Class Update: Benign Prostatic Hyperplasia (BPH)

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1 Copyright 2012 Oregon State University. All Rights Reserved Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35, Salem, Oregon Phone Fax ClassUpdate:BenignProstaticHyperplasia(BPH) Month/YearofReview:November2012 DateofLastReview:September2010 PDLClasses:BenignProstaticHyperplasia SourceDocument:ProviderSynergies CurrentStatusofPDLClass: PreferredAgents: o Alpha Blockers:DOXXAZOSIN,TAMSULOSINHCL,TERAZOSINHCL o 5 AlphaReductaseInhibitors:FINASTERIDE NonPreferredAgents: o Alpha Blockers:ALFUZOSIN(UROXATRAL ),SILODOSIN(RAPAFLO ),PRAZOSIN(MINIPRESS ),DOXAZOSINER(CARDURAXL ), PHENOXYBENZAMINE(DIBENZYLINE ),INDORAMIN(BARATOL ) o 5 AlphaReductaseInhibitors:DUTASTERIDE(AVODART ) o Combination:DUTASTERIDE/TAMSULOSIN(JALYN ) ResearchQuestions: IsthereanynewevidenceofsuperiorityinefficacyorsafetyofoneagentforBPHoveranother? Isthereanynewrelevantevidencetochangecurrentpolicy? Conclusions: Thereisnonewevidencesuggestingsuperiorityofoneoftheneweralpha blockersor5 alphareductaseinhibitorsoveranotherinefficacyor safety. Tadalafildemonstratedimprovementsinurinarysymptomscomparedtoplaceboinpatientswithlowerurinarytractsymptoms,but demonstratednodifferenceinpostvoidresidualvolumeorurinaryflowrate. TadalafilisalsoindicatedforpatientswithconcurrentBPHanderectiledysfunction(ED).EDisnotacovereddiagnosisundertheOregonHealth Plan. Thereisinsufficientevidencetodemonstratesuperiorityoftadalafiloverstandardtreatment(alpha blockers). 1

2 Recommendations: Maintainatleastonealpha blockerandone5 alphareductaseinhibitoraspreferredonthepdl. Recommendmakingtadalafilnon preferredforthetreatmentofbph.becausemedicationstotreatimpotencyorerectiledysfunctionarenot coveredbytheoregonhealthplan,updatepacriteriaforindicationoftadalafilforthesimultaneousoccurrenceofbphanderectiledysfunction. ContinuetorequirepriorauthorizationinaccordancewiththeOregonHealthPlanlistofprioritizedhealthservicesandtolimitcosmeticuse. PreviousRecommendations: PreviousevidencedoesnotsupportadifferenceinefficacyoreffectivenessbetweendifferentBPHmedications. Accordingtopriorevidence,nodifferenceswerefoundbetweenmedicationsintermsofharmsandadverseevents. ItisrecommendedthatatleastoneAlpha blockerandone5 AlphaReductaseInhibitorbeincludedonthepreferreddruglist(PDL). Considerpriorauthorizationcriteriatolimitcosmeticuse. Background: InBPH,theenlargedglandcontributestolowerurinarytractsymptoms(LUTS)throughdirectbladderoutletobstructionandincreasedsmooth muscletoneandresistance. 1 ThemaincausesofLUTSincludeabnormalitiesofthebladder,prostate,urethra,orsphincters. 2 Theprimarytreatment goalhasbeentoalleviateinconvenientlutsandmorerecentlytoaddressthepreventionofdiseaseprogression.lutsincludesstorageand/or voidingdisturbancescommoninagingmenduetostructuralorfunctionalabnormalities. 1 TheAmericanUrologicalAssociation(AUA)guidelineson themanagementofbphrecommendalpha blockersforpatientswithbothersome,moderatetoseverelutsandtheyhaveequalclinical effectivenesswithslightdifferencesinadverseeventprofiles. 1 Thecombinationofanalpha blockerwitha5 alpha reductaseinhibitoris recommendedwhenthelutsisassociatedwithprostaticenlargementand5 alphareductaseinhibitorsshouldnotbeusedwhenbphisnot associatedwithprostateenlargement. 1 GuidelinesfromtheNationalInstituteforHealthandClinicalExcellencerecommendanalphablocker (afluzosin,doxazosin,tamsulosin,orterazosin)tomenwithmoderatetosevereluts,ananticholinergictomenwiththesymptomsofoveractive bladder,anda5 alphareductaseinhibitortomenwhohaveprostatestobelargerthan30gorapsalevelgreaterthan1.4ng/mlandwhoare consideredtobeathighriskforprogression. 2 TheOregonHealthPlan(OHP)onlycoversBPHwithurinaryobstructionwhenpostvoidresidualsareat least150cc sandunspecifiedurinaryobstructionandbphwithobstructionisanunfundeddiagnosis. 3 CurrentpriorauthorizationcriteriafortheBPH medicationsarefoundinappendix1. Methods: AMEDLINEOVIDsearchwasconductedusingallincludeddrugswithbenignprostatichyperplasiaandlimitsforhumans,Englishlanguage,and controlledclinicaltrialsorrandomizedcontrolledtrialsfrom2010tocurrent.thecochranecollection,pubmedhealth,dynamed,thecanadian AgencyforDrugandTechnologiesinHealth(CADTH),andtheCentreforReviewsandDissemination(DARE)weresearchedforhighqualitysystematic reviews.thefdawebsitewassearchedfornewdrugs,indications,andsafetyalerts,andtheahrqnationalguidelineclearinghouse(ngc)andthe AmericanUrologicalAssociation(AUA)weresearchedforupdatedandrecentevidence basedguidelines. 2

