American Cademy of
`
`A DERMATOLOGY
`
`quit»:
`
`it mt:
`
`J3;
`Mill
`
`’,[) L;'i'15'.'-‘L illiki-ILItS CFNIEH
`uHl;‘«N.lI AV~MMl|SUH. WI 53751?’
`
`VOLUME 40 NUMBER 6 PART 2
`
`0 Novel treatment strategies for
`
`superficial mycoses
`
`Proceedings of a symposium held at the
`World Congressof Dermatology
`
`Sydney, Australia
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2056 - “I/8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 1/8
`
`

`

`SUPPLEMENT TO
`
`Journal of the
`
`American Academy of
`DERMATOLOGY
`
`Copyrig/It © I999 II_\' the Americmz Am(Ient_\' ofDern1uro/og_\', Inc.
`
`Jeffrey D. Bernhard. MD
`Associate Editors
`
`Thomas G. Cropley, MD
`Karen Wiss. MD
`
`Editorial Office
`University of Massachusetts Medical School
`55 Lake Avenue North
`Worcester. MA 0l655
`508«856—2583
`
`Assistant Editors
`Michael E. Bigby, MD
`Boston, tl’I(ISS(l('/IIINEIIS
`Jeffrey P. Cullen, MD
`Lottisrillc, Kelttmrky
`Luis A. Diaz, MD
`Milwaukee. Wisron.t‘iIt
`Jane M. Grant—Kels. MD
`Farmingmn, C(IIIlI(’('fi('lll
`Mark Lebwohl, MD
`New York. }\’mt' York
`Mary E. Maloney, MD
`[‘I€)‘.\‘/l(’_\’. P€lIIIS_\'i\’(Illi(I
`Alan Menter, MD
`Dallas. TEXIIS
`Scott A. Norton, MD
`Fort Huac/tum, Arizmm
`Elise Olsen. MD
`Durltam. North Carolina
`Amy S. Pallet‘, MD
`Chicago, Illinois
`Sharon Ann S. Raimer. MD
`GuIt'e.\'ron, Te.\‘u.\'
`Thomas L. Ray, MD
`Iowa Cir)‘. lmrrt
`Stuart J. Salasche, MD
`Tucson, /-lrizonu
`Martin A. Weinstock, MD, PhD
`Pmvidelurr. Rhode Island
`
`Founding Editor
`J. G"aham Smith. Jr., MD
`Mobile. Alabama
`Editor Emeritus
`
`Richaud L. Dobson, MD
`C/tm‘Ie.rton. South Carolina
`
`the Journal of the
`Vol. 40. No. 6, Part 3. June 1999.
`American Academy of Derm:1tolog_\' (ISSN 0190-9622)
`i.\‘ published titotttltly (.\'l.\ issues per volume. two volumes
`per year) by Moshy. Inc.
`I I830 Westline Industrial Dr.
`St Louis, MO 63|-I6-3318. Pcriotiicztls postage paid at
`St Louis’. Missouri. and additional mailing offices.
`Postmas‘IeI': Send uddr-:s's changes‘
`to Journal of the
`.'—\mv.-ricun Academy ol‘ Det'tnutoIogy. I\'Iosby. Inc.
`I I830
`Westline Industrial Dr. St Louis. MO o3|4(x-BIS.
`Annual subscription rates: $167.00 for
`individuals,
`
`June, Part 2, 1999
`
`NOVEL TREATMENT STRATEGIES FOR
`SUPERFICIAL MYCOSES
`
`Novel treatment strategies for
`superficial mycoses: introduction
`Boni E. Elewski, MD. and
`Roderick J. Hay, DM, FRCP
`C/evelztml, Ohio, and London,
`United Kingdom
`
`Diagnosis of onychomycosis made simple
`David H. Ellis, PhD
`North Ade/(title, At(SI‘I‘(Iii(I
`
`Optimal growth conditions for the
`determination of the antifungal susceptibility
`of three species of dermatophytes with the
`use of a microdilution method
`
`Heather A. Norris, MT (ASCP),
`Boni E. Elewski, MD. and
`.
