CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2091 - 1/19
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`
`JOURNAL OF THE AMERICAN ACADEMY OF
`
`DERMATOLOGY
`
`AUGUST 1999
`
`VOLUME 41
`
`NUMBER 2 ' PART 1
`
`{TcI,q1!r{_L,*!tr if; J:-‘I115? 13,1.’ Iftc‘ .*lmr'H'cttii .=ICcie’c‘m1 I’ gf'1.icm:ttro{cgy mt‘.
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`c_p.N.a(_.
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`4.
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`ms
`''~‘
`0.5,
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`
`CONTINUING MEDICAL EDUCATION
`
`Loss of heterozygosity in human skin
`R-.:doll' Hupple, MD :1-iai*i:i.ii§t:. (}'ei‘mrm_ 1'
`
`CME examination
`
`Answers to CME examination (Identification No. 899-107).
`July 1999 issue of the American Academy of Dermatology
`
`Laser-assisted hair removal: Side effects of Q-switched Nd:YAG.
`long-pulsed ruby, and alexandrite lasers
`Cl1I‘i.'iE(ip}i(:I‘ A. _\.';1nni, MD, and Tina B. Alster. MD iii-moi‘:-i_:g!oiz. DC
`
`A new method to improve penetration depth of dyes into the
`follicular duct: Potential application for laser hair removal
`Cln'ys|;:in C. Sumizin, Fl"dT"lCl< B. Pitre. Phi). Béeitricc E. (jautlmr, IJVM.
`l\-1'.~1rtinc- Bnuclier. PhD. and Serge R. MUl'Lli.i1"l. PhD Scipbfci :'iit!i',i2cu’i's two‘
`Lilli‘, Fr.rmc'e
`
`Laser hair removal affects sebaceous glands and sebum excretion:
`A pilot study
`\\’/omphoitg MilI‘ll.l.'.il\'iE]iEl, MI). Chri.sl'ine C. Dic-riclor, MD. S:ll\-'flL'IDi‘ Gonzzilez. MD. PhD.
`'Tai—‘i"'tJ2m Dzlvid ljn, MI), PhD, V;1lc.*ri'.t B. C;in1pt,}.~:. MD, !'II‘nt:.-iu) Ci:_mz;ilez_. MD, uncl
`R. Rox Ande1‘son_. MD Hosirm. .-l-ict.x'~';'iu.'biiselix
`
`Primary cutaneous marginal zone B-cell lymphoma: A report of 9 cases
`A. cle I.-“I Fouclta1‘diei‘e, MD, B. Balme, MD. B. Ch:_:u\-'et, l\-ll), C. Scblann, Mi),
`H. Pc-rmt. MD, PhD. A. Cluucli-', MD, PhD, 1'’. A. Bl"\-'ClI'l. MD, PhD. B. Coifl'1e1'. NID. PhD.
`and F. Berger, MD, I’l1D.{_i'cm_.
`.-‘~‘i‘mtce
`
`Coiiii'n.iie:i’ cm ,i_:rige T".-i
`
`Vol. 41, No. 2, Part 1, August 1999. the Journal of the American Academy of Dermatology IISSN 0190-9622] is published monthly {six issues
`per volume, two volumes per year] by Mosby. Inc.. 11330 Westiine Industrial Dr, St Louis, MO 63146-3313. Periodicals postage paid at St Louis.
`Missouri. and additional mailing offices. Postmaster: Send address changes to Journal of the American Academy of Dermatology. Mosby. inc.,
`i1S3C|Westiine Industrial Dr, St Louis, MO 6314633 1 8.Annual subscription rates: 51o}‘.0l} for individuals, S2S9.DDfor institutions. Subscription prices
`effective through 5Ept.3Cl, 1999. Printed in the U.S_A_Copyright ©1999 by the American Academy of Dermatology, Inc., PO Box 4014. Schaurnburg.
`lL5Di58—4[l14.
`
`Nfl Mosby
`CFAD V. Anacor, IPRZO15-01776 ANACOR EX. 2091 - 2/19
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2091 - 2/19
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`

`
`Contents
`
`crmtirmed
`
`The impact of onychomycosis on quality of life: Development of an
`international onycltomycosis-specific questionnaire to measure
`patient quality of life
`l.ynn A. Drzikc, M F), Donultl L. Patrick, PhD. Philip Fit‘L‘i£l'1l'.-'iI’1, MD_._loset'te Anclrré. MD.
`Robert Bairain, MD. Ecl<;u‘1' H:lI1L".l\'C'. MD. Clzmclinc Sapctle, and Al'l[I_1I'l|.3ll£l
`'l't:.-ati, MD
`h'r.=5!on.,
`.I-f:¢.<.~:.:rcb.tiseH.~‘,- 5eam’e.
`ii’-ir.s£1:’i'.:Qtr:i1_.- l')’m.s<t-.'l'.a'_. Bel[er‘nm,- C1<t,=.tr'.re.s' (rm!
`;'._1'ou. !-‘r:.rnce.- ii’-‘wipe:"tar!-l;‘l:rg{i2Zd. (;'ern.=nir'1_r.- and lirifrigmr. r'(m[y
`
`Prevalence of skin disease in a cohort of shelter-based homeless men
`
`Alcx2imler_l. Sl'r:1tign:~'_. MI], Robert Ste-rn_. MD. Ernesto Goitxzilez. MD,
`Ril.‘l‘i{l.I‘(.i A||i:n_|i'i|1n~;nn, .\-1D,_l:1mt:s O‘Cr.innc-.l|, MD. ;mdJefTre_\_' 5. Dover, MD. FRCPC
`Bm'tr)n.