3 NewTrials: Atotalof43citationsresultedfromtheinitialMEDLINEsearchandafterreviewforinclusion,15potentiallyrelevantclinicaltrialswereidentified (Appendix2).Theothertrialswereexcludedduetolackofrelevantoutcomes,comparisonstoothernon pharmacologicaltreatmentsand/orno head to headstudies.thesetrialsarebrieflydescribedintable1. Table1:Studydetails Study Comparison Population PrimaryOutcome Results Karadag,etal. 4 Randomized crossover comparison study Chung,etal. 5 Multicentre, prospective, randomized study Nickel,etal. 8 RCT,doubleblind,doubledummy, multicentre Tamsulosin(10mg) toalfuzosin(0.4mg) vs.alftotam Doxazosingastrointestinal therapeuticsystem GITS4mgvs. Tamsulosin0.2mg Silodosin4mgbid vs.tamsulosin 0.2mgqam+ placeboqpm Doxazosin GITS4mg vs.tasmulosin 0.2mg Dutasteride0.5mg vs.finasteride5mg MenwithBPH admittedwithlower urinarytract symptoms(luts) Maleambulatory patientsover50 yearsofagewith LUTS. MenwithBPHaged >40yearswithan IPSSof>13 Chinesemenaged >50yearswith LUTS/BPH. Menaged>50years withaclinical diagnosisofbph Effectivenessofswitching alphablockersbasedon improvementinipss,qol, averageflowrateandvoided urinevolume. Comparisonofearlyonset (overa12weekperiod) efficacybetweenthetwo drugsusingipssscores. Meanchangefrombaselineto endpointinipss. Yu,etal. 6 RCT,doubleblind, multicentre Zhang,etal. 7 Prospective, multicenter, randomized, open,parallel study Changefrombaselineinselfreportednocturiaaccording totheipssandfvc,qualityof sleepandqualityoflife. Changeinprostatevolume Beforeswitch(Successrate)Afterswitch(Improvement) TamtoAlf:42%Tam27.5%Alf AlftoTam:47%Alf14%Tam TamandAlfshowedequaleffectivenessinthetreatment ofbph.ifabphpatientdoesnotrespondtoonealphablocker,thenswitchingtoadifferentalpha blockermay providebenefitfor %ofpatients.(P<0.001) ImprovementintotalIPSSscorefrombaseline VisitDoxazosin GITSTamsulosinpvalue Week1( 7.62), 37.5%( 5.02), 27.5%0.021 Week4( 8.56), 42.2%( 6.34), 34.8%0.030 Week12( 9.27), 45.6%( 5.48), 27.3% DecreaseinIPSS(>25%)MeandifferenceinIPSSchange S:86.2% 0.60,95%CI( 2.15,0.95) T:81.9% P=0.53 Reductionfrombaselineinmeannocturia(FVC/IPSS) Week4:D:1.7,T:1.3(P=0.001)/D:1.5,T:1.1(P=0.001) Week8:D:2.1,T:1.7(P=0.001)/D:2.0,T:1.6(P<0.001) Percentagereportedimprovedsleep Week4:D:43.6%,T:27.4%(P=0.020) Week8:D:81.9%,T:67.4%(P=0.022) Improvementinqualityoflife(Lowernumber=betterQoL) Week4:D:2.5,T:2.8(P=0.001) Week8:D:2.1,T:2.5(P<0.001) Meanpercentreductioninprostatevolume 3months:F:18.5%,D:18.3%(P=0.76) 12months:F:26.7%,D:26.3%(P=0.65,CI ) Reductioninprostatevolumeat12months >40cm 3 baseline:f:27.7%,d:27.6%(p=0.90) <40cm 3 baseline:f:24.2%,d:22.6%(p=0.37) 3