`Mahmoud A. Ghannoum, PhD
`Cleveland, Ohio
`
`Pharmacokinetics of fluconazole in skin
`and nails
`
`Jan Faergemann, MD. PhD
`Got/zenburg, Sweden
`
`Onychomycosis: therapeutic update
`Richard K. Scher. MD
`New York, New York
`
`Treatment of tinea capitis: beyond griseofulvin
`Boni E. Elewski, MD
`C](i\’€i(IH(i, 0/tio
`
`Oral therapy of common superficial fungal
`infections of the skin
`Jack L. Lesher, J11. MD
`/-lIlgH.S'f(I, Georgia
`
`The management of superficial candidiasis
`Roderick J. Hay, DM. FRCP, FRCPath
`London. United Kingdom
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 2/8
`
`

`

`Onychomycosis: therapeutic update
`
`Richard K. Scher, MD New York, New York
`
`Oiiychoinycosis is a common disease of the nail unit caused by derinatophytes, yeasts, and
`molds. In more than 80% of cases, onychomycosis is caused by the dermatophytes
`Tricliop/iytoii rubrzim and Tric/lop/iy1‘0n iizeiztagropliytes. The prevalence of onychoinyco-
`sis in the world's population is 2% to 18% or higher and accounts for approximately 50%
`of all nail disorders. Until recently, available therapies were inadequate because of low
`cure rates, high relapse rates, and often dangerous side effects. An increased understand-
`ing of nail pharmacokinetics has led to the development of safer, more effective systemic
`therapies for onychomycosis, such as itraconazole, fluconazole, and terbinafine. These
`new oral antifungal agents allow shorter periods of treatment, provide rapid efficacy, and
`may improve patient compliance and attitudes regarding therapy. Treatment selection will
`depend on several factors, including appropriate spectrum of activity, adverse effects, and
`potential drug interactions plus patient preferences for specific dosing regimens. (J Am
`Acad Dermatol 1999;40:S2l-6.)
`
`OI1YCh0H1)/C0313 is 3 C0mm0f1 fungal i11f€Cti0f1
`of
`1 or more components of the nail unit.‘
`Although the exact prevalence is unknown, ony—
`chomycosis accounts for up to 50% of all nail dis—
`ease and affects 2% to 18% 01‘ more of the world’s
`population.2'4 The incidence of onychomycosis
`increases with age, and some studies suggest that
`up to 48% of the p0pu1.ati.On .may. be affected by
`age 70 years.‘ Toenail infection 1S several times
`more common than fingernail infection and is gen—
`erally more difficult to treat because of the slow
`rate of toenail growth.‘
`In the United States and other developed coun—
`tries, the incidence of onychomycosis niay have
`increased dramatically in recent years. This is like—
`ly the result of such factors as the aging of the pop—
`ulation, possible higher incidence of diabetes mel-
`litus, greater use of immuiiosuppressive and antibi-
`otic agents,
`increased exposure to infecting
`organisms, and the acquired immunodeficiency
`syndrome epidemic.1=2
`
`From the Department of Dermatology, Columbia-Presbyterian
`Medical Center, New York, New York.
`
`This work was supported by a research grant from Pfizer Inc. The
`author has also served as an investigator, consultant, and a speak—
`er for Novartis, Pfizer, and Janssen. CMD, Inc. assisted in the \vrit—
`mg ofmisamcie,
`Reprint requests: Richard K. Scher, MD, Department of Dermatology,
`Cl
`b"-P bt'iMd‘1Ct‘,161FtWz‘l‘
`1 Ar,
`R:O‘;:1“7‘5‘:)’I’§':\vyY‘:)‘r'l::‘N&f l‘g3‘32‘e" 6‘
`°’
`“"3 O”
`‘C
`Copyright © 1999 by the American Academy of Dermatology, Inc.
`0190~9622/99/$8.00 + o
`16/0/98108
`
`Table I. Principal causes of onychomycosis
`_
`DelTI1]’fi(t[())§£?;teS
`T,,,e,,,(,g,.0p/mes.
