colchicine in dermatology f051 - schneider - 13551...•colchicine primarily works by inhibiting...

ColchicineinDermatologyJeremyA.Schneider,MDAssistantClinicalProfessor

UCSanDiegoDepartmentofDermatology

• Conflictsofinterest:none.• Disclosures:• Nopersonaldisclosures.• Thispresentationincludesdiscussionsofoff-label usesofcolchicine.• Discussionofdrug-druginteractionsisnotcomprehensive.Pleasereviewpotentialinteractionsbetweencolchicineandyourpatients’medicationspriortoprescribing.

Colchicine• Colchicumautumnale• Bestknownforuseingoutandfamilial

Mediterraneanfever(FMF)• Dermatologicdiseases:

• Amyloidosis• Behçet disease• Psoriasis• Sweetdisease• Aphthous ulcers• LinearIgAdermatosis• Epidermolysisbullosaacquisita• Vasculitides• Morphea• Dermatomyositis• Primaryanetoderma• Relapsingpolychondritis• Dermatitisherpetiformis• Pachydermoperiostosis• TypeIIlepra reaction• Actinickeratoses• Condyloma

(Wolverton SE,2013,Bhatetal.AnnNYAcad Sci.2009,Bibas etal.J.Drugs Dermatol.2005.)

Pharmacokinetics• Oral;bioavailability:~45%;absorbedinjejunumandileum• Volumeofdistribution5-8L/kg• Halflife:27-31hours;twiceaslonginrenalfailure,10-foldinpresenceofcirrhosis+renalfailure• Timetopeak:30-120minutes;secondpeakinplasmavaluewithin6hours(enterohepaticrecirculation)• Proteinbinding:~39%• Metabolism:Hepatic(oxidativedemethylationbyP450system,isoformCYP3A4);2primary,1minormetabolites• Elimination:majoritybileinfeces;10-20%eliminatedunchangedinurine• Distribution:leukocytes(upto10daysafteroraladministration),kidney,spleen,liver(nodistributioninheart,skeletalmuscle,brain)

(Wolverton SE,2013andBhatetal.,AnnNYAcad Sci.2009)

MechanismofAction• Inhibitsβ-tubulinpolymerizationintomicrotubulesàmitoticarrestatmetaphase,decreasedcellmotilityandchemotaxis;preventsactivation,lysosomaldegranulation,andmigrationofneutrophils(endothelialadhesion)• MayalsointerferewithNALp3(cryopyrin)inflammasome activationandintracellularassemblyofneutrophilandmonocyteinflammasome complex(resultingindecreasedactivationofinterleukin-1β)• Inhibitssynthesisoftumornecrosisfactor-α,leukotrieneB4,prostaglandinE2,thromboxaneA2• Inhibitsactivityofcyclooxygenase-2activity• Inhibitsdelayedhypersensitivityreactions• Inhibitsreleaseofinsulin,histamine,andparathyroidhormone• Inhibitsmelanosomemovementinmelanophores (i.e.,dermalmelanocytesofamphibians)

(Wolverton SE,2013,Bhatetal.AnnNYAcad Sci.2009,Lexicomp)

Contraindications•ConcomitantuseofP-glycoproteinorstrongCYP3A4inhibitorinpresenceofrenalorhepaticimpairment•Knownallergy/hypersensitivity(Canadianlabeling)• Leukopenia,Thrombocytopenia,Blooddyscrasias• Seriousgastrointestinal,renal,hepatic,cardiacdisease(Canadianlabeling)

(Wolverton SE,2013,Lexicomp)

PregnancyCategory• FDACategoryC(riskcannotberuledout):

“Animalreproductionstudieshaveshownanadverseeffectonthefetusandtherearenoadequateandwell-controlledstudiesinhumans,butpotentialbenefitsmaywarrantuseofthedruginpregnantwomendespitepotentialrisks”

• Theoreticalteratogenicityduetoinhibitionofmitosis;howeverwomenwithfamilialMediterraneanfeverreceivingcolchicinehavebeenreportedtohavenormaldeliveriesandnormalnewborns• Presentinseraandbreastmilk;amountingestedbynursingbabyis<1/10th therapeuticdosegiventoadults