4 Watanabe,et al. 9 RCT,crossover, comparative, open label Montorsi,etal. 10 posthocanalysis Roehrborn,et al. 11 Posthocanalysis Tamsulosin(0.2mg) tosilodosin(4mg) vs.silototam Dutasteride0.5mg vstamsulosin0.4mg vs.combination Dutasteride0.5mg vs.tamsulosin 0.4mgvs.combined therapy UntreatedJapanese mendiagnosedwith LUTS/BPHandan IPSS>8andIPSS QoL score>2 Men>50yearswith moderate to severe LUTSduetoBPHat riskofdisease progression Menaged>50years withdiagnosisof BPH Patient reportedpreferred drugfortreatment continuationat8weeks Meanchangesfrombaseline inipss. TimetofirstAURorBPHrelatedsurgery PatientpreferredDrug Tamsulosin:59/84(70.2%) Silodosin:18/84(21.4%) P=NS MeanchangesfrombaselineinIPSSat4years Combination: 6.3 Dutasteride: 5.3 Tamsulosin: 3.8 P<0.001 Combinedtherapy(dutasteride+tamsulosin)was statisticallybetterthantamsulosinaloneinreducingthe riskofaurorbph relatedsurgery(p<0.001).the incidenceofsurgerywashigherwithtamsulosinthanin dutasterideorcombinedtherapy(p<0.001). Miyakita,etal. 12 RCT,crossover Montorsi,etal. 13 Posthocanalysis Yanqun,etal. 14 RCT,DB,parallel group,placebo controlledwith anopenlabel extension Shin,etal. 15 Retrospective study Kruep,etal. 16 Retrospective study Silodosin(4mg)to Tamsulosin(0.2mg) vs.tamtosil Dutasteride0.5mg vs.tamsulosin 0.4mgvs.combined therapy Dutasteride(D/D) 0.5mgvs.placebo(6 months)to dutasteride(p/d) Alphablockervs. combination(alpha blocker+5 alpha reductaseinhibitor) 5 alphareductase inhibitorearly (within30daysof BPHpatients complainingofluts Menage>50years withmoderate toseveresymptomsof BPH Chinesemenaged >50yearswith diagnosisofbph Patients>40years withanipssof<7 andpreviously treatedforbph withoutaurorbphrelatedsurgery. Men>50yearsof agewithbphoran enlargedprostate ChangeintotalIPSSfrom baseline ChangefrombaselineinIPSS andbiiscoreswith combinationvs.monotherapy Percentagechangeintotal prostatevolume(tpv)from baselineat6months Differenceinincidencesof AURandBPH related surgeriesbetweenthetwo groups AUR,prostatesurgery,and clinicalprogression (combinationofthetwo ChangeinIPSStotalscoreafterfirstdrug S: 7.7±5.9,T: 4.6±5.4(P<0.05) ChangeinIPSSaftercrossover S: 2.6±3.8,T:0.3±4.3(P<0.01) MeanchangeinIPSSfrombaseline Combo: 1.5,D: 1.3,T: 1.1(P<0.001) MeanchangefrombaselineinBIIscores Combo: 2.2,D: 1.8,T: 1.2(P<0.001) MeanreductioninTPVat6months D/D:17.14% P/D:3.71% P<0.05 IncidenceinAUR Alphablocker:50/368(13.6%) Combination:7/252(2.8%) P<0.001 IncidenceofBPH relatedsurgeries Alphablocker:31/368(8.4%) Combination:8/252(3.2%) P=0.008 PercentageofpatientswithAUR Early:10.2%,Late:13.8% P<

5 Madani,etal. 17 RCT,doubleblinded Oelke,etal. 18 RCT,doubleblinded startinganalpha blocker)vs.delayed therapy( daysafterstarting alphablocker) Standardtreatment +tadalafil10mgvs. standardtreatment alone(placebo) Tadalafil5mgvs. Tamsulosin0.4mg vs.placebo Patientswith obstructiveand irritativeurinary tractsymptomsdue tobph,ipss>8 Men>45yearsof agewithluts/bph above) DifferencesinIPSS,Qmaxand QoLafter3monthsbetween groups EfficacybasedonIPSSand BPHImpactIndex(BII) Percentageofpatientswhounderwentsurgery Early:5%,Late:7% P= Percentageofpatientswithclinicalprogression Early:12.8%,Late:17.4% P< Meanvaluesaftertreatmentofthetwogroups PlaceboDrugP value IPSS11.37± ± QoL2.19± ± Qmax8.73± ± IPSSmeandifferencefromplacebo Tadalafil: 2.1(95%CI 3.3to 0.8,p=0.001) Tamsulosin: 1.5(95%CI 2.8to 0.2,p=0.023) BIImeandifferencefromplacebo Tadalafil: 0.8(95%CI 1.3to 0.3,p=0.003) Tamsulosin: 0.6(95%CI 1.1to 0.1,p=0.026) IPSS=InternationalProstateSymptomScore;FVC=frequencyvolumechart;AUR=Acuteurinaryretention;QoL=qualityoflife Newdrugs: TheFDAapprovedtadalafil(Cialis )inoctoberof2011totreatthesignsandsymptomsofbphandforthetreatmentofsimultaneousoccurrenceof BPHanderectiledysfunction. 17,18 Intwoclinicaltrials,menwithBPHonstandardtreatment(alpha blockers)werecomparedtostandardtreatment inadditionto5mgoftadalafilonreductionofsymptoms.themeanchangeintheinternationalprostatesymptomscore(ipss)frombaselineto endpointfortadalafilversusplacebowas 5.00versus 2.67.AccordingtotheAUAguidelines,a3 pointimprovementinipsswassuggestedasthe minimumperceivedbypatients. 19 However,itfailedtoshowasignificantimprovementinmaximalurinaryflowrate(Qmax)orpostvoidresidual urinevolume.therewasnosignificantdifferenceinseriousadverseevents.arecentsystematicreviewfoundthattadalafilorother phosphodiesterase 5inhibitorscouldsignificantlyimprovesymptomsinpatientswithcomorbidBPHandED,howeverinthosewithoutEDtherewas nosufficientdatatoprovesuperioritytoalpha blockersforfirst linetreatment. 19 NewCombinationProducts: TheFDAapprovedthecombinationofdutasterideandtamsulosinhydrochloride(Jalyn)inJune2010forthetreatmentofBPH.Thelabelinghasthen beenrevisedtoincludetheriskofhigh gradeprostatecancerduetodutasteride,itseffectsonserumprostatespecificantigen,andinformation regardingmalebreastcancer. 16,17 NewFormulations/Indications: TheFDAapprovedgenericalfuzosinhydrochloride10mgextended releasetabletsinjulyof2011.thedivisionofbioequivalencehasdeterminedthat the10mgdoseistherapeuticallyequivalenttouroxatral10mgextended releasetablets. 5