`.'l*1'c¥S.<c?t;'il?it$t’ff5
`
`The antifungal agent butenafine manifests anti-inflammatory activity in vivo
`Wztlter K. Nzihm. MD. PhD. Ida (Jrerigo. MD. Illlti Ted Rmsen. MI) HC.'tL5'fr)1I, }’£».-tut
`
`THERAPY
`
`Treatment of progressive pigmented purpura with oral bioflavonoids and
`ascorbic acid: An open pilot study in 5 patients
`I.-'. Rcinhnlcl. Ml), S. Sciter, MD. 5. L.|'gur:.'l. MD. and W lilgcn. MD
`Hr;;itr‘)traj2g!.S'rirr:: C-'ei‘m.».'rr.{1'
`
`Pharmacokinetics of doxepin in subjects with pruritic atopic dermatitis
`L}-"I111 A. DI'£ll\'t..’. MD.
`l.(JL|l.‘iC Ctnhcn, Pliztrrnf). Robert Gillies, Phi).
`_lame.~¢ G. Flr.mt|_. [?hD. Anne T. Riordan. MD, Scott B. I=‘l1illip:5, MD. :.1ml
`.\'Ia-ltthewj. Stiller, M D Bristrm. .lfrr.tscrctiu.r.s‘ett.<
`
`DE RMATOPATHOLOGY
`
`Targetoid hemosiderotic hen1angioma—a dynamic vascular tumor:
`Report of 3 cases with episodic and Cyclic changes and comparison with
`solitary angiokeratomas
`j. Amlrew Czirlstin, MD. FRCPC. Snume Datulat, MD. and Herhc=1't P GUt'i(ll“1L‘.;li'1, MI)
`.~i:':’Ja:t1'arrdi’otrq£i£?eepsr'e. Neu..= ion?
`
`DERMATOLOG [C SURGERY
`
`Microcystic adnexal carcinoma: Collaborative series review and update
`Paul M. Fi‘iCLilTI1lI‘I. MD, Rohin H. Frietlrnzm, MD. 5. Bri:in_]iang, MD,
`Key»-an .\'ouri. MD, Rex Amnneue, MD. and Perry Robins. MD r\-‘en-' lhrie, i-'\z'c'u= l'i;=r'k',
`mid .-'ller1i;;-br‘s‘. }‘&+i.u.!e.~;.~‘ce
`
`Statements and opinions expressed in the articles and communications herein are those ofthe authortsj and not necessarily those ofthe
`Editortsl. publisher, or Academy. and the Editor(s), publisher, and Academy disclaim any responsibility or liability for such material. Neither
`the Editortsi, publisher. nor the Academy guarantees, warrants. or endorses any product or service advertised in this publication, not do
`they guarantee any claim made by the manufacturer of such product or service.
`
`t;"u,=rtr'mn-cl’ ()7? fm'__Qe 9.-i
`
`i AM ./\t:.w DE'l‘xM-*\TL_'J|
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2091 - 3/19
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`7A
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2091 - 3/19
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`

`
`(,untents
`
`cormnued
`
`The birhombic transposition flap for soft tissue reconstruction
`"Fm: :t|1y M. _]: :ImsnI1, MD, '['imn1'I1y S. \IC*';1ng. MD, E'U'|LI D:1I‘rI:1I_]. F:1LIcr'.
`-.\2lI‘_J
`Arrrr m'br;:: .-'J:'c‘hr'gc:.u
`
`CLINICAL REVIEWS
`
`Drug interactions with itraconazole, fluconazole, and terbinafine and
`their management
`Adiryal K. Gupta. MD, FRCPC, H. Irving Kzltz, MI). anti Neil H. S|1e:1:'_. Ml’). FRCPC
`T&mJu!o. O:-.rmr:'o, 6'5:-mr.d.sz. amt‘ .-1-if:-:r:ea;;r;{is.
`.-‘.-J';'.m:ce.~:r_u‘rr
`
`Lupus turnidus
`Catherine 1.. Dekte. Ml’). Keith D. M:1nne.~‘._. MD_. Loretta S. Da\-is, MD, and
`Omar P. Sanguwa. MD Augusta. Georgsh
`
`CURRENT ISSUES
`
`T-cell receptor gene analysis in the diagnosis of Sézary syndrome
`Robin Russell-Jones and Seam \X-'hitt;1kerLo1m'tm. {_’m'm.:f lx'fn,;,Idr);3z
`
`Clinical Pearl: Vitamin E (Gt-tocopherol), 800 IU daily, may reduce
`retinoid toxicity
`Mark Lebwoh]. MD New Ibrfe. New lfinh
`
`[otaderma #67
`
`BRIEF REPORTS
`
`Lichen scrofulosortun-like eruption localized to multipuncture BCG
`vaccination site
`
`Young Min Park, line-n K:-lng. Sang Hyun Cho. and Baik KCL‘ Chm
`Sermf. Korea
`
`Transillumination blisters in a neonate
`
`F. Paul Saihen. MD, Neil F. Gibbs, MD. and Sheila Fallon Frietllrmcler. MD
`5(JJ'1})Er3g0. C'w’.f'for-rzfcr
`
`Increased risk of bullous pemphigoid in male and very old patients:
`A population-based study on incidence
`M:u'tinJLIng, \X-"e1'|1e1'Kippes. Gemlcl Mcssei‘, MD. DetIeI‘Zi||iker1s. MD. and
`Berthold R;-zany, MD, SCM .-ldanrmeirn,
`\1’r’r'irzb:r.:r;q, m-m"J,=.1'zn'.r.r.'c;'.7. Germcm'._1’
`
`Relation between antibodies to BP180 and gender in bullous pemphigoid
`[Dis-lncjizln, MI), ;1mI_Ic:1n—C1;1L1<Ie B)-'stI'yn. MD New IbP'JI’..