(Bhatetal.AnnNYAcad Sci.2009andLexicomp)

Adverseeffects• GI:diarrhea(upto77%),vomiting(17%),nausea(4-17%)• CNS:fatigue(upto4%),headache(2%)• Endocrine/metabolic:gout(4%)• Pulmonary:pharyngolaryngeal pain(3%)• Rarereportsofalopecia,aplasticanemia,azoospermia/oligospermia,,bonemarrowsuppression,dermatitis,depression,DIC,granulocytopenia,hepatotoxicity,hypersensitivityreaction,increasedCPK,ALT,AST,lactoseintolerance,leukopenia,myalgias,myasthenia,myopathy,myotonia,neuropathy,peripheralneuritis,purpura,rhabdomyolysis,thrombocytopenia,toxicepidermalnecrolysis,toxicneuromusculardisease


Overdose• Colchicinecanbefatalinoverdose(estimatedat0.9mg/kg);stopimmediatelywhenGIsymptomsoccur(usuallywithinthefirst24hoursoftoxicdose);itisnotdialyzableorhemoperfusable (largevolumeofdistribution)butcolchicinespecificantigen-bindingimmunoglobulin(Fab)maybeused


Toxicity

• Firststage(first24hoursafteringestion):gastrointestinalsymptoms+/- leukocytosis,dehydration;mayleadtohypokalemia,hyponatremia,metabolicacidosis• Secondstage(24-72hours):bonemarrowtoxicity,hepatotoxicity,renalfailure,DIC,cardiacarrhythmia,acuterespiratorydistresssyndrome,neuromusculardisturbances• Thirdphase(recovery):reboundleukocytosis,resolutionoforgansystemderangement,alopecia

(Wolverton SE,2013,Bhatetal.AnnNYAcad Sci.2009,Lexicomp)

Formulations

• Oral• Capsule

• Mitigare:0.6mg• Generic:0.6mg

• Tablet• Colcrys:0.6mg• Generic:0.6mg

• Intravenousformulation• Shorterhalf-life• Nolongeravailableduetotoxicity

• FDA2/6/2008;23deaths(pancytopenia,acuterenalfailure,disseminatedintravascularcoagulation)


Dosing• Usualdose:0.6mgPOBID-TID;taperasdiseaseactivityallows• Amyloidosis:1-2mg/day(Ben-Chetritetal.Semin.ArthritisRheum.1991)

• Behçet disease:1-1.5mg/day(Aktulga etal.Haematologica 1980,Davatchi etal.ModRheumatol.2009,Hazenetal.ArchDermatol.1979,Kaklamani etal.Semin ArthritisRheum.2001,Kazokoglu etal.AnnOphthalmol.1991,Saenzetal.CocrhaneDatabaseSyst Rev.2000,Yurdakul etal.ArthritisRheum.2001)

• Psoriasis(plaqueandpustular):0.02mg/kg/day;0.5-3mg/day;1%colchicineointment (Kaidbey etal.Arch.Dermatol 1975,Wahba etal.Acta.Derm.Venereol.1980)

• Sweetdisease:0.5-1.5mg/day(0.5mgTID)x10-21days(CohenPR.J.RareDis.2007,Masmoudi etal.Presse Med.2007)

• Recurrentaphthous ulcers:1.5-1.8mg/day(0.6mgTID)(Bibas etal.J.DrugsDermatol.2005)

• LinearIgAdermatosis:0.6-1mgBID-TID(Fortunaetal.Clin Dermatol.2012)

• Epidermolysisbullosaacquisita:0.5-3mg/day(max6mg/dayifnormalrenalandhepaticfunction) (Cunninghametal.JAmAcad Dermatol.1996,Megahed etal.ArchDermatol Res.1994)

• Vasculitis(LCCV/CSVV,idiopathiccryoglobulinemia,urticarialvasculitis):0.6mgBID-TID(Hazenetal.ArchDermatol.1979,Martinez-Teaboada etal.AmJMed.1997,Plotnick etal.ArthritisRheum.1989,Plaisieretal.Blood,2012,Venzor etal.Clin RevAllergyImmunol.2002,Wilesetal.ArchDermatol.1985)

• Morphea :upto3mg/day(Alarcon-Segoviaetal.JRheumatol.1979,Mintz etal.Int JRheumDis.2013)

Dosing• Dermatomyositis(calcinosis):1mg/day(children) (Fuchsetal.Clin.Rheumatol.1986,Stalder etal.