6 TheFDAalsoapprovedgenericdutasteridecapsules0.5mginDecember2010.TheDivisionofBioequivalencedeterminedthatthe0.5mgdutasteride capsuleistherapeuticallyequivalentandbioequivalenttoavodartcapsules0.5mg. NewFDAsafetyalerts: TherewasanewFDAdrugsafetycommunicationinJuneof2011regardingtheincreasedriskofbeingdiagnosedwithamoreseriousformof prostatecancer(high gradeprostatecancer)withtheuseof5 alphareductaseinhibitors.theriskappearstobelow,buthealthcareprofessionals shouldweightheknownbenefitsagainstthepotentialriskwhendecidingtostartorcontinuetreatmentwiththeseagentsinmen. 18 NewSystematicReviews(Appendix3): Tworecentsystematicreviewswerepublishedevaluatingthenewindicationofphosphodiesterase 5(PDE 5)inhibitorsforBPHasmonotherapyand combination. AreviewbyLiuetal.,includedatotalof5studies(2054participants)andassessedtheefficacyandsafetyofPDE 5inhibitorsfortreatingLUTS secondarytobph. 19 TheprimaryoutcomesincludedchangesintheIPSSandmaximalurinaryflowrate(Qmax)aftertreatmentwithPDE 5inhibitors. Threeofthe5studiesinvestigatedtadalafilversusplacebo(1499patientswithBPHalone),andvardenafilandsildenafilwereevaluatedintheother twostudies.theirpooledmeanchangeinipssfrombaselinewas 5.24forPDE 5inhibitorsvs. 2.64forplacebo,whichdemonstratedastatistically significantdifferenceinfavorofthepde 5inhibitor(95%CI 3.12, 2.07;P< ).The5studiestheninvestigatedthechangeintheQmaxfrom baselineandfoundthatthepde 5inhibitorsandplacebohadasimilareffect(95%CI 0.21,0.64;P=0.32).EventhoughPDE 5inhibitorsshowedan improvementinipss,theyfailedtoresultinsignificantimprovementinqmax. 19 Thestudydidnotmentionaprotocolandeventhoughitstatedthe publicationbiaswasevaluatedusingafunnelplot,itdidnotshowordiscusstheresults.overall,thiswasagoodsystematicreviewanditsresultscan beextrapolatedduetothethoroughdiscussionofthestudieslimitationsandthatallotherdatawasreported. InthereviewbyGaccietal.,12studieswereassessedwhichlookedatuseofPDE5 inhibitorsaloneorincombinationwithalphablockersinpatients withluts/bph. 20 StudiescomparingtheeffectofPDE5 inhibitorsalonevs.placeboincludedatotalof3,214patients.thesestudiesfoundthatpde 5 inhibitorssignificantlyimproveipss( 2.8;p<0.0001),butnotQmaxwhencomparedwithplacebo( 0.00;p=notsignificant).Thesestudiesalsofound that16%ofmentakingthepde 5inhibitorhadadverseeffectsversus6%ofmentakingplacebo.Thestudiesthatcomparedtheeffectofalpha blockersalonevs.thecombinationofalphablockersandpde 5inhibitorsincluded216patients.Thecombinationofthetwomedicationssignificantly improvedipss( 1.8;p=0.05)andIIEFscore(+3.6;p<0.0001)aswellasQmax(+1.5;p<0.0001)whencomparedtoalphablockersalone.Thereported adverseeventsinthecombinationtherapygroupwere6.8%and5.1%inthegrouptreatedwithalphablockeralone. 20 Thiswasawelldone systematicreviewwithproperdataandresultsprovided,butitlackedtheprincipalsummarymeasuresandriskofbiasacrosseachstudy. 6

7 References: 1. Allison DB, Gadde KM, Garvey WT, et al. Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP). Obesity. 2011;20(2): Jones C, Hill J, Chapple C, on behalf of the Guideline Development Group. Management of lower urinary tract symptoms in men: summary of NICE guidance. BMJ. 2010;340(may19 2):c2354 c Oregon Heatlh Authority. Oregon Health Plan Prioritized List of Health Services. Oregon Health Policy and Research Available at: Accessed May 1, Karadag E, Oner S, Budak Y, Atahan O. Randomized crossover comparison of tamsulosin and alfuzosin in patients with urinary disturbances caused by benign prostatic hyperplasia. International Urology & Nephrology. 2011;43(4): Chung M, Lee S, Park K, Yoo S, Chung B. Comparative rapid onset of efficacy between doxazosin gastrointestinal therapeutic system and tamsulosin in patients with lower urinary tract symptoms from benign prostatic hyperplasia: a multicentre, prospective, randomized study. Journal of Clinical Practice. 2011;65(11): Yu H, Lin A, Yang S, et al. Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). BJU International. 2011;108(11): Zhang K, Yu W, Jin J, et al. Effect of doxazosin gastrointestinal therapeutic system 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms: a prospective, multicenter, randomized, open, parallel study. Urology. 2011;78(3): Nickel J, Gilling P, Tammela T, et al. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU International. 2011;108(3): Watanabe T, Ozono S, Kageyama S. A randomized crossover study comparing patient preference for tamsulosin and silodosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia.[erratum appears in J Int Med Res. 2011;39(3):1122]. Journal of International Medical Research. 2011;39(1): Montorsi F, Roehrborn C, Garcia-Penit J, et al. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study. BJU International. 2011;107(9): Roehrborn C, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial. BJU International. 2011;107(6):

