London correspondence. ] Cut GU Dis 1888; 388-391.