`OBSERVATIONS," SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT
`FROM JANSSEN PHARMACEUTICA
`
`New therapies for onychomycosis
`
`Richard B. Odom, MD San Francisco, California
`
`Until recently, the treatment of onychomycosis was discouraging because of the relatively
`low success rate, the need for prolonged therapy, and the laboratory monitoring necessary
`with the traditional oral antifungal agents, griseofulvin and ketoconazole. The advent of a new
`generation of oral antifimgal drugs, including two triazoles (itraconazole and fluconazole) and
`an allylamine (terbinafine), has greatly improved the outlook for patients with fimgal nail in-
`fections, particularly those with toenail involvement. Recently, the broad-spectrum triazole,
`itraconazole, has been approved for the treatment of onychomycosis in the U.S. Numerous
`studies have demonstrated its efficacy when administered either continuously for 3 months
`or in "pulse" dosing. Preliminary findings suggest that fluconazole and terbinafine are also
`promising, although their spectrum of activity is not as broad as that of itraconazole. (J Am
`Acad Dermatol 1996;35:$26-$30.)
`
`Broad-specmma, oral antifungal drugs are the
`most effective agents available for the treatment of
`moderate to severe onychomycosis. However, these
`drugs vary considerably in their pharmacologic and
`clinical characteristics. Table I lists some properties
`of an "ideal" oral antifungal agent. The pharmaco-
`kinetics of a given drug axe important, because the
`drag must be incorporated into the nail matrix and
`diffuse through the nail bed epithelium to reach the
`nail bed hyperkeratosis and penetrate into the ventral
`surface of the nail plate. Ideally, the drug should also
`achieve a high clinical and mycologic cure rate, to-
`gether with a low relapse rate. It should be effective
`when used for short-term therapy and have a low in-
`cidence of side effects. Because certain oral antifun-
`gal drugs interact with other commonly used drugs,
`it is also important to recognize the potential drug
`interactions of an anfimycotic agent, particularly
`when treating older patients. In addition, the drug
`should be cost-effective.
`This article describes the clinical experience with
`a new generation of oral antifungal agents that
`
`From the Department of Dermatology, University of California, San
`Francisco.
`
`Reprint requests: Richard B. Odom, MD, Professor of Clinical
`Dermatology and Interim Chairman, Department of Dermatology,
`A328, University of California, 400 Parnassus Avenue, San Fran-
`cisco, CA 94143.
`Copyright © 1996 by the American Academy of Dermatology, Inc.
`
`0190-9622/96 $5.00 + 0 16/0/74729
`
`$26
`
`appears to offer an advantage over traditional treat-
`ment approaches and to fulfill many of the criteria of
`an "ideal" drug.
`
`LIMITATIONS OF TRADITIONAL ORAL
`ANTIMYCOTIC AGENTS
`
`Oral antifungal agents have been used for the
`treatment of onychomycosis for almost half a cen-
`tury. One of the major limitations of treatment with
`either griseofulvin or ketoconazole is the long dura-
`tion of therapy required.1-3 In addition, the clinical
`and mycologic cure rates are low,4’ 5 and there is a
`greater than 75% probability that the patient will re-
`lapse within 2 years.4
`The potential for significant side effects is another
`problem, particularly with ketoconazole.69
`
`A NEW GENERATION OF ANTIFUNGAL
`AGENTS
`
`The first new agent to be introduced was the tri-
`azole fluconazole, which was approved for the
`treatment of HIV-positive patients with the systemic
`fungal infections cryptococcal meningitis and oral,
`pharyngeal, and esophageal candidiasis. A second
`triazole agent, itraconazole, was subsequently ap-
`proved for the treatment of blastomycosis, histoplas-
`mosis, and aspergillosis. At present, itraconazole and
`allylamine terbinafine are approved for the treatment
`of onychomycosis in the United States.
`
`ARGENTUM EX1034
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`Page 1
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`Jotlmal of the American Academy of Dermatology
`Volume 35, Number 3, Part 2
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`Odom $27
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`Table I. Properties of an "ideal" oral antifungal
`agent used for the treatment of onychomycosis
`
`Table II. Fluconazole: intermittent therapy in
`toenail onychomycosis14
`
`Favorable nail kinetics
`Incorporated into nail matrix
`Diffuses through nail bed
`High clinical cure rate
`High mycologic cure rate
`Low incidence of relapse
`Effective when used for short-term therapy
`Low incidence of side effects
`Few drug interactions
`Cost effective
`
`The pharmacokinetics of the newer agents are of
`particular significance because the drug is incorpo-
`rated via both the nail matrix and nail bed, allowing
`a shorter duration of therapy.