8 12. Miyakita H, Yokoyama E, Onodera Y, et al. Short-term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia. Journal of Urology. 2010;17(10): Montorsi F, Henkel T, Geboers A, et al. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 4-year data from the CombAT study. Journal of Clinical Practice. 2010;64(8): Na Y, Ye Z, Zhang S. Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia: a randomized, double-blind, parallel-group, placebo-controlled study with an open-label extension. Clin Drug Investig. 2012;32(1): Shin TJ, Kim CI, Park CH, Kim BH, Kwon YK. α-blocker Monotherapy and α-blocker Plus 5-Alpha-Reductase Inhibitor Combination Treatment in Benign Prostatic Hyperplasia; 10 Years Long-Term Results. Korean J Urol. 2012;53(4): Kruep EJ, Hogue SL, Eaddy MT, Chandra MD. Clinical and economic impact of early versus delayed 5-alpha reductase inhibitor therapy in men taking alpha blockers for symptomatic benign prostatic hyperplasia. P T. 2011;36(8): Madani AH, Afsharimoghaddam A, Roushani A, et al. Evaluation of Tadalafil effect on lower urinary tract symptoms of benign prostatic hyperplasia in patients treated with standard medication. Int Braz J Urol. 2012;38(1): Oelke M, Giuliano F, Mirone V, et al. Monotherapy with Tadalafil or Tamsulosin Similarly Improved Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia in an International, Randomised, Parallel, Placebo-Controlled Clinical Trial. European Urology. 2012;61(5): Liu L, Zheng S, Han P, Wei Q. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review and meta-analysis. Urology. 2011;77(1):

9 Appendix 1: Current PA Criteria Benign Prostatic Hypertrophy (BPH) Medications Goal(s): BPH with urinary obstruction treatment is covered by OHP only when post-void residuals are at least 150ml. Cosmetic use for baldness is NOT covered. Erectile dysfunction is not covered by OHP * Note: Finasteride is also available as Propecia, which is FDA-approved for alopecia/male pattern baldness. Alopecia and male pattern baldness are not approvable diagnoses for 5-Alpha Reductase (5AR) Inhibitors. Length of Authorization: 1 year Preferred Alternatives: All preferred alternatives on PDL list: Requires PA: Non-preferred drugs Approval Criteria 1. What is the diagnosis? Record ICD9 code. 2. Will the prescriber consider a change to a preferred product? Message: Preferred products do not require a PA. Preferred products are evidence-based reviewed for comparative effectiveness and safety by the Health Resource Commission (HRC). Reports are available at: html. Yes: Inform Provider of covered alternatives in class. HS/healthplan/tools_prov/ dl.shtml. No: Go to #3 3. Is the request for an alpha blocker, and does client have a diagnosis related to functional and mechanical disorders of the genitourinary system including bladder outlet obstruction? (592.1, 595.1, 596.0, , , , 598, ) Yes: Go to #4 No: Go to #5 4. Has the client tried and failed a 2-month trial of a covered alternative Yes: Approve an alpha No: Deny until 9

10 alpha blocker (terazosin, doxazosin, prazosin, tamsulosin)? blocker only for 1 year client has tried and failed a covered alternative 5. Does client have a diagnosis of BPH (Benign Prostatic Hypertrophy) or enlarged prostate with obstruction? (600.01, , , and ; xx see RPH notes) Yes: Approve for the shorter of 1 year or length of the prescription No: Go to #6 6. Does client have a diagnosis of unspecified urinary obstruction or benign prostatic hyperplasia without obstruction? (599.6, , , , and ) Yes: Pass to RPH; Deny, (Not Covered by the OHP) No: Pass to RPH; Go to #7 7. RPH Notes only - All other indications need to be evaluated to see if they are above or below the line: Above the line covered diagnoses related to prostate may be approved for 1 year Below the line diagnoses (e.g. Hair growth, erectile dysfunction) should be denied (Not Covered by the OHP). Alpha Blockers and 5-alpha reductase inhibitors (ARI) may be used concurrently for BPH up to 1 year. Alpha-blockers may be discontinued once prostate is reduced to normal size (retention of urine, obstructive); Ask for more specific diagnosis. If along with , , or , then may approve. Refer questions of coverage to DMAP. Renewal Therapy 1. Is the request for an alpha blocker, and does client have a diagnosis related to functional and mechanical disorders of the genitourinary system including bladder outlet obstruction? (592.1, 595.1, 596.0, , , , 598, ) Yes: Go to #2 No: Go to #3 10