Presse Med.1984)

• Primaryanetoderma:1mg/day(Braunetal.JAmAcad Dermatol.1998)

• Dermatitisherpetiformis:1.2-2.4mg/day(Silversetal.Arch.Dermatol.1980)

• Relapsingpolychondritis:0.6mgTID(plusprednisoneandindomethacin)(Marketal.J.Am.Acad.Dermatol.2002)

• Pachydermoperiostosis:0.5mgdailyx1week,thenBIDx3weeks (Matucci-Cerinic etal.,Rheumatol Int. 1988)

• Type2lepra reaction:nostandarddosing (Kar HK,RoyRG,Lepr Rev.1988)

• Actinic keratoses:colchicine 1%gel BIDx1month (Grimaitre etal.Dermatology 2000)

• Penile condylomata:8%solution (may apply second application 1week after first)(VonKrogh G,Ruden AK.ActaDerm Venerol.1980)

Interactions• RiskX(donotcombine):antihepaciviral combinationproducts[1],conivaptan [2],fusidic acid[2],idelalisib [2]• RiskD(considermodificationoftherapy):CYP3A4inhibitors[1],fosamprenavir[1],HMG-CoAreductaseinhibitors[3.4],MiFEPRIStone [2],P-glycoprotein/ABCB1inhibitors[1,5,6,7],stiripentol [2],telaprevir [1],tipranavir [1]• RiskC(monitortherapy):CholineC11[8],cyanocobalamin[9],dasatinib [2],digoxin[1],fibric acidderivatives[3],fasaprepitant [2],luliconazole [2],lumacaftor[5,10],multivitamins[11],palbociclib [2]

Grapefruitjuicemayalsoincreaseserumconcentrationsofcolchicine.

1. Mayincreasecolchicineserumconcentration2. MayincreaseconcentrationofCYP3A4substrates3. Mayenhancemyopathic effect4. MayincreaseserumconcentrationofHMG-CoAreductaseinhibitor5. Maydecreaseserumconcentrationofp-glycoprotein/ABCB1substrates6. Colchicinemaylimitdistributionofp-glycoproteinsubstratestospecificcells/tissues/organs(suchasbrain,T

lymphocytes,testes)7. Mayincreasedistributionofcolchicinetocertaintissues(e.g.brain)8. Colchicinemaydiminishtherapeuticeffect9. Colchicinemaydecreaseserumconcentration10. Mayincreaseserumconcentrationofp-glycoprotein/ABCB1substrates)11. DecreasedabsorptionofB12(reducedintrinsicfactorreceptorsonintestinalmucosa),A,D,E,K,folate,iron

MonitoringParameters

• CBC,urinalysis,renalandhepaticfunction(baseline,considercheckingmonthlyforfirstfewmonths,thenatleastevery3months)• MayalsoconsiderCPK/CK(especiallyifconcurrentstatinorfibric acidderivativetherapy)• Extravigilanceinrenalpatientswithspecificattentiontodruginteractionsknowntoincreasetheriskoftoxicity


Managingadverseeffects

• Tolerancemaybeenhancedbystartingoncedailyandgraduallyincreasingfrequency(overweeks)• Myelosuppression(thrombocytopenia,leukopenia,granulocytopenia,pancytopenia)andaplasticanemia:drugdiscontinuation• Gastrointestinalsymptoms(anorexia,diarrhea,nausea,vomiting):dosereduction;diarrheacanbecontrolledwithaluminum-containingantacidsorantidiarrhealmedications• Myotoxicity/rhabdomyolysis(especiallyrenaldysfunction,elderly,concomitantcyclosporine,diltiazem,verapamil,fibrates,statins):discontinuation,symptomsusuallyselfresolvewithin1week-severalmonths