`The specmma of activity of these newer agents is
`of particular relevance in the treatment of fungal nail
`infections, because an antimycotic agent should
`ideally be active against the full range of patho-
`gens (e.g., dermatophytes, molds, and yeasts) that
`can potentially cause onychomycosis. Itraconazole
`is active against dermatophytes, yeasts, and most
`moldsJ° Fluconazole is also active against der-
`matophytes, yeasts, and some molds, although there
`are reports of resistance in patients with HIV and in-
`fections caused by Candida sp.n, 12 Terbinmfine is
`primarily active against dermatophytes. Its effec-
`tiveness against yeasts and molds is being investi-
`gated, but it appears to be less active than the triaz-
`oles.
`
`Fluconazole
`
`Kuokkanen and Alavat3 treated 20 patients with
`a severe dermatophyte infection of the fingernails
`and toenails. Patients received fluconazole 150 rag/
`week for a mean duration of 9.3 months after
`pretreatment with 40% urea cream. All fingernails
`and 92% of toenails were clinically and mycologi-
`cally flee of infection at the end of this time, and all
`fingernail infections continued to be clinically cured,
`as did 83% of toenail infections, at the 6-month fol-
`low-up visit.
`Fraki et al.t4 administered fluconazole 150 rag/
`week for 5 to 12 months, with and without urea
`cream, to 111 patients. Fluconazole in combination
`with urea cream resulted in a clinical cure rate of
`74% and a mycologic cure rate of 80% (Table 1I). In
`the absence of urea cream, however, there was only
`a 65% clinical cure rate and a 60% mycologic cure
`
`150 rag/week for 5 to 12 months
`(n = 102)
`
`Results
`
`1
`
`+Urea
`
`Mycologic cure
`Cfinical cure or
`markedly improved
`
`~
`
`80%
`74%
`
`-Urea
`
`65%
`60%
`
`rate. Thus, fluconazole appears to be a promising
`agent in the treatment of onychomycosis, although
`there is no consensus as to the optimal dosage, fre-
`quency, or duration of therapy.
`The most common side effects of fluconazole are
`gastrointestinal symptoms and headache. There have
`been several reports of Stevens-Johnson syndrome,
`most commonly in patients with AIDS.15 As with
`other oral azoles, drag-drug interactions may oc-
`Cllr.16
`
`Itraconazole
`
`Numerous studies have been conducted in the
`U.S. and Europe to investigate the effects of vari-
`ous doses and dosing regimens of itraconazole in
`the treatment of onychomycosis. Investigators in
`Belgium compared 3 months of therapy with itra-
`conazole, either 100 or 200 mg/day, in 39 patients
`with toenail or fingernail onychomycosis.17 The re-
`spective cure rates with these two regimens in
`toenail infections were 26% and 79% at the 6-
`month follow-up evaluation. They also found that
`therapeutic concentrations of the drug were still
`present in the nail plate 6 months after the end of
`treatment. However, the drug concentrations were
`10-fold higher in patients who had received the 200
`mg dose of itraconazole. It was concluded that
`itraconazole reaches the nail by incorporation into
`the nail matrix, as well as by diffusion from the nail
`bed.
`Fig. 1 sunmaarizes the results of worldwide clin-
`ical experience with itraconazole 200 mg daily for 3
`months,is Of the 12 studies in 558 patients with toe-
`nail infections, three were placebo controlled, two
`were comparative, and seven were open label. The
`majority of study participants had distal and lateral
`subungual onychomycosis or total dystrophic ony-
`chomycosis. Itraconazole was administered daily for
`3 months, followed by a 9-month follow-up period.
`The clinical cure rate was 60%; the mycologic cure
`
`Page 2
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`$28 Odom
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`Journal of the American Academy of Dermatology
`September 1996
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`Fig. 1. Short-term continuous treatment in onychomy-
`cosis.
`
`Fig. 2. Pulse therapy in onychomycosis.
`
`rate was 74%. However, the overall clinical response
`(i.e., the number of patients who were cured plus
`those who achieved marked improvement [minimal
`nail involvement with significantly decreased signs])
`was 82%. The relapse rate at the end of the follow-up
`period was 14%.