`Epiderniopliyfoii floccosiim
`N0I1d6I‘m3f0P11Yt€5
`2C"e’l’0_;7]f“”’
`0‘jf))’eC']]Ig(;CLl7lfY(l caizadeiisis
`5 b',.e,,,-Cm,/I-S
`5C_,,»m],',/,',,,,, (1,',,,,'(1,'am,,,
`S lzyalimun
`Yeasts
`_
`C "lb’C"”S
`From Elewski BE, Cliarif MA, Daniel CR III. Onycliomycosis. Iii:
`Sf“""‘ }‘§’dD‘:1"il‘:'l .10:
`I\f“:JlSf
`‘“l“9*='9“7°5iS‘l‘5’f“6‘;‘e1‘;‘:
`e i
`H a 6 PM
`at n 615’
`
`In more than 80% of cases, onychomycosis is
`caused by the dermatophytes Tricliopliyron
`rzibrmn and Tnienrrigrop/tyres and is then referred
`to as tinea unguium.2 Yeasts are responsible for
`between 5% and 17% of Cases of onychomycosis’
`and in over 70% of these cases Candida albicans
`
`is the infecting O1-ganisnl The nondermatophyte
`molds S60] [aria sis Sc ,mh.dI.um Acremonimn
`I U
`P
`’
`-3
`’
`Aspergillus, and Fusciriiim cause approximately
`3% [0 5% of fungal nail disease (Table 1).]-3
`..
`-
`.
`--
`Fai fiom being meiely a cosmetic issue, ony—
`chomycosis may have Serious emotional and Phys"
`ical consequences for the patient.25 The condition
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2056 - 3/8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 3/8
`
`

`

`Table II. Treatment selection criteria in
`
`onychomycosis
`
`Causative pathogen
`Potential adverse effects
`
`Potential drug interactions
`Dosage schedule
`Patient compliance
`Age and health of patient
`Allergic history
`Prior antifungal therapy
`
`From Elewski BE. Charif MA, Daniel CR 111. Onychomycosis. ln:
`Scher RK. Daniel CR III. editors. Nails: diagnosis.
`treatment.
`surgery. 2nd ed. Philadelphia: WB Saunders. 1997. p.
`l5l—62.
`
`may be associated with significant pain and dis-
`comfort; in severe cases, onychomycosis could lead
`to disfigurement and loss of dexterity and mobility.
`As a recent quality—o'f—life study by Lubeck et al6
`has demonstrated, onychomycosis can impose sig-
`nificant psychologic and social limitations.7 In this
`study, supported by Sandoz Research Institute,
`patients with fungal nail disease reported avoiding
`intimate and social situations for fear of exposing
`their disfigured nails and experienced difficulties
`with work—related activities requiring them to use
`their fingers or to be on their feet for long periods
`
`Treatment of onychomycosis has traditionally
`been difficult,
`in part because of the unique
`absorption properties of the nail unit. To be effec-
`tive, antifungal drugs must penetrate the affected
`nail tissue and remain in high concentrations until
`the pathogen is eradicated.8 Topical antifungal
`drugs, which poorly penetrate the nail plate, have
`only limited use in onychomycosis treatment.4
`The early systemic treatments, griseofulvin and
`ketoconazole, have also proved unsatisfactory.4~8
`Griseofulvin has a narrow spectrum of activity and
`requires prolonged courses of treatment; low cure
`rates and high relapse rates further limit its useful-
`ness in onychomycosis.4~3 Although ketoconazole
`has demonstrated higher cure rates than griseofulvin,
`prolonged therapy (12 to 18 months for toenails) is
`required, and relapse rates have been high. In addi-
`tion, ketoconazole carries a risk of drug interactions
`and serious adverse effects, such as hepatotoxicity.3
`
`NEW TREATMENT OPTIONS
`
`Journal of the American Academy of Dermatology
`June 1999
`
`fungal nail disease. Pharmacokinetic studies indi-
`
`cate that these drugs reach the distal end of the nail
`shortly after therapy begins? When selecting
`among these agents, however, several factors need
`
`to be considered, including efficacy against the
`causative pathogen, potential adverse effects and
`drug interactions, dosage regimens, cost, and com-
`pliance issues (Table II).'