`.-'\-'eu' }Em'.?
`
`I f\:\-1A-.'.»\D Dl|{|\|.r\IOL
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`CFAD V. Anacor, IPRZO15-01776 ANACOR EX. 2091 - 4/19 _
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`I‘)‘7'~)
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`9A
`
`C’rm£:'rmea’ on ;>a_ge IUA
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2091 - 4/19
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`

`
`Contents
`
`cumirzued
`
`Epidermotropie cutaneous B-cell lymphoma mimicking mycosis fungoides
`C;u‘ie T. Chui. MD, Ricltilrtl T. [-lu]JpL‘, MI), Sabim: Kohlcr. MD. aml Ynun H. Kim. MD
`Szanfimr’. C.}.r:’.f,:‘?.J:'r.*.:‘u
`
`Treatment of hyperkeratosis areolae mammae naeviformis with the
`carbon dioxide laser
`
`Andnzzi.-5 Iitissc, MD, .\-1;1nfi‘ec| PI;"..‘iL‘T’I6I'|, MD. Erwin SL‘l1i_‘)|Jf. MD, and
`\‘O'o1fg&L:1g V‘.lI1.*i(.‘.h{.‘i(l[. MD !’re;'b.rng. Germt:m_1-'
`
`REVIEWERS FOR. VOLUMES 39 AND 40
`
`LETTERS
`
`Topical negative pressure in the treatment of pressure ulcers
`51152111 .-'\-lz1n_-' Cooper. .\-'IRCPLTK. M RCGP, and Elspeth Young. FRCP
`:‘m3er.s‘i9am,. {_.-'r.!.ia'ed Kf1zg.do1':r
`
`A case of Iidocaine absorption from topical administration of
`40% lidocainc cream
`
`Dale P. Gtmtlwin, RN. .\*1IEt'l. and Th(')111:=1s O. 1VlL‘J\"lt:€'.kiI1. MD
`Rr)cbesn91: Near }f'mi'e
`
`An estimate of the annual direct cost of treating cutaneous melanoma
`Martha-.w H, Ka112.ler_. MD Star‘,-’ose. C'a‘f{'fo:'nz'a
`
`Reply
`Hensin '1l~1ao, MD. PhD. Arthtlrj. Snher. MD. and Gary S. Rogers. MD
`ljoslon, .1-Iassctcbruezts
`
`What patients with psoriasis believe about their condition
`S. W’ I.anig:1n. MD. FRCF! DCI-I 13!‘f({_£{eJ£(.’,
`(..-"mired Kingdom
`
`Reply
`Donal G. Fortune. 135:, Helen L. Riclmrds, DC|inP5y, Sue Bowcock,
`Dip Higher Ed, Clam]. -.\121in, PhD. and Cl'II‘i5fU})l1t,‘I‘E. M. Griffitlts. Ml")
`Mancbesreag i.-fizftea’ Kmgcion-.'
`
`CORRECTION
`
`Correction to Tomaszewski M, Moad JC, Lupton GP
`G Am Acad Dermatol 1999;40:6A)
`
`ANNOUNCEMENTS
`
`American Board of Dermatology
`
`Call for Patients with Inherited Diseases of the Skin
`
`National Registry for lchthyosis and Related Disorders
`
`10A AlJL‘.LJS]'.
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2091 - 5/19
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`I A!»-1/\LT.-\1‘ Druwymn
`
`Cozttinrwd on page 1221
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`

`
`Contents
`
`co-ntinued
`
`READER SERVICES
`
`Information for authors
`
`Information for readers
`
`Dermatology calendar
`
`Dermatology opportunities
`
`Instructions for Category I CME credit
`
`CME examination answer sheet
`
`Statement of advertising in the Journal
`
`Index to advertisers
`
`24A, 25A, and 26A
`
`31A
`
`9 IA
`
`97A
`
`38A
`
`41A
`
`26A
`
`102A
`
`Access tables of contents and abstracts of articles from 1997
`
`forward on the Journal’s home page at:
`
`wwvv.mosby.com,/iaad
`
`Complimentary subscriptions to the Journal of the American Academy of Dermatology are available to
`dermatology residents, fellows, and osteopathic trainees in the United States and Canada as an educationai
`service by Westwood Squibb Pharmaceuticals, a division of Bristol—Myers Squibb Company.