11 2. Has the patient also been taking a 5-alpha reductase inhibitor for the last year? 3. Does client have a diagnosis of BPH (Benign Prostatic Hypertrophy) or enlarged prostate with obstruction? (600.01, , , and ; xx see RPH notes) Yes: Recommend against combination therapy exceeding 1 year Yes: Approve for 1 year No: Approve for the shorter of 1 year or length of the prescription No: Go to #4 4. Does client have a diagnosis of unspecified urinary obstruction or benign prostatic hyperplasia without obstruction? (599.6, , , , and ) Yes: Pass to RPH; Deny, (Not Covered by the OHP) No: Pass to RPH; Go to #5 5. RPH only All other indications need to be evaluated as to whether they are above the line or below the line diagnosis. Alpha Blockers and 5-alpha reductase inhibitors (ARI) may be used concurrently for BPH up to 1 year. Alpha-blockers may be discontinued once prostate is reduced to normal size (retention of urine, obstructive); Ask for more specific diagnosis. If along with , , or , then may approve. If above the line or clinic provides supporting literature: approve for one year. If below the line: Deny, (Not Covered by the OHP). DUR Board Action: 9/16/10 (KS), 3/18/10(KK), , Revision(s): 1/1/11, 4/20/10, (Aebi), , Effective: (previously excluded) 11

12 Appendix2:NewTrialAbstracts 1. KaradagE,OnerS,BudakY,AtahanO.Randomizedcrossovercomparisonoftamsulosinandalfuzosininpatientswithurinarydisturbances causedbybenignprostatichyperplasia.internationalurology&nephrology.2011;43(4): OBJECTIVE:Tocomparetheefficacyandsafetyofalfuzosin(Alf)andtamsulosin(Tam)inpatientswithlowerurinarytractsymptoms(LUTS) associatedwithbenignprostatichyperplasia(bph).methods:onehundredmenwereenrolledinthisrandomizedcross overstudy.during enrollment,adetailedmedicalhistorywasrecorded,andinternationalprostatesymptomscore(ipss),digitalrectalexam,urinaryultrasound, prostatespecificantigen(psa)level,anduroflowmetryweredetermined.thosewithipssgreaterthan8andamaximumurinaryflowrate(qmax) lowerthan15ml/swererandomlydividedintoeitheralf TamgrouporTam Alfgroup(takingeachmedicationfor8weeks)withnowashoutperiod betweenswitchingdrugs.results:duringthefirst8weeks,eachdrugsignificantlyimprovedipssandqmax.afterthecrossover,bothgroups continuedtohaveimprovementinipssandqmax.bothdrugssignificantlyloweredipssandincreaseqmaxfrombaseline(p<0.001).neitherdrug affectedtheserumpsalevels.conclusion:similarfavorableoutcomeswereassociatedwithtamandalf.whenonealphablockerdoesnot provideadesiredeffectinthetreatmentofbph,switchingtoanotherintheclassseemstobebeneficial. 2. ChungM,LeeS,ParkK,YooS,ChungB.Comparativerapidonsetofefficacybetweendoxazosingastrointestinaltherapeuticsystemand tamsulosininpatientswithlowerurinarytractsymptomsfrombenignprostatichyperplasia:amulticentre,prospective,randomisedstudy. JournalofClinicalPractice.2011;65(11): OBJECTIVE:Tocomparetherapidityofimprovementinlowerurinarytractsymptoms(LUTS)forthedoxazosingastrointestinaltherapeuticsystem (GITS)andtamsulosininBPHpatients.METHODS:Therewere207patientsrandomizedfora12 weekdailytreatmentwitheitherdoxazosin GITS4 mgortamsulosin0.2mg.theprimaryoutcomewastocomparetheearlyonsetsofefficacybetweenthetwodrugs.thiswasdonebyanalyzingthe changesfrombaselineipss.thesecondaryoutcomesincludedcomparingimprovementsinobstructive/irritativesubcoreandqualityoflife(qol) betweenthegroups,andtoevaluateadverseeventswiththedrugs.results:bothgroupsshowedsignificantimprovementsinipssscoresafterthe 12weeksoftreatment(p<0.0001).Thedoxazosin GITSgroupshowedsignificantlygreaterimprovementsintotalIPSSandobstructivesubscorethan thetamsulosingroupduringthebeginningofthetrial(p<0.05).improvmentsinirritativesubscoreandqolsocredidnotshowsignificantdifferences betweenthetwogroups.thegroupshadsimilaradverseeventsincidences.conclusion:doxazosin GITSshowedsignificantlymorerapidonsetof efficacyandsimilaradverseeventswhencomparedwithtamsulosin.thismayhelpimprovepatientcompliance.furtherstudiesneedtobe conductedwithalargerpopulationandlongerfollow upperiodtoconfirmthefindingsofthisstudy. 3. YuH,LinA,YangS,etal.Non inferiorityofsilodosintotamsulosinintreatingpatientswithlowerurinarytractsymptoms(luts)associated withbenignprostatichyperplasia(bph).bjuinternational.2011;108(11): OBJECTIVE:TotestthehypothesisthattheefficacyofsilodosinwouldnotbeinferiortotamsulosinintreatingpatientswithLUTS/BPH.METHODS: Thestudywasconductedat9medicalcentreswithatotalof209patientswithanIPSSof>13.Thepatientswererandomizedtoeithersilodosin4mg twicedailyortamsulosin0.2mgoncedailyfor12weeks.theprimaryoutcomewasthemeanchangeinipssfrombaselinetoendpoint.the secondaryoutcomesmeasuredchangeinqmaxandqolscore.results:ofthepatientswhocompletedthestudy86.2%takingsilodosinvs.81.9% takingtamsulosinachieveda>25%decreaseinipss(p=0.53).themeandifferenceinipsschangefrombaselinewas 0.60(95%CI 2.15,0.95), 12