`
`Itraconazole
`
`Itraconazole, like fluconazole, is a triazole anti-
`
`fungal agent. The 3 nitrogen atoms in the 5—1nem—
`ber triazole ring may be responsible for itracona—
`zole’s broad spectrum of activity, which includes
`dermatophytes, yeasts,
`and nondermatophyte
`molds; improved tissue penetration; and lower tox-
`icity compared with ketoconazole. Unlike keto-
`conazole, an imidazole derivative, the triazoles
`
`have increased specificity for fungal rather than
`mammalian cytochrome P—450 enzymes at thera-
`peutic levels, which significantly decreases the
`risk of drug interactions.9
`Mechanism of action. Itraconazole is fungista—
`tic in vitro; it impairs ergosterol synthesis in fun-
`gal cells by blocking the cytochrome P—450—
`dependent enzyme lanosterol cl4—ot—demethylase.
`This results in decreased ergosterol and increased
`lanosterol in the fungal cell membrane, which
`alters its function and permeability. This mecha-
`nism of action is common to all azoles.9
`Pharmacokinetics. Itraconazole is well absorbed
`
`when administered orally with food but is erratically
`absorbed with changing gastric pH. However,
`it
`achieves excellent tissue distribution. The pharma-
`cokinetic properties of itraconazole are related to its
`pronounced lipophilicity.3 The plasma half—life
`varies between 15 and 25 hours; the peak plasma
`concentration is reached within 2 to 4 hours after a
`
`single l00—mg dose. Itraconazole also binds firmly
`to protein and has a marked affinity for lipids.3 The
`slow elimination of itraconazole from tissues may
`explain its continued therapeutic efficacy after treat-
`ment is discontinued.3 Itraconazole also has a strong
`affinity for keratinized tissue, which results in high
`drug concentrations in the nails and explains the
`drug’s efficacy in onychomycosis.3 The concentra-
`tion of itraconazole in nails, 90 days after a 7-day
`course of medication. greatly exceeds the minimum
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 4/8
`
`

`

`daily for 12 weeks in onychomycosis of the toenail
`and for 8 weeks in fingernail disease. Studies
`demonstrate that although the nail is not yet nor-
`mal when therapy ends, the new nail will grow free
`of fungus because of the continued presence of
`itraconazole in the nail.‘ Pulse or intermittent ther-
`
`apy is based on the rationale that the drug reaches
`the nail within 7 days of therapy and remains there
`for 6 to 9 months, although serum levels of the
`drug are no longer detectable 1 week after discon-
`tinuation of therapy.‘ The Food and Drug Admin-
`istration recently approved 2 pulse doses of itra-
`conazole for onychomycosis of the fingernails, but
`no pulse therapy has been approved for toenails at
`present. Intermittent cycles of 400 mg daily for 1
`week per month can be continued for 2 months for
`fingernail infection and 3 months for toenail infec-
`tion.‘ Cure rates approaching 80% have been
`reported in European studies with these regi-
`mens,” although cure rates have been lower in
`other studies. 12
`
`Efficacy. Results of US studies of itraconazole
`effectiveness in the toenail have shown a mycolog—
`ic cure rate of 54%, a clinical success rate of 65%,
`
`and an overall success rate (clinical success and
`mycologic cure) of 35%.‘ Investigators using itra-
`conazole in toenail infections at doses of 200
`
`mg/day for 3 months have reported mycologic
`cure rates of 86% at 9 months and 79% at 12
`
`months? At 18-month follow—up, mycologic cure
`rates decreased to 67%. Relapse rates in toenail
`infections at 9 and 12 months after treatment with
`
`this regimen have been reported to be 9% to 11%?
`Safety. The principal safety concern regarding
`itraconazole relates to its potential for serious drug
`interactions. Elevated liver function tests have been
`
`reported in 0.3% to 5% of patients receiving itra-
`conazole therapy, but symptomatic hepatic injury
`has rarely been reported. In general, liver function
`tests return to normal 4 to 10 weeks after therapy is
`discontinued. Itraconazole should be avoided dur-
`
`ing pregnancy (Food and Drug Administration
`Pregnancy Category C), and women of childbear-
`ing age should be advised to take adequate contra-
`ceptive precautions during therapy?