`
`12A ALJGlJs"I'. PART 1, 1999
`
`I Am :\:;.m l)I_u.\-1.-xml
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`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`CLINICAL REVIEWS
`
`
`
`Drug interactions with itraconazole, fluconazole,
`and terbinafine and their management
`
`Aditya K. Gupta, MD, FRCPC_.‘‘ H. Irving Katz, MD}? and Neil H. Shear, MD, FRCPC”
`Ibrontti. ()ntm*£o, Canada, and Minm3apolr’s, Minnesota
`
`A drug iI'|It'|‘2'lCl.lC>1"I develop.-2 when the ei’Fet't ofa drug is increased or deci'easei_l or when 3 new effect is
`protlucetl hv the prior, concurrent. or sulnseqtieiit aclmini.~:ti'ation of the other. Before prescril‘iin_t§ a drug. it
`is important to obtain a l.'l‘it)I'("ILlgl1 drug histtnjv oithe pi'e.~.:cription and nonprescription medications talten
`by the patient. The nonprescription medications may include items such as nutritional suppiernents and
`herbal medications. The risk of sitle eliects is an inevit:-lhle consequence of tlrug use. The frequency of
`aclverse reactions is increasetl in those patients receiving multiple ntetlications. Drug interactions reported
`in animal oi‘ in vitro sttttlies [Titty not rtecesmrilv develop in l‘|LlI‘l‘1(iI‘i5. When drug in teractions are observetl
`with a paI‘tit'ultt1‘ agent, it cannot be zttltonmtieallt-' assttmecl that all closely related drugs will necessarily
`prot'lut‘(: the s:-Ame inte1‘2lt'tion. Hr_twe\'ei'_. caution is aclvisecl until sufficient experience accrues. The
`presct'iber shnultl not (J\«'L‘l‘L‘.S[ii'l12l[L‘ or untlerestimztte the potential for :1 given tlrug intemction on the hasis
`of [Jersonal expei'ienee alone. Drug interactions will not necessarily occur in every patient who is given a
`pai‘tit"u|ar combination of tlrugs known to protluce an interaction. For a clinically significant tlrug
`interaction to be manifest. several other factors may he relevzint other than just using the two tlrugs. In
`niztnv instances drug interactions can he pretlictetl and theI'efo1'e avuitlecl if the pha1'n1:icodvn:1mic effects,
`the pharniacokinetic properties. and the rnechanisms ofaetion ofthe 2 drugs in tiuestion are known. In the
`case of contraintlicatetl drugs. it may be possible to use an alternrttive agent.
`(_I Am Aeatl Dertnatul
`1999;41;33?-49._i
`
`he newer tiral antifungal agents flucnnazole,
`itraconazoie. and teihinafine were First intro-
`
`tiuceci into clinical practice less than Iii ve;1rs
`ago. Their comhinetl use wnrlciwitle for all indicta-
`tinns including systemic and super[‘icial niycoses
`because their initial launch is :1pproxin1atel}-' 100 mil-
`lion patients (:fluconazole_. 30 million patients; itra—
`cona7.o|e_. 40 million patients: terlnnaiine. Ill million
`patients}. Jtractinazole, ilut‘ort:17.o|e. anti terbinafine
`have prnvetl to be extremely safe with a high benefit-
`[U-I‘iSl{ ratio.‘ With these oral antifungal agents only,
`some of the expected :1t|verse reactions can he
`t1Ell‘il)tiit:‘Cl to clrug interactions.~’ The risk oi‘:tr;lverse
`
`From the Division of Dermatology, Department of Medicine,
`Sunnybrooit and Women's Health Science Center {SLinnybrool<
`site) and the University of Toronto Medical School,Tt:-rontoa; the
`Department
`of Dermatology, University of Minnesota,
`Minneapolis“; and the Division of Clinical Pharmacology,
`Department of Medicine and Department of Pharmacology.
`Sunnybrook and Women's Health Science Center {Sunnybrook
`site) and the University of Toronto Medical Schoo|,Toronto.‘
`Reprints are not available from the authors.
`Correspondence: Aditya K. Gupta, MD. FRCPC, 490 wonderland Rd
`South. Suite 6. London, Ontario, NEK 1L6, Canada. E—mail: agupta
`@execu1ink.corn.
`Copyright E1 1999 by the American Academy of Dermatology, Inc.
`0i9El—9622f99f$8.lJ0 + 0
`16i'1i‘9?351
`
`reacticms can he minimizecl h_v nhtaining a cletailetl
`history oi‘ both pt‘escription anti
`i‘iOI1[)I‘€5L‘1‘ipI’itJl‘I
`drugs t:1ken by the patient. In niany instances it is
`[mssilile to pretlict a drug interztction when the
`meclianism of action oi‘ the interacting agents. the
`pharmacotlynaiitic effects. anti the ph:trmacokinetic'
`properties are known. When 21
`tlrug lI“i[C'i‘3C[lUl'I
`involves 3. contraintiicatetl drug,
`in many instances
`1-1lLt.:‘.I‘t‘Ifl[iVt:‘ agents can he used safely. Improved
`undet'stancling regai'tling the mechanism of drug,
`interactions and their successful management is an
`important step in maintaining the high heneFit~to—
`risk ratio of the newer antifungal agents.
`
`WHAT IS A DRUG INTERACTION?
`
`A potential drug interaction refers to the po.ssil.1il-
`it}; that one drug rnay alter the intensity of pharma-
`t:o|ogit: effects of another tlrug tliat is given concur
`rently. The result may either he en|'iant'ecl or recluceci
`activity of the :1t'fet'tetl drug that may leacl tn toxicity
`or therapeutic failure. respetztively. It is also p:;is.silTIle
`that there is the appe:3u';1nce ofa new effect that is
`not seen with either drug alone.
`
`FREQUENCY OF DRUG INTERACTIONS
`The liequency of significant heneilcial or adverse
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2091 - 7/19 237
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`238 Gtrprcr. Krttz. arm’ .S‘bear
`
`I AM Amt) DERMATUJ
`Atloust‘ I999
`
`Table 1. Drug interactions: Myths and realities
`
`Myth
`
`Reality
`
`If a drug—drug interaction is listed on a chart or in a
`reference text, then coadministration is contraindicated.