13 inferringnon inferiorityofsilodosintotamsulosin.themeanchangesintheqmaxandqolsocrefrombaselinewerecomparablebetweengroups (P>0.05).CONCLUSION:Thisstudyshowsthenon inferiorityofsilodosin4mgtwicedailytotamsulosin0.2mgoncedailyinpatientswithbph. 4. ZhangK,YuW,JinJ,etal.Effectofdoxazosingastrointestinaltherapeuticsystem4mgvstamsulosin0.2mgonnocturiainChinesemenwith lowerurinarytractsymptoms:aprospective,multicenter,randomized,open,parallelstudy.urology.2011;78(3): OBJECTIVE:Tocomparetheefficacyofdoxazosin GITS4mgandtamsulosin0.2mgonnocturiainChinesemenwithLUTS/BPH.METHODS:Thestudyis aprospective,multicenter,randomized,open,parallelstudyofchinesemenaged50 84yearswithLUTS/BPH.Twohundredpaitentswere randomizedtoreceiveeither4mgdoxazosin GITSor0.2mgtamsulosinfor8weeks.TheIPSS question7andfrequencyvolumechart(fvc)wereused toassessnocturiaatweeks4and8.patientsalsoself reportedqualityofsleepandqualityoflife.results:thereductioninmeannocturiafrom baselinewasgreaterwithdoxazosin GITSthantamsulosinbytheFVC(P=0.001)andIPSS question7(p<0.001).thereweremorepatientson doxazosin GITSwhoreportedimprovedqualityofsleepthanpatientstakingtamsulosin(P=0.020at4weeks;P=0.022at8weeks)andsimilarresults wereseenwithreportsofqol(p=0.001at4weeks;p<0.001at8weeks).conclusion:chinesemenwithluts/bphhaveshownaslightlybetter responseinreductionoffrequencyofnocturiawithdoxazosin GITSthantamsulosin. 5. NickelJ,GillingP,TammelaT,MorrillB,WilsonT,RittmasterR.Comparisonofdutasterideandfinasteridefortreatingbenignprostatic hyperplasia:theenlargedprostateinternationalcomparatorstudy(epics).bjuinternational.2011;108(3): OBJECTIVE:ToassesstheefficacyandsafetyofdutasteridecomparedwithfinasterideintreatingmenwithsymptomaticBPHfor12months. METHODS:Thestudywasamulticenter,randomized,double blind,12 month,parallelgroupstudy.theparticipantsweremenaged>50yearswitha clinicaldiagnosisofbph.theparticipantseitherreceivedonce dailytreatmentwithdutasteride0.5mgorfinasteride5mg.patientsunderwenta4 weekplaceborun inperiodandthenwererandomizedtooneofthetwogroupsfor48weeks,followedbyanoptional24month,open labelphase wherethepatientsreceiveddutasteride0.5mgoncedaily.theprimaryoutcomewaschangeinprostatevolume.thesecondaryendpointsinclude improvementinqmax,symptomscores,andsafetyinthe24monthopen labelphase.results:bothdutasterideandfinasteridewereeffectiveat reducingprostatevolumewithnosignificantdifferencebetweenthetwo.similarpercentageofadverseeventswasexperiencedinbothtreatment groups.conclusion:forthe12monthsthatdutasterideandfinasteridewereadministered,theyshowedsimilareffectivenessinreducingprostate volumeandimprovingqmaxandurinarysymptoms. 6. WatanabeT,OzonoS,KageyamaS.Arandomizedcrossoverstudycomparingpatientpreferencefortamsulosinandsilodosininpatientswith lowerurinarytractsymptomsassociatedwithbenignprostatichyperplasia.[erratumappearsinjintmedres.2011;39(3):1122].journalof InternationalMedicalResearch.2011;39(1): OBJECTIVE:TocomparepatientpreferencefortamsulosinandsilodosininpatientwithLUTS/BPH.METHODS:Thestudywasarandomized, crossover,comparative,open labelstudy.thestudyincludedjapanesepatientswithlutsassociatedwithbphandhadanipss>8andaqolscore >2.TheyrandomlyassignedthepatientstoeitheraTam SilorSil Tamforatotalof8weeks.Theprimaryoutcomewasthepreferreddrugfor treatmentcontinuationat8weeks,accordingtothepatient reportquestionnaire.results:therewereatotalof102patientswhoenrolledinthe studyand82completedthe8weeks.therewasasignificantdifferencebetweenthepatientswhopreferredtamsulosin(59/84;70.2%)andthose 13