`Adverse effects. The adverse effects reported
`for itraconazole by more than 1% of patients in
`clinical trials for the treatment of onychomycosis
`of the fingernail are as follows: headache (5%),
`
`reported include dizziness, fatigue. fever, somno—
`lence, impotence, decreased libido, and malaise?
`Drug interactions and contraindications.
`Itraconazole and its major metabolite are potent
`inhibitors of the cytochrome P—45O 3A4 enzyme
`system. Concomitant use of itraconazole with
`drugs metabolized by this enzyme system may
`result in increased plasma concentrations of these
`drugs, leading to potentially serious or life—threat—
`ening events. Coadministration of itraconazole and
`drL1gs such as terfenadine, astemizole, simvastatin,
`lovastatin, midazolam, triazolam, and cisapride are
`
`specifically contraindicated. Coadministration of
`itraconazole with drugs such as digoxin, cyclo-
`sporine. and phenytoin requires close monitoring.
`When oral warfarin or hypoglycemic agents are
`coadministered with itraconazole, prothrombin time
`and blood glucose levels may also require monitor-
`ing.2»3e13 Food increases the gastrointestinal absorp-
`tion of itraconazole, whereas antacids and gastric
`
`acid secretion suppressors that lower gastric acidity
`decrease absorption of itraconazole?
`
`Fluconazole
`
`Fluconazole is an oral antifungal agent with
`
`activity against dermatophytes, Candida, and
`some nondermatophyte molds. It has only recently
`been studied as a potential therapy for onychomy-
`cosis. Fluconazole has a distinct chemical struc-
`
`ture and unique pharmacologic and pharmacoki—
`netic properties.
`Fluconazole is a bis—triazole, having 2 triazole
`
`groups with each containing 3 nitrogen atoms.
`Fluorine atoms in the 2 and 4 positions of the
`phenyl ring contribute to fluconazole’s decreased
`lipophilicity and protein binding (approximately
`12%), resistance to metabolism, increased speci-
`
`ficity, and higher potency compared with other
`azole antifungal agents.9 A hydroxyl group and
`low molecular weight also make fluconazole more
`water—soluble than the other azoles, which results
`
`in rapid absorption, high bioavailability (>90%),
`and wide tissue distribution. Fluconazole has a
`volume of distribution similar to that of water in
`
`the body, a long half—1ife (30 hours), and dose—pro—
`portional serum concentrations.9
`Mechanism of action. The mechanism of
`action is similar to the other azoles. As with itra-
`
`conazole, fluconazole is fungistatic in vitro. The
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2056 - 5/8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 5/8
`
`

`

`triazoles have a high affinity for fungal cyto-
`chrome P—450 enzymes but a very weak affinity
`for mammalian P—450 enzymes. In C albicans, the
`azoles inhibit transformation of blastospores into
`the invasive mycelium form.9
`’
`Pharmacokinetics. Studies have demonstrated
`
`that fluconazole penetrates nails rapidly. In a small
`pilot study, Hay’4 found that fluconazole was
`detectable in nails within 2 hours after a single 50-
`mg oral dose. Fluconazole accumulates well in or
`on the stratum corneum of nails, reaching levels up
`to 50 times those found in plasma, and remains
`there even after the drug is no longer detectable in
`plasma. This factor is believed to contribute to the
`continued improvement observed in some patients
`even after the end of active treatment.4 Recent
`studies have demonstrated that concentrations of
`
`fluconazole are found 2 weeks after the onset of
`
`treatment and throughout the treatment and post-
`treatment period were well above the MIC for der-
`matophytes and nondermatophytes.8 Unlike keto—
`conazole and itraconazole, food intake and gastric
`pH do not affect fluconazole absorption or bio-
`
`Dosing. The most common dosage regimen of
`fluconazole prescribed for skin and nail infections
`world—wide is 150 to 300 mg once weekly.”