`
`All drugs in the same chemical or structural class interact
`with other drugs in the same manner.
`All drug interactions have been carefully evaluated and
`proved to occur through prospective trials and detailed
`pharmacokinetic studies.
`All patients experience the same interactions in the
`same manner.
`
`Some interactions are contraindications; others may be
`managed by dosage adjustments andfor serum level
`monitoring.
`Drugs in the same chemical or structural class may or may
`not"cross interact” with other drugs in the same manner.
`Many drug interactions have been substantiated by small
`pharmacokinetic studies or derived from collections of
`analyzed case reports after clinical experience.
`Significant interpatient variability in drug metabolism often
`creates variable degrees of response and ciinical signif-
`cance among patients.
`
`to assess. Surveys that
`drug interactions is tlilTicult
`irtclLtt‘le tlatzl obtained in vitro, in animals, and in case
`
`reports tend to predict a frequency of interactions
`that is higher than actually occurs.-5 In one sun=ei.|-
`lance program there were 5601) aclverse drug reac-
`tions (_='i.:}'.3t3) in 8j,l.lI.iIJ drug exposttres." Drug inter-
`ttctions were Iielieverl to occur in 254 cases (l_l.;-’if?tI-I.
`
`In general, the incitlence of clinic:tl|_v significant Llrug
`interactions tlepentls on several factors including the
`age of the intlivitlua|_ pre-existing medical status,
`concomitant polvpharmaceutic exposures. nature of
`the specific tlrugs being taken. antl whether an inpa-
`tient or outpatient population is being consider-etl.
`
`ASSESSMENT OF RISK IN THE CLINICAL
`OUTCOME OF DRUG INTERACTIONS
`
`A plivsician may underestimate or overestimate
`the clinical impormnce ofa specillc drug interaction,
`because such an assessment is often hasetl on the
`
`clinical experience gainecl from the use ofthe partic-
`ular drug combination.‘ For ex:-Jmple, if no aciverse
`effect is observed after several patients have heen
`prescrihetl a particular tlrug combination, then there
`nary he :1 tendency to consider the interaction clini-
`callv unitnportant although in fact the interaction
`niay ptrocluce serious adverse effects in a small pro-
`portion of the patients.‘'‘ Alternatively, if the physi-
`cian I1-as :1 patient who experiences a serious aclverse
`effect after the use of a particular tiring comhination_.
`there may he the tendency to :lVUlLl this combination
`t'Ji'clrttgs; however, in pntctit.'e, the incidence ofsuch
`a reaction is actually uncon1tnon.‘3 Some tiring inter-
`action myths and realities are listetl in Tahle l.
`
`PATIENTS AT INCREASED RISK FOR
`DRUG INTERACTIONS
`
`Some patient groups m:t_v he at an increasetl risk
`It ur the t'leveloprnent oftlrug interact'ions. Ultier incli-
`
`vicluals are more likely to experience an adverse
`effect hecausr: of the pltysic-log,it‘ changes associated
`with the aging process and the higher fI'6C]l1L‘*.t'l(T_V of
`the use of multiple clrugs For a wide range of ail-
`ments. many of which require long-term treatment.“
`Patients who are st-.'ein_t1 multiple prescrilJet's_.
`patients who are infrequently or inaclequzttely moni-
`tored. patients with impaired pathways of drug elim-
`ination, and patients with certain pharmactrgenetic
`patterns are at increased rislv: for clrttg interactions
`In general, patients with the Following diseases that
`may require more than one medication are mort-
`
`likely to ltave an adverse drug reaction: carclirn-'ascu—
`lar, connective tissue. gastrointestinal, lipid,
`infec-
`tious, ps_vc.hiatric. respiratory. or seizure clisort‘lers.-7
`
`DRUG-DRUG INTERACTIONS
`
`Unclerstantling the mechanism of drug intet'at‘—
`tions may help the prescriber to avoid them. Drug
`interactions are considered clinically significant ifthe
`thc-t'ape.t1lic effectiveness of one of the interacting
`clrugs is decreased or if an adverse reaction mani-
`fests itselffi‘ The more important adverse clrttg,-drug
`interactions occur with tlrugs that have a serious tox-
`icity and low therapeutic index.3 In such instances
`relatively small changes in the clrug level may have
`ilT||)U1'I2ll'][ adverse consequences. Drug interactions
`may be either pharmacolcinetic or pharmacoclynarn-
`ic.-I In a pharmacokinetic clrug-tlrug interaction, a
`drug ntav alter the absorption, tlistrihtition. metabo-
`lism, or elimination of another mec|ication.‘3’ As a
`
`ct mseqttence, there may he an increase or decrease
`in the concentration of drug at the site of action.
`Beczzuse intlivitluals may v:1rv in the rate of disposi-
`tion of it given drug, the extent ofa drug interaction
`that alters pharmacokinetic parameters are not
`always pret'lict:ible.5 However. the consequences can
`be quite signilieant. A pharrnacotlvttamic intentction
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`
`tmu ALI.-\|3 l'Ji=Iw.AIoI
`\’-.IItmu -ll. NIJMIHR .2.