`In a comparative study, 53 patients were treated
`with either itraconazole 200 rag/day or terbinafine
`250 mg/day for 3 months, with a follow-up visit
`scheduled 9 months after cessation of therapy.19
`Treatment was highly effective in both groups and
`the clinical and mycologic cure rates for each of
`the two agents were not significantly different
`(60.9% in the itraconazole group, 64.7% in the
`terbinafme group). However, the incidence of ad-
`verse effects was significantly higher in the terbin-
`afme group (47% vs only 21% in the itraconazole
`group). Adverse events for itraconazole included
`gastric upset, headache, edema, and transient trans-
`aminase elevation. Terbinafine side effects consisted
`of stomach upset, headache, nausea, pruritus, facial
`eruption, abdominal pain, menorrhalgia, and dys-
`geusia.
`Other investigators have explored the use of
`itraconazole 100 or 200 rag/day for 3 or 6 months
`to treat Candida onychomycosis. Of the 15 patients
`who participated in one study, the infections were
`cured in 93% and improved in the remainder.2°
`More than 1.5 million patients have been treated
`with itraconazole for systemic and superficial infec-
`tions in doses ranging from 100 to 600 nag/day. Itra-
`conazole is well tolerated; the most common side
`effects are gastrointestinal disturbance and head-
`ache.21 The drug-drug interactions with itraconazole
`are not well defined, but the presence of food appears
`to increase itraconazole’s gastrointestinal absorp-
`
`tion.16 Itraconazole may inhibit the metabolism of
`both cyclosporine and digoxin, elevating blood lev-
`els of both drugs. Itraconazole may reduce plasma
`concentrations of phenytoin, rifampin, and H2 an-
`tagonists. The coadministration of terfenadine,
`astemizole, or cisapride with itraconazole is con-
`traindicated.16
`One of the newest and most promising approaches
`to the management of onychomycosis is based on the
`concept of intermittent or "pulse" dosing with itra-
`conazole. This regimen consists of administering
`itraconazole 200 mg twice daily with meals for only
`7 consecutive days of each month. Toenail infections
`can generally be cured within 3 to 4 months, while
`fingernail infections usually require only 2 to 3
`months.iS, 22, 23 There are several potential benefits
`associated with the use of intermittent therapy. First,
`the progressive accumulation of drug and persistent
`levels in the nail help prevent the potential develop-
`ment of resistance. Second, because plasma levels of
`drug decline in less than a week, the risk of side ef-
`fects may decrease, which probably reduces the in-
`cidence of patient noncompliance.
`Fig. 2 summarizes the clinical experience with
`pulse itraconazole in 909 patients with toenail ony-
`chomycosis.]8 The clinical outcome was similar, re-
`gardless of whether the patients received three or
`four pulses of therapy. The overall clinical response
`was identical (92%) in both groups. Less than 4%
`relapsed in the three-ptflse group and no patients re-
`lapsed in the four-pulse group.
`Fig. 3 summarizes the clinical experience with
`pulse itraconazole in the treatment of 328 patients
`with fingernail onychomycosis,is The clinical
`outcome was virtually identical, independent of
`whether the patients received two or three pulses of
`
`Page 3
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`Journal of the American Academy of Dermatology
`Volume 35, Number 3, Part 2
`
`Odom $29
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`Fig. 3. Pulse therapy in onychomycosis.
`
`Fig. 4. Terbinafine (Lamisil®) 250/mg day. Effect of
`treatment duration on cure rates at follow-up, 1 year after
`treatment.
`
`therapy. The clinical cure rate associated with the
`two-pulse regimen was 89%, as compared with
`91% in the group receiving the three-pulse regimen.
`A total of 95% of patients receiving two cycles of
`therapy demonstrated a clinical response, as did
`97% of patients receiving three cycles. The respec-
`tive mycologic cure rates for the two regimens were
`94% and 98%, and there were no relapses in either
`group.
`From a cost perspective, it is important to note that
`three pulses of itraconazole appear to be as effective
`as four in eradicating toenail and two as effective as
`three in eradicating fingernail onychomycosis. Pulse
`dosing not only provides effective treatment, but it
`also reduces the patient’s exposure to the drug. Re-
`duced drug exposure, in turn, may minimize the po-
`tential for drag interactions and result in improved
`patient compliance.