`However, depending on the clinical situation,
`dosages may vary. The duration of treatment is
`usually 2 weeks for tinea corporis, 4 to 6 weeks for
`tinea pedis, and 6 to 12 months for toenails until
`r‘egrown.16 Different doses of fluconazole have
`been investigated in the treatment of onychomyco—
`sis but none have yet been FDA approved. Doses
`of 50 to 100 mg daily or on alternate days until the
`normal nail has grown out have been shown to be
`effective? In a study of ll patients with ony-
`chornycosis of the toenail and fingernail, 8 patients
`received fluconazole 300 mg once weekly,
`1
`patient received 200 mg once weekly, and 2
`patients received alternate—day therapy with 100
`mg or 200 mg of fluconazole. Eight of the patients
`also received a topical antirnycotic treatment. All 6
`patients with toenail involvement were clinically
`cured after a mean duration of 6 months. All 5
`
`patients with fingernail involvement were cured
`after 3.7 months. No adverse laboratory or clinical
`adverse events were recorded.17
`The use of chemical urea nail avulsion with flu-
`
`Journal of the American Academy of Dermatology
`June 1999
`
`respond to treatment, the dose of fluconazole can
`be increased to 300 or 450 mg once weekly.‘ This
`once—weekly regimen may be especially useful for
`patients who are receiving multiple medications
`and for whom compliance may be an issue.‘
`Efficacy. The efficacy of fluconazole in ony-
`chomycosis is well studied. Montero—Gei et al13
`demonstrated that fluconazole 150 mg once week-
`ly for 3 to 12 months for dermatophyte infections
`of the fingernails and toenails produced a favor-
`able clinical response in 97% of patients at the end
`of treatment and in 87% at follow—up. A multicen—
`ter trial by Fraki et al19 in Finland reported similar
`results. Treatment with 150 mg of fluconazole
`once weekly for 5 to 12 months was effective and
`well tolerated and produced a favorable clinical
`response in 77% of patients at follow—up.
`In a recent study by Scher et al,15 treatment of
`onychornycosis of the toenail with dosages of flu-
`conazole ranging between 150 and 450 mg once
`weekly for a mean period of 6 to 7 months result-
`ed irr a clinical success rate greater than 86% with
`a low relapse rate.
`Safety. More than 50 million adult and pediatric
`patients worldwide have taken fluconazole for fun-
`gal
`infections (including vaginal candidiasis,
`oropharyngeal and esophageal candidiasis), skin
`and nail infections, systemic carrdidiasis, and cryp-
`tococcal meningitis. The use of doses of 400 rng/
`day in severely ill, immunocompronrised patients
`confirms the safety and tolerability of flucona-
`zole.4 Fluconazole is well tolerated, and hepato—
`toxicity is rare. Daily doses as high as 1600 to
`2000 mg have been shown to be effective and well
`tolerated in severely ill patients, although these
`higher doses are not yet approved for use in most
`countries. Thus doses used in skin and nail infec-
`tions are well below the maximum doses in this
`
`wide dosage—safety margin.
`Adverse effects. Most researchers acknowl-
`
`edge that analyzing the adverse reactiorrs associat-
`ed with fluconazole is difficult because the drug
`has been used primarily in patients with severe
`underlying disease? In studies involving 4000
`patients receiving fluconazole therapy for 7 days
`or more for various indications. the incidence of
`side effects was 16%.“ Treatment was discorrtin—
`
`ued in 1.3% of patients because of laboratory test
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 6/8
`
`

`

`exfoliative ski-n eruptions. abnormal liver function
`tests, and, in some instances, hepatotoxicity.’6
`Drug interactions and contraindications.
`Rifampin enhances
`fluconazole metabolism.
`whereas fluconazole increases the prothrombin
`time of COLll]i£ll‘il1-l)/[)8 anticoagulants and iiicreas—
`es the plasma concentrations of phenytoin and
`cyclosporine.‘6 In addition. fluconazole increases
`serum theophylline concentrations
`and may
`increase the bioavailability of oral hypoglycemic
`agents. As with other azole antifungal drugs, coad—
`ministration of fluconazole with terfenadine,
`
`asteinizole, or cisapride is contraindicated.2~3»‘6
`Unlike itraconazole, absorption of fhicoiiazole is
`not affected by antacids or by drugs that increase
`gastric pH.16
`
`Terbinafiiie
`
`Terbinafine is a member of the allylamine class
`of antifungal agents. It exerts its antifungal effects
`at an earlier phase in fungal—cell membrane devel—
`opment than do the azoles.”