`
`lfluo 1
`
`Gzi.p!ct. Kzttz. and Sbem‘ 259
`
`.:ct'urs when :1 metlieation iI1tlLlt,'(:,‘5 a change in il
`patient's response to a drug without altering the
`phatrmacokjnetics ol‘ the obiect drug. for example,
`tlecreasetl receptor sensitit'itj,-2" It has been 5Llgg£3.'-il-
`etl t|‘I:1t such I‘t-ratflitms Ina}-' not he tlrtig inte1"'.lt_‘.tions
`unless an at'lvet‘se reaction ot'L‘Lu‘s.‘3
`
`HOW DRUG METABOLISM MAY RESULT
`IN DRUG INTERACTIONS
`
`Drugs may he tlivitletl into water-soluble (bolar)
`anti lipiti-soluble mmpountis.“‘ Altl1ou_tgh polar corn-
`pountls are usually t:‘X(.Tt‘i;‘lL‘tl tmcl1an_t;etl through the
`l\'lLlFI€."g.’.‘.i.
`lipitl cotttpountls generally have to be metab-
`olized to more polar metabolites before they can be
`e_\:L‘I'e[t".'Ll in the urine."’ Drug metabolism takes place
`mainly in the liver but to a lesser extent in other tis-
`sues (eg, the intestine, sltin. lutigs, l<it'lnejrs. blood. and
`h1‘:1in').'“ \‘0'lten :-t tlrug, is being metabolized to more
`polar comp: iuntls, 2| range of biochemical reactions
`can ot‘.t.’ur.
`|\1etabolic reactions may be subtlividetl into
`phase I and phase II readions. In the former, polar
`groups are ineorporateti into the clrug (eg. by oxida-
`tion. reduction. or hydrolysis], with o:-titlation being
`the most: common |.11:1[l‘I\\«':J.}-'.l'-' Phase 11 reactions
`include cnimiugation reactions. OXl[lilll\-"C metabolism
`of man_~.' drugs and t:[l'ic'l' compt_1LInLls tjeg, prosta-
`glantlin. Fatty acitls and steroids) occurs through the
`Lryttagliroine P—-—i_sti system. This is a collective term for
`.1 group of relatetl t'i'HZ}.-'l‘J‘t(':‘.‘§ or lSi‘)7._\-'l‘l’IIi‘.‘i.1U
`
`CYTOCHROME P-450 ISOENZYME
`NOMENCLATURE
`
`The cg-'tot‘hrome P--"Fit: isoenzj.-anes (isoforms) I-1l'('.' a
`group of henie-containing proteins that exist as gene
`supe1'l'ami1ies. They encode isoforms with distinct but
`overlapping substrate specificities. When carbon
`monoxide bintls to the (:I‘1Z}’lTI(: in the retlucetl state.
`the l1'I;LVlI'I‘ILlm spectral absorhance is observed at or
`near -151) nm, hence the name.” Cjr’L(,JCl‘lt'()mL‘ P--—}7_’>t.l
`isoforms are present in many tissues, with t.be highest
`L‘ont‘enlt‘;1l'itJn in the ent.lt_1p|asmit.‘ t‘ctit'ulum of hepa-
`tocytes. These metabolic enzynies are also present in
`high concentrations in enterottytes of the small intes-
`tine with smaller amounts in extrahepatit' tissues such
`as the ltitlneys. lung and hr;tin.l3 The nomenclature
`for c_v1ot-hronte P--150 iso|’orms that is widely usetl
`|t)('l:l_V was lirst suggestetl by Nebert et al"-" in 198? a ntl
`tliseossctl by J\-Iit:ha|ets‘—’ in 1998. It uses a _’2~Lier clas-
`siiic;1tion."'-1‘ The first tier of c|assil'ication is the litm-
`
`ily ('Ar:tbit‘ nt1mt',‘ral, >§l5‘?:’.a |1o1i1til(')gy in amino acid
`seqttenee): the secontl tier is the subfamily t_(.'apital
`letter. ‘,-’?‘.-‘i''» liiimolrag}-‘J. tmtl the thirtl tier is the int|i-
`vitlual gene (Arabic ntuneral). At least 12 cytottltrome
`I’--F30 gene families and 51 app;11'entl_v functional gene
`protlucts have been itlentifietl
`in hun1ans.‘*- The
`
`maior cytoclirome P-430 isoforms responsible for
`human tlrug metabolism are CY1’ 3A-‘i. CYP -_‘D{i. CIYP
`JAE. CYP 2C9, and CYP 2Cl9.