KeyPoints• Colchicineprimarilyworksbyinhibitingβ-tubulinpolymerization,therebyinhibitingmicrotubule-dependentcellularfunctions• Itisparticularlyeffectiveintreatingdiseasescharacterizedbypolymorphonuclear leukocyteinfiltration• WhilemultipleDermatologicdiseaseprocessesmayrespondtocolchicinetreatment,useoutsideofgoutandFMFareoff-labelandtypicallysecond-line,tobeusedwhenfirst-linetherapyeitherfailsoriscontraindicated/nottolerated• Dosingshouldbetitratedbasedontolerabilityandcomorbidities• PotentialinteractionswithotherP4503A4substrates,inhibitors,andinducersshouldbeconsideredpriortoandduringtherapy

References• Aktulga E,AltaçM,Müftüoglu A,Ozyazgan Y,Pazarli H,Tüzün Y,Yalçin B,YaziciH,Yurdakul S.Adoubleblindstudy of

colchicine inBehçet's disease.Haematologica.1980;65(3):399.

• Alarcon-SegoviaD,Ramos-Niembro F,IbanezdeKasep G,Alcocer J,TamayoRP.Long-termevaluationofcolchicineinthetreatmentofscleroderma.JRheumatol.1979;6(6):705.

• Ben-Chetrit,E.&M.Levy.ColchicineprophylaxisinfamilialMediterraneanfever:reappraisalafter15years.Semin.ArthritisRheum.1991;20:241–246.

• Bhat A,Naguwa SM,Cheema GS,Gershwin ME.Colchicine revisited.AnnNYAcad Sci.2009Sep;1173:766-73.

• Bibas,R.,N.K.Gaspar &M.Ramos-e-Silva.Colchicinefordermatologic diseases.J.Drugs Dermatol.2005.4:196–204.

• BraunRP,Borradori L,Chavaz P,MasouyéI,French L,Saurat JH.Treatment ofprimary anetoderma with colchicine.JAm Acad Dermatol.1998Jun;38(6Pt 1):1002-3.

• CallenJP,af Ekenstam E.Cutaneousleukocytoclastic vasculitis:clinicalexperiencein44patients.SouthMedJ.1987;80(7):848.

• CallenJP.Colchicineiseffectiveincontrollingchroniccutaneousleukocytoclastic vasculitis.JAmAcad Dermatol.1985;13(2Pt1):193.

• Colchicine.Lexi-Drugs.Lexicomp.WoltersKluwerHealth,Inc.Riverwoods,IL.Availableat:http://online.lexi.com.

• Cohen,P.R.2007.Sweet's syndrome–acomprehensive review ofanacute febrile neutrophilic dermatosis.Orphanet.J.Rare Dis.2:34.

• CunninghamBB,Kirchmann TT,WoodleyD.Colchicineforepidermolysisbullosaacquisita.JAmAcad Dermatol.1996May;34(5Pt1):781-4.

• Davatchi F,Sadeghi Abdollahi B,TehraniBanihashemi A,Shahram F,Nadji A,ShamsH,Chams-Davatchi C.ColchicineversusplaceboinBehçet's disease:randomized,double-blind,controlledcrossovertrial.Mod Rheumatol.2009;19(5):542-9.Epub 2009Jul 14.

• FortunaG,Marinkovich MP.LinearimmunoglobulinAbullousdermatosis.Clin Dermatol.2012;30(1):38.

• Fuchs,D.,L.Fruchter,B.Fishel,etal .Colchicine suppression oflocal inflammation due tocalcinosis indermatomyositis andprogressive systemic sclerosis.Clin.Rheumatol.1986;5:527–530.

• Grimaitre M, Etienne A, Fathi M,etal.: Topical colchicine therapy foractinic keratoses. Dermatology. 2000;200:346-348.

• HazenPG,MichelB.Managementofnecrotizingvasculitiswithcolchicine.ImprovementinpatientswithcutaneouslesionsandBehcet’s syndrome.ArchDermatol.1979;115(11):1303.

• Kaidbey,K.H.,J.W.Petrozzi &A.M.Kligman.1975.Topical colchicinetherapy forrecalcitrant psoriasis.Arch.Dermatol.111:33–36.

• Kaklamani VG,Kaklamanis PG.Treatmentof Behçet's disease--anupdate.Semin ArthritisRheum.2001;30(5):299.