`Mechanism of action. Terbinafine’s 1necha—
`
`nism of action is different than the azoles. It blocks
`
`ergosterol synthesis by inhibiting squalene epoxi—
`dase. This inhibition results in an increase in squa-
`lene, which is toxic to fungal cells.
`In vitro,
`terbinafine is primarily fungicidal against der-
`matophytes, Aspergillus species, Scopu/ariopsis
`brevicaulis, Sporor/7ri,\‘ sc/ienckii, and the dimor-
`
`phic fungi Blcistoniyces dermariridis and Histo-
`plasma capsularzmi. Activity against yeasts is vari-
`able. Terbinafine is more active against Cparap—
`silosis than C albicans.3
`Pharmacokinetics. Oral terbinafine reaches the
`
`nail plate by diffusion from both the nail bed and
`nail matrix.9 When 250 mg/day of terbinafine was
`administered to healthy volunteers, the drug was
`detected in peripheral nail clippings after 7 days.9
`The concentration of terbinafine in nails 90 days
`after a 7-day course of medication greatly exceed-
`ed the MIC of common dermatopliytes.9
`Dosing. A 6-week course of 250 mg/day of
`terbinafine is effective in fingernail disease; a 12-
`week course at the same dose is generally effective
`in toenail disease.1-9
`
`Efficacy. In standard long—term treatment (6
`months for fingernails, 12 months for toenails),
`250 ing/day of terbinafine demonstrated inycolog—
`
`1 year after
`patients achieved inycologic cure at
`treatment. When treatment regimens of 250 mg/day
`for 6,
`l2, and 24 weeks were compared,
`shown that for onycliomycosis of the toenail, a 12-
`week course of treatment was comparable to 24
`weeks of therapy. A regimen of 250 ing/day for 6
`weeks in fingernail infection and 12 weeks in toenail
`infections achieved 90% and 80% cure rates, respec-
`tively. At l2 months, relapse rates were between 6%
`and 12% for fingernails and toenails, respectively?
`Safety. Terbinafine is generally safe and well
`tolerated, and there are few significant drug inter-
`actions. Although hepatotoxic reactions are rare,
`many experts believe that periodic monitoring of
`liver function and hematopoietic parameters is rea-
`sonable, as for itraconazole and fluconazole.1
`Adverse effects. The most common adverse
`
`effect reported with terbinafine in 3 US/Canadian
`clinical trials was headache, occurring in 12.9% of
`patients. Gastrointestinal disturbances and skin
`reactions accounted for most other adverse effects:
`
`diarrhea (5.8%), dyspepsia (4.3%), and nausea
`(2.6%); and rash, including urticaria (6.7%), and
`pruritus (2.8%).30 Less common side effects re-
`ported included fatigue, inability to concentrate,
`pain (back,
`leg, and flank), taste disturbances,
`erectile dysfunction, transient hypoglycemia, and
`elevated liver function tests. No specific muta-
`genic effects have been reported with terbinafine,
`and animal studies reveal no evidence of embry-
`onic or fetal toxicity or teratogenicity.2
`Drug interactions and contraindications.
`Terbinafine does not significantly induce or inhib-
`it
`the clearance of drugs metabolized by the
`
`cytochrome P-450 enzyme system; therefore at
`therapeutic levels, the potential for drug interac-
`tions is much lower for terbinafine than for the
`
`azoles. However, drugs that induce these enzymes,
`such as rifampin or phenobarbital, will increase
`plasma clearance of terbinafine, whereas drugs
`that inhibit these enzymes, such as cimetidine, will
`reduce terbinafine clearance. Bioavailability of
`terbinafine is not affected by the presence of
`food.2‘20 The only contraindication is hypersensi-
`tivity to terbinafine.20
`
`CONCLUSIONS
`
`Systemic treatment of onychomycosis has
`improved dramatically with the availability of the
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2056 - 7/8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 7/8
`
`

`

`newer antifungal agents itraconazole, fluconazole,
`and terbinafine. These drugs are generally safe and
`well tolerated and may allow shorter treatment
`periods. Selection of agents will depend on sever-
`al factors including spectrum of activity, potential
`for drug interactions, adverse effects, and patient
`preferences for specific dosage regimens. Treat-
`ment regimens range from continuous treatment
`with terbinafine for brief periods to pulse dosing
`with itraconazole 1 week each month or once-
`
`weekly dosing with fluconazole.