`
`Substrates
`
`Some drug are metabolized by more than one iso-
`form. For example. the |)l'1flI‘l'I1:1L‘Ul(JglL‘:1ll}-' active
`enantiomer S-warfartn is metabolized by the CYP
`2C9 isoform antl R-warfitrin is metabolized by the
`CY!’ 3:-'t.='i and CYP 1A2 isofo1'i11.1-’»“J»17 It is also possi-
`ble for a tlrug to inhibit or induce the activity of one
`isoform although it is not :1 suhstrate at that particu-
`lar site (_e_g_. quiniciine is metabolized by the CYP 5A4
`isoform but is a potent inhibitor of CYP 2D6).”-‘3v""
`
`Enzyme induction
`The time cout'se ofintluction is in part tlepenclent
`on the half-life ol’ the inducer (eg. rifarnpin has a
`short half-1il'e with enzyiiie intluction [CYP 5A4, CYP
`EC]
`tleveloping within 2-} hours); Iiowever. pheno-
`harbital has a longer half—|ife offi to -'3 tlays. a.ntl con-
`sequently it takes approximateit-' T? claws For induction
`(CYP 5A4. CYP 1A2, CYP EC} to become maniFest.13
`Another limiting factor Inay be the time it takes
`for (lf:g,I‘fl{_l£1[i{)l'1 of the cytochrome P-450 (eg. CYP
`3A~"i
`i5UI:I‘IK}-'l‘t‘1t‘ and new enzyme production). For
`CYP 3A4 this is typically '1 to 6 clays.”-'9
`Emsynte intluction may also be reduced in subjects
`with hepatitis or cirrhosis. Subsequentl_v. the ability to
`intluce tlrug metabolism may he retlucet|.13-3"
`
`Enzyme inhibition
`Enzynne inhibition may be the result of competi-
`tive or nont‘ompetitive bintling at the (SIT/__\’l'l'l{:‘ bin£l—
`ing site. When the inhibition is competitive. the
`onset and offset ofenzyme inhibition depend on the
`half-life and the time to steady state of the inhibitor
`drug (eg, cimetitline |C‘t'P JAE]. chloramphenieol
`|CYP .?.C9|_. antl acute ethanol ingestion typically
`inhibit tlrug metabolism within 24 hours ofa sin_t;le
`close). In contrast, amiotlarone {CYP 2C9) has a long
`ltztlf-|il'e; conset[ttet1tl_t-'. inhibitory interactions may
`not manifest lor months.13--’1
`
`The time periotl elapsed before the drug interac-
`tion is I‘l11;L‘*(iI‘|‘I2il (tmset anti terminittion) and is also
`dependent on the time period required for the
`inhibited tlt'tIg, to reach a new steady state (eg, when
`cimetitline inhibits theophjrlline. maximal ineleases
`in tlieophylline concentration are not obsewetl for 2
`clays because this is the time periotl over which theo-
`pbylline :tcltie\:es a new steady state).l3v33v3~”
`Nonrompetitivc inhibition occurs less commonly.
`antl the clot”.-ttion of inhibition may last for :1 longer
`periotl If new CYP is¢.1l't.1I't‘n has to he synthesizetl
`after tlisuintinuation of the inhibitor drtI_.r.:,. H-3“
`
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`
`240 Gttpict, :'\’t't.tz_. and failaero‘
`
`I no Acixo DH'\lvl!\TI.a
`Ar_ic;usT 19%
`
`Table II. Contraindicated drugs with itraconazole and possible alternatives
`Possible alternatives
`Corttraindicated drug
`
`
`Antihistamines:
`astemizole. terfenadine
`
`GI motility agent:
`cisapride
`
`Cho|estero|—|owering agents:
`simvastatin, lovastatin
`
`Hydroxyzine. cetirizine, fexofenadine, loratadine. other antihistamines
`
`Antacids or H2-antagonists litraconazole administered 1 or 2 h beforehand), lifestyle
`modifications. (Note: The cisapride alternatives do not truly duplicate what is accom-
`plished pharmacologicaliy by cisapride.)
`
`Pravastatimfluvastatin, or temporarily withhold cholesterol-lowering agent.
`(Note: Atorvastatin and cerivastatin are metabolized in the liver by cytochrome P450
`3A4.The use of these two drugs should be temporarily discontinued during
`itraconazole therapy.)
`
`Benzodiazepines:
`oral triazolarn, midazolam
`
`Zolpidem
`
`Note: This is only a guideline. Consult product monograph or up-to-date source for contraindicated drugs because the list may change witt-
`time.The list of possible alternatives may be updated as more information regarding drug interactions becomes available. Authoritative and
`current sources should be consulted before patient use.
`(Adapted from Gupta AK, Shear NH. An update: the risk-benefit of the newer antifungal agents in the management of onychomycosis. Drug
`Safety In press.)
`
`ITRACONAZOLE AND FLUCONAZOLE
`Absorption interactions
`
`The absorption of it1*acon2t‘x.r_tle, when administered
`
`as the capstile formulation. is enhanced by eoadminis-
`[nation with food.3‘*"-‘*‘5 Agents that increase gastric alka-
`linity (eg,
`l'll."'iT£l1T|lI"lC‘3 [I-13]-ljlockers, antacids. proton
`pump lI1l1llJi[O1'5, and oral ciiclaitositte) reduce itr2t-
`conazole capsule ;1l‘isorption. Itracortazole should he
`atlntinisterecl 1 to .33 hours before an H3—b|oclcer reg,
`cirnetidine, 1'anitidine') or an antacicl. Coadntinistmtiort
`
`ofztn acicllc bet-’er:1ge with ltl‘“.J.L‘0n:1Z0lf.‘ rnzty improve
`its l)iU3\«'tltl:Jl)ilit)-‘ in patients who have hvpochlot'hy-
`clria,39-5“ Itraconuzole is :1 weak base (_pKa = 5.7} and :1
`525-tnL can of Coca Cola Classic or Pepsi (pH 2.5)
`enables the tn':17_ole to he ionizetl.-“' Some beverages
`L'ltIJ not have at pH of less than 5. .-suggesting that these
`may not he as effective teg, Diet Coca Cola, Diet Pepsi.
`Diet 7'-Lip, Diet Canada Dry Ginger Ale. Diet Canada
`Dr_v Orange juice, 7-Up, Cunacla Dry Ginger Ale, and
`Canatla Dry Orange itiice).-’”--“>3 Diclztnosinr: is formu-
`lated with l1ttffei's to prevent its cle.stt'ttction by gastric
`acitl.-"5 ltraconztzole shoulcl be spacecl at least 2 hours
`apart from the cliclanosine for optimal alasottttiort.-*5--5*"
`Proton pump inhibitors ntav reduce absorption ol‘iti~.1—
`coitazole. Tlterefore when a patient is receiving 21 pro-
`ton pump lI'Il‘lll')ll‘(}I" it is especially iITlpDi'[£'lI'1t to ertsure
`that itraconztzole is taken after a full meal or 21 Coke
`
`Itrztco-nazole .-solution
`Classic or Pepsi beverage.