`As indicated in itraconazole’s prescribing infor-
`marion, hepatic enzyme test values should be mon-
`itored periodically in all patients receiving continu-
`ous treatment for more than 1 month or at any time
`a patient develops signs or symptoms suggestive of
`liver dysfunction. Therefore a baseline liver function
`test should be done before the initiation of therapy.
`
`Terbinafine
`
`Terbinafine, a member of a new class of antifun-
`gals, the allylaxnines, has recently been approved for
`treatment of onychomycosis in the United States.
`One study in 112 patients with toenail onychomy-
`cosis showed that terbinafine 250 mg/day for 3
`months produced a cure rate of approximately 70%
`(Fig. 4).24 However, the overall cure rate after 24 to
`52 weeks of therapy was approximately 90%.
`Faergemann et al.25 conducted a study in which 85
`
`patients with toenail onychomycosis were treated
`with one of two therapeutic regimens: terbinafme
`250 rag/day for 16 weeks or griseofulvin 500 rag/day
`for 52 weeks.25 In the terbinafme group, 84% of in-
`fections were mycologically cured and 42% were
`completely (both clinically and mycologically) cured
`at the end of 16 weeks. In contrast, oniy 45% of in-
`fections were mycologically cured and 2% were
`completely cured in the griseofulvin group. More
`than twice the number of patients receiving griseof-
`nlvin experienced side effects than those receiving
`terbinafme (29% vs. 11%, respectively).
`Hofmann et al.26 conducted a randomized, dou-
`ble-blind study in 195 patients with severe dermato-
`phyteinfection of the toenails. Patients were assigned
`to either 24 weeks of treatment with terbinafme 250
`mg/day or 48 weeks of treatment with microsized
`griseofulvin, 1000 rag/day. At the end of 48 weeks,
`there was a 67% cure rate in the terbinafme group
`and a 56% cure rate in the griseofulvin group. At the
`6-month follow-up visit, there was a 60% clinical
`cure rate and an 81% mycologic cure rate in the ter-
`binafine group. The respective figures in the griseo-
`fulvin group were 39% and 62%. In another com-
`parative study, 180 patients with dermatophyte-
`related fingernail infections were treated for 12
`weeks with either terbinafme 250 mgiday, micro-
`sized gfiseofulvin 500 mg/day, or placebo.27 At the
`end of the 6-month follow-up period, the cure rate in
`the terbinafme group was 76%, compared with 39%
`in the griseofulvin group. Both treatments were well
`
`tolerated.
`Oral terbinafine appears to be well tolerated. The
`most common side effects are gastrointestinal dis-
`
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`tress and skin reactions.28 Loss of taste, neutropenia,
`and pancytopenia have also been reported.29, 3o
`
`REFERENCES
`
`1. Roberts DT. Oral therapeutic agents in fimgal nail disease.
`J Am Acad Dermatol 1994;31:$78-81.
`2. Pi6rard G, Arrese-Estrada J, Pi6rard-Franchimont C. Treat-
`ment of onychomycosis: traditional approaches. J Am
`Acad Derrnatol 1993;29:$41-5.
`3. Seller RK. Diseases of the nails. In: Conn H, editor. Cur-
`rent therapy. Philadelphia: W.B. Saunders, 1990:736.
`4. Davies RR, Everall JD, Hamilton E. Mycological and
`clinical evaluation of gfiseofulvin for chronic onychomy-
`cosis. Br Med J 1967;3:464-8.
`5. Frain-Bdl W, Riddell RW, Stevenson C J, et al. Chronic
`ringworm infection of the skin and nails treated with
`griseofulvin. Lancet 1960;1:1141-7.
`6. Davies RR. Griseofulvin. In: Speller DCE, editor. Anti-
`fungal chemotherapy. New York: John Wiley, 1980:149-
`82.
`7. Dollery C. Griseofulvin. In: Therapeutic drugs. Edinburgh:
`Churchill Livingstone, 1991:G66-9.
`8. Janssen PAL Symoens JE. Hepatic reactions during keto-
`conazole treatment. Am J Meal 1983;74:80-5.
`9. Hay RJ. Risk/benefit ratio of modem antifungal therapy:
`Focus on hepatic reactions. J Am Acad Dennatol 1993;29:
`$50-4.