`
`REFERENCES
`
`l. Elewski BE, Charif MA, Daniel CR III. Onychomycosis.
`In: Scher RK, Daniel CR III, editors. Nails: diagnosis,
`treatment, surgery. 2nd ed. Philadelphia: WB Saunders,
`1997. p. 151-62.
`. Chiritescu MM, Chiritescu M-E, Scher RK. Newer sys-
`temic antifungal drugs for‘ the treatment of onychomyco-
`sis. Clin Podiatr Med Surg 1996; l3:74l—58.
`. Elewski BE, Hay RJ. Update on the management of ony-
`chomycosis: highlights on the Third Annual Inter-
`national Summit in Cutaneous Antifungal Therapy. Clin
`Infect Dis 1996;232:505-13.
`. Elewski BE. Once—weekly fluconazole in the treatment
`of onychomycosis. JAm Acad Dermatol l998;38:S73-6.
`. Scher RK. Onychomycosis is more than a cosmetic prob-
`lem. Br J Dermatol l994;l30(suppl):l5.
`. Lubeck DP, Patrick DL, McNulty P, Fifer SK, Birnbaum
`J. Quality of life of persons with onychomycosis. Qual
`Life Res l993;2:34l-48.
`. Drake LA, Scher RK, Smith EB, et al. Effect of ony-
`chomycosis on quality of life. J Am Acad Dermatol
`l998;38:702—4.
`. Rich P, Scher RK, Breneman D, et al. Pharmacokinetics
`of three doses of once-weekly fluconazole (150, 300, and
`450 mg) in the treatment of distal subungual onychomy-
`
`Journal of the American Academy of Dermatology
`June 1999
`
`cosis of the toenail. J Am Acad Dermatol l998;38:Sl03-
`9
`. Gupta AK, Scher RK, De Doncker P. Current manage-
`ment of onychomycosis: an overview. De1'1natol Clin
`l997;l5:l2l—35.
`. Meinhof W. Kinetics and spectrum of activity of oral
`antifungals: the therapeutic implications. J Am Acad
`Dermatol l993;29:S37-4l.
`. DeDoncker P, Decroix J, Piérard GE, et al. Antifungal
`pulse therapy for onychomycosis: a pharmacokinetic and
`pharmacodynamic investigation of monthly cycles of 1-
`week pulse therapy with itraconazole. Arch Dermatol
`1996;132:3441.
`. Epstein E. How often does oral treatment of toenail ony-
`chomycosis produce a disease-free nail? An analysis of
`published data. Arch Dermatol 1998;134:1551-4.
`. Sporanox® (itraconazole) 100 mg capsules: package
`insert. Titusville (NJ): Janssen Pharmaceutica Inc.
`. Hay RJ. Onychomycosis: agents of choice. Dermatol
`Clin l993;ll:l6l—9.
`. Scher RK, Breneman D, Rich P, et al. A placebo—con—
`trolled, randomized, double-blind trial of once-weekly
`fluconazole (150, 300, or 450 mg) in the treatment of
`distal subungual onychomycosis of the toenail. J Am
`Acad Dermatol l998;38:S77-86.
`. Diflucan® (fluconazole tablets). Package insert. New
`York: Pfizer Inc.
`
`. Assaf RR, Elewski BE. Intermittent fluconazole dosing
`in patients with onychomycosis. J Am Acad Dermatol
`l996;35:2l6—9.
`. Montero-Gei F, Robles—Soto ME, Schlager H. Flu-
`conazole treatment of severe onychomycosis. Int J
`Dermatol l996;35:587—8.
`I
`. Fraki JE, Heikkila HT, Kero MO, et al. An open—label,
`noncomparative, multicenter evaluation of fluconazole
`with or without urea nail pedicure for the treatment of
`onychomycosis. Curr Ther Res l997;58:48l-91.
`. Lamisil® (terbinafine hydrochloride tablets). Package
`insert. East Hanover (NJ): Novartis Pharmaceuticals
`Corporation.
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2056 - 8/8
`
`