`absorption is not signif"1t'antly iitfltienceiil by the
`clegree of gastric acitlit}t5‘-'u-‘*5 In fact. for best absorp-
`tion the ill'EltL'Ol111.'{0ll'_‘ solution shoultl be €t{.lI‘I‘|lrl
`lS[E1‘€'L‘l
`
`in the fasting state.
`
`When lluconazole is Rlclrninisterecl with the
`
`antacid ntttgnesitim hytlroxicle. there was no effeczt
`on the ztbsorption or elimination of flticonaztile.-“-"'
`The pKa of fluconazole is '15. whereas that of kero-
`conazole has two values, 2.9 and 6.S.5"*‘“’Cin1etidine
`
`antl antacids can ntarlcetllv reduce ketoccma:r_:'_ilt
`absor_ption.'“ -‘13 When antatiitls tire given (.‘0I1L‘Ul'l'<.‘I‘II'—
`iv with fluconazole. plasma levels of llueona/.ole 1112!.)
`be i‘et'lticecl_. possibly as a result of clecreasecl absorp-
`tii:in.4"43 However. this change nt-av not be clinit:alh-
`significant.“-i Treatment with orneprazole may not
`interfere with the absorption and plasma ph:t1'mac.o-
`kinetics of l'lucon2tzole.'“
`
`Interactions with CYP enzymes
`The CYP jA~’l
`isolorm is
`the most common
`cvtochronie isoform found in the liver. it :1ct:otint.~:
`
`for 60% and 70% of hepatic and entetoclx-'tc
`t‘_vtot:hrome enzvines, respectively. With itrac"ona—
`‘stile. the basis nfsome of the drug inter:1c‘tion is thc
`inhibitionxincluction of CW’
`-'i5l.l
`3A4"
`isoforrn.
`
`Fluconztzole m;t_v inhibit both the CYP 4'50 3A4 :-.lI’1£l
`3C9 isoforms. The interactions between tltic'ot1a:r.olc'
`
`and phenytoin, 1'o]butatnide_. an-ti wztrfarin may he
`explttinecl bv the t1'i-azrile-inltiljiting CYP 3C9 isoform.
`l-iigher doses of flttcoimzole may inhibit CYP 3A4 to
`:1 greater‘ extent comparetl with lower doses of the
`triazole. The drugs that are contralnclic:;tted with iti‘a-
`f.‘.(.}I121?.{_)l{:‘ and possilale alternatives are listed in 'Ii1h|e
`1135 For both itraconazole ancl llucona;r.ole, the drug
`interactions clescribecl are tltose reported with con-
`tinuous closing sclieclules.
`
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`
`;'\.\-1 Ac,-tb Dt:w.M'ni.
`i
`\:’uI_t.IM1E 41. Nummzlt 2. PAM I
`
`ltraconazole
`
`Anticonvulsants (cg, phenytoin, phenobar—
`hital, carbamazepine).'-"v""“"*” C{J;i(lrl'lll1lS[l‘2l[lC!n
`-.\'itl‘I
`lEl‘:;1t.'(]l‘l:.12'.(_IlE:‘ rnay he ;tssr.)ei;1I-et'| with tetlucetl
`serum concentration of the triztzole. Phenytnin nttw
`_'I‘Il‘1‘.-ll1Ci:'
`the lii‘st-pzlss nietztholistn anti hepatic
`tmmibolism of the tri;1;r.o|e by CYP SA-—i._'-‘"7 The |f!l‘I:1I'—
`nwculogie ei"feets of hyclzintoins (_phenvtoin_. etho-
`.t_Jin, and mephen}-'toin_) Inay be increitseti as 3. ['C‘..‘SLll[
`ofinhihition of hytlttntuin nietahnli.-am.”-“
`Antihistalnioes (astemizole, terfenadi11e).*"“-'15
`'.‘.m1current '.1L"1ITilI1i5l'l‘:-lllt'J!‘i of astemizole and itr9.—
`t:cin:1zole is eonl'1'aintlieatetl hectttlse elevated con-
`
`.:,:entr¢ttions r,~fasten1izt_ile and its principztl n1etahn—
`lite. tiesmethvlztstemimle, may I'estIlt."*-95"’ Sin'Iil:li‘l}".
`mtlclntiitistmtiun with
`terfenatline
`results
`in
`
`intireztsetl pktsmu levels of the antihistzirnine. Both of
`these ;tntihist:tmines are centifsiitttlieatetl with itm-
`mnazole becziuse of an increased risk of torsatles tle
`
`pointes \«’E:‘l1[l‘lL‘LllEil‘ t:1t‘ltvc;Lt't'li:1.‘1-33
`Antimycobacterial agents (rifampin, isoni-
`azid, rifabutin).”‘*““"l C{)2i(lI'i‘il[‘1l.'~'[1'£l.lIlIZ‘ll'| with itr:1-
`emnazole may be ‘¢l."§SOL"l[lt€{l with decI'e;iset| serum
`itraconztzole L‘tJl1L‘t3'I‘i[l‘£ilLi(li"I because the metztbolism
`
`til’ the triazole is inclucetl. In El(.l(llii01'1,
`inziy increase serum ril‘.-tbutin levels.
`Benzodiazepines (cg, midazolam, triazolam,
`alprazolam).59"’7 (‘