`10. Odds FC. Spectrum of orally active antifungals. J Eur Acad
`Dermatol Venereol 1993;2(suppl 1):S12-8.
`11. Powderly W, Finkelstein D, Feinberg J. A randomized trial
`comparing fluconazole with clotrimazole troches for the
`prevention of fungal infections in patients with advanced
`HIV infection. N Engl J Med 1995;332:700-5.
`12. Cameron ML, Schnell WA, Bmch S, et al. Correlation of
`in vitro fluconazole resistance of Candida isolates in rela-
`tion to therapy and symptoms of individuals seropositive
`for human immunodeficiency virus type 1. Antimicrob
`Agents Chemother 1993;37:2449-53.
`13. Kuokkanen K, Alava S. Fluconazole in the treatment of
`onychomycosis caused by dermatophytes. J Dermatol
`Treat 1992;3:115-7.
`14. Fraki J, Heikkila H, Kero M, et al. Fluconazole in the treat-
`ment of onychomycosis: an open non-comparative multi-
`center study with oral 150-mg fluconazole once weekly. In:
`Future trends in the treatment of dermatomycoses. Derma-
`tology 2000, Vienna, abstract book, poster, May 1993.
`15. Osterloh IH. Safety. In: Powderly WB, Van Wout JW, ed-
`itors. Fluconazole. Camforth, United Kingdom: Marias
`Press, 1992:40.
`
`16. Bickers DR. Antifungal therapy: potential interactions with
`other classes of drags. J Am Acad Dermatol 1994;31:$87-
`90.
`17. Willemsen M, De Doncker P, Willems J, et al. Posttreat-
`ment itraconazole levels in the nail. J Am Acad Dermatol
`1992;26:731-5.
`18. Data on file, Janssen Pharmaceutica (Beerse, Belgium).
`19. Arenas R, Dominguez-Cherit J, Fernandez LM. Open ran-
`domized comparison of itraconazole versus terbinafine in
`onychomycosis, hat J Dermatol 1995;34:138-43.
`20. Roseeuw D, De Doncker P. New approaches to the treat-
`ment of onychomycosis. J Am Acad Dermatol 1993; 29:
`$45-50.
`21. Alcantara R, Garibay JM. Itraconazole therapy in dermat-
`omycoses and vaginal candidiasis: effects and adverse ef-
`fects profile in a large multi-center study. Adv Ther 1988;
`5:326-34.
`22. De Doncker P, Van Lint J, Dockx P, et al. Pulse therapy
`with one-week ittaconazole monthly for three or four
`months in the treatment of onychomycosis. Cuffs 1995;56:
`180-3.
`23. De Doncker P, Decroix J, Pi6rard G, et al. Anfifimgal pulse
`therapy for onychomycosis. A pharmacokinetic and phar-
`macodynamic investigation of monthly cycles of 1-week
`pulse therapy with itraconazole. Arch Dermatol 1996;
`132:34-41.
`24. Goodfield, MJD. Short-duration therapy with terbinafme
`for dermatophyte onychomycosis: a multicentre trial. Br J
`Dermatol 1992;126(suppl 39):33-5.
`25. Faergemarm J, Anderson C, Hersle K, et al. Double-blind,
`parallel-group comparison of terbinafine and griseofulvin
`in the treatment of toenail onychomycosis. J Am Acad
`Dermatol 1995;32:750-3.
`26. Hofmann H, Br~iutigam M, Wiedinger G, et al. Treatment
`of toenail onychomycosis. A randomized, double-blind
`study with terbinafine and griseofulvin. Arch Dermatol
`1995;131:919-22.
`27. Haneke E, Tausch I, Br~iutigam M, et al. Short-duration
`treatment of fingernail derrnatophytosis: a randomized,
`double-blind study with terbinafine and griseofulvin. J Am
`Acad Dermatol 1995;32:72-7.
`28. ViUars VV, Jones TC. Special features of the clinical use
`of oral terbinafine in the treatment of Amgal diseases. Br J
`Dermatol 1992;126(suppl 39):61-9.
`29. Stricker BH, De-Jong PA, Schreuder F, et al. Loss of taste
`sensation in terbinafine administration. Ned Tijdschr Ge-
`neeskd 1992;136:2438-400.
`30. Kovacs MJ, Alshammari S, Guenther L, et al. Neutropenia
`and pancytopenia associated with oral terbinafme. J Am
`Acad Dermatol 1994;31:806.
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