• Kar HK, Roy RG: Comparison of colchicine and aspirin inthe treatment of type2lepra reaction. Lepr Rev. 59:201-203 1988

• Kazokoglu H,Saatçi O,Cuhadaroglu H,Eldem B.Long-term effects ofcyclophosphamide andcolchicinetreatmentinBehçet'sdisease.AnnOphthalmol.1991;23(4):148.

• Mark,K.A.&A.G.Franks,Jr.Colchicine andindomethacin forthe treatment ofrelapsing polychondritis.J.Am.Acad.Dermatol.2002;46:S22–S24.

• Martinez-Teaboada VM,BlancoR,Garcia-FuentesM,Rodriguez-Valverde V.Clinicalfeaturesandoutcomeof95patientswithhypersensitivityvasculitis.AmJMed.1997;102(2):186.

• Masmoudi,A.,H.Chaaben,K.Hamdouni,etal.2007.Sweet syndrome:retrospective study of54cases.PresseMed.36:419–424.

• Matucci-Cerinic M, Fattorini L, Gerini G,etal.: Colchicinetreatmentinacaseofpachydermoperiostosis withacroosteolysis.Rheumatol Int. 1988;8:185-188.

• Megahed M,Scharffetter-Kochanek K.Epidermolysisbullosaacquisita—successfultreatmentwithcolchicine.ArchDermatol Res.1994;286(1):35-46.

• Mintz EM,MorelKD.Clinicalfeatures,diagnosis,andpathogenesisofchronicbullousdiseaseofchildhood.Dermatol Clin.2011Jul;29(3):459-62,ix.

• NohJW,KimJ,Kin JW.Localized scleroderma:aclinical study atasinglecenterinKorea.Int JRheum Dis.2013Aug;16(4):437-41.

• Plotnick S,HuppertAS,KantorG.Colchicineandleukocytoclastic vasculitis.ArthritisRheum.1989;32(11):1489.

• SaenzA,Ausejo M,Shea B,WellsG,WelchV,Tugwell P .PharmacotherapyforBehcet's syndrome.CochraneDatabaseSyst Rev.2000.

• Silvers,D.N.,E.A.Juhlin,P.H.Berczeller &J.McSorley.Treatment ofdermatitis herpetiformis with colchicine.Arch.Dermatol.1980;116:1373–1384.

• Stalder,J.F.,A.David,J.Y.Cohen&H.Barriere.Dermatomyositis inchildren.Use ofcolchicine inoutbreaks ofcalcinosis.PresseMed.1984;13:441.

• TerrierB,Krastinova E,MarieI,Launay D,Lacraz A,Belenotti P,deSaint-MartinL,Quemeneur T,Huart A,BonnetF,LeGuenno G,KahnJE,Hinschberger O,Rullier P,Diot E,LazaroE,Bridoux F,Zénone T,Carrat F,HermineO,LégerJM,MarietteX,SenetP,Plaisier E,Cacoub P.Managementofnoninfectiousmixedcryoglobulinemia vasculitis:datafrom242casesincludedintheCryoVas survey.Blood.2012;1119(25):5996.

• Venzor J,LeeWL,HustonDP.Urticarialvasculitis.Clin RevAllergyImmunol.2002;23(2):201.

• VonKrogh G, Ruden AK: Topicaltreatmentofpenilecondylomata acuminata withcolchicineat48–72-hourintervals. Acta DermVenereol. 1980;60:87-89.

• Wahba,A.&H.Cohen.1980.Therapeutic trialswithoral colchicineinpsoriasis.Acta.Derm.Venereol.60:515–520.

• WilesJC,HansenRC,LynchPJ.Urticarialvasculitistreatedwithcolchicine.ArchDermatol.1985;121(6):802.

• Wolverton,StephenE. ComprehensiveDermatologicDrugTherapy.Edinburgh:Saunders/Elsevier,2013.

• Yurdakul S,MatC,Tüzün Y,Ozyazgan Y,Hamuryudan V,Uysal O,Senocak M,Yazici H.Adouble-blindtrialofcolchicineinBehçet'ssyndrome.ArthritisRheum.2001;44(11):2686.

colchicine in dermatology f051 - schneider - 13551...•colchicine primarily works by inhibiting...

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