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
(Bhatetal.AnnNYAcad Sci.2009andLexicomp)
Overdose• Colchicinecanbefatalinoverdose(estimatedat0.9mg/kg);stopimmediatelywhenGIsymptomsoccur(usuallywithinthefirst24hoursoftoxicdose);itisnotdialyzableorhemoperfusable (largevolumeofdistribution)butcolchicinespecificantigen-bindingimmunoglobulin(Fab)maybeused
(Bhatetal.AnnNYAcad Sci.2009andLexicomp)
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)
(Bhatetal.AnnNYAcad Sci.2009andLexicomp)
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
(Wolverton SE,2013,Lexicomp)
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
(Wolverton SE,2013,Lexicomp)
KeyPoints• Colchicineprimarilyworksbyinhibitingβ-tubulinpolymerization,therebyinhibitingmicrotubule-dependentcellularfunctions• Itisparticularlyeffectiveintreatingdiseasescharacterizedbypolymorphonuclear leukocyteinfiltration• WhilemultipleDermatologicdiseaseprocessesmayrespondtocolchicinetreatment,useoutsideofgoutandFMFareoff-labelandtypicallysecond-line,tobeusedwhenfirst-linetherapyeitherfailsoriscontraindicated/nottolerated• Dosingshouldbetitratedbasedontolerabilityandcomorbidities• PotentialinteractionswithotherP4503A4substrates,inhibitors,andinducersshouldbeconsideredpriortoandduringtherapy
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