14 thatpreferredsilodosin(18/84;21.4%).incidenceofadverseeffectswassignificantlylowerwithtamsulosin(3/91;3.3%)thanwithsilodosin(25/88). CONCLUSION:ThefindingsofthestudyindicatethattamsulosinisveryeffectiveforBPH,hasfewadverseeffectsandispatient preferred. 7. MontorsiF,RoehrbornC,Garcia PenitJ,etal.Theeffectsofdutasterideortamsulosinaloneandincombinationonstorageandvoiding symptomsinmenwithlowerurinarytractsymptoms(luts)andbenignprostatichyperplasia(bph):4 yeardatafromthecombinationof AvodartandTamsulosin(CombAT)study.BJUInternational.2011;107(9): OBJECTIVE:Toassesstheeffectsofcombinationtherapywithdutasterideandtamsulosinonvoidingandstoragesymptomswiththoseofdutasteride ortamsulosinalone.methods:thestudyincludedmenaged>50yearswithmoder to severelutsduetobph,aprostatevolumeof>30ml,anda PSAof ng/mL.Thiswasaposthocanalysisofamulticenter,double blind,parallelgroupstudy.patientsreceivedeitheroraldutasteride0.5mg ortamsulosin0.4mgaloneorincombinationfor4years.theoutcomesanalyzedincludedmeanchangesformbaselineinstorageandvoiding symptomsat4years,whichwereassessedusingtheipss.results:themeanreductioninthestoragesubscorewassignificantlygreaterinthe combinedgroupversusthedutasterideandtamsulosinmonotherapygroups(p<0.001).themeanreductioninthevoidingsubscorewassignificantly greaterinthecombinationgroupversusthedutasterideandtamsulosinmonotherapygroup(p<0.001).conclusion:itappearedthatcombined therapywithdutasterideplustamsulosinprovidedbetterlong termcontrolofstorageandvoidingcomparedtotamsulosinmonotherapyinmenwith aprostatevolumeof>30ml.combinedtherapywasalsobetterthandutasteridemonotherapyinmenwithprostatevolumesof>30and<58ml,but notinmenwithaprostatevolumeof>58ml. 8. RoehrbornC,BarkinJ,SiamiP,etal.Clinicaloutcomesaftercombinedtherapywithdutasterideplustamsulosinoreithermonotherapyin menwithbenignprostatichyperplasia(bph)bybaselinecharacteristics:4 yearresultsfromtherandomized,double blindcombinationof AvodartandTamsulosin(CombAT)trial.BJUInternational.2011;107(6): OBJECTIVE:Toinvestigatetheinfluenceofbaselinevariablesontheacuteurinaryretention(AUR),BPH relatedsurgeryandoverallclinical progressionovera4 yearperiodinmentreatedwithtamsulosin,dutasteride,orcombinationtherapy.methods:aposthocanalysisofa multicenter,randomized,double blind,parallelgroupstudyinmenaged>50yearswithsymptomaticbph.theprimaryendpointwastimetofirst AURorBPH relatedsurgery.thesecondaryendpointsincludedclinicalprogressionofbphandsymptoms.baselineprostatevolumes(pv)and prostatespecificantigen(psa)levelsweremeasured.results:therewere4844menparticipatinginthestudy.combinedtherapywasstatistically betterthantamsulosinaloneinreducingtheriskofaurorbph relatedsurgeryinsubgroupsofbaselinepv>42mlandinallsubgroupsofbaseline PSAlevels(P<0.001).Combinedtherapyreducedtherelativerisk(RR)ofclinicalprogressioncomparedwithtamsulosinaloneacrossallbaseline subgroups.conclusion:menwithbaselinepvof>40mlandanybaselinepsalevelof>1.5ng/mlhadgreaterreductionsintherrofaurorbphrelatedsurgeryandgreaterreductionintherrofclinicalprogressionandsymptomdeteriorationoncombinedtherapyordutasteridemonotherapy thanontamsulosinmonotherapy.thissupportsthelong termuseofcombinedtherapywithdutasterideplustamsulosininmoderate to severebph. 9. MiyakitaH,YokoyamaE,OnoderaY,etal.Short termeffectsofcrossovertreatmentwithsilodosinandtamsulosinhydrochlorideforlower urinarytractsymptomsassociatedwithbenignprostatichyperplasia.journalofurology.2010;17(10):

15 OBJECTIVE:TocomparetheefficacyandsafetyofsilodosinandtamsulosininpatientswithLUTS/BPH.METHODS:Thisrandomizedcrossoverstudy analyzesbphstudentswiththecomplaintofluts.thepatientsarerandomlydividedintoeitherasilodosin precedinggroup(4weeksoftwicedaily silodosin4mg)followedby4weeksofoncedailytamsulosinat0.2mgoratamsulosinprecedinggroupfollowedbyasilodosingroup.nodrug withdrawalperiodoccurredwhenswitchingthedrugs.results:bothdrugssignificantlyimprovedtheipssscore,buttheimprovementbysilodosin wassignificantlysuperiortothatbytamsulosin.afterthecrossovertreatment,significantimprovementwasobservedonlywithsilodosintreatment. SilodosinalsosignificantlyimprovedQoLscoreinbothtreatmentperiods,whiletamsulosinonlysignificantlyimprovedQoLscoreinthefirst treatmentperiod.conclusion:silodosinexhibitsbetterefficacyinimprovingsubjectivesymptomsinbothinitialandcrossovertreatment,andit appearstoimprovetheqolofpatientsthantamsulosin. 10. MontorsiF,HenkelT,GeboersA,etal.Effectofdutasteride,tamsulosinandthecombinationonpatient reportedqualityoflifeandtreatment satisfactioninmenwithmoderate to severebenignprostatichyperplasia:4 yeardatafromthecombatstudy.journalofclinicalpractice. 2010;64(8): OBJECTIVE:Toinvestigatetheeffectsofcombinationtherapy(dutasterideplustamsulosin)comparedwitheachmonotherapyinmenwithmoderateto severelutsduetobph.methods:subjectswererandomizedtoreceiveeitherdutasteride0.5mg,tamsulosin0.4mgoracombinationofthetwo for4years.theprimaryoutcomeat4yearswasthetimetoeventandproportionofsubjectswithacuteurinaryretentionorbph relatedsurgery. SecondaryendpointsmeasuresBPHImpactIndex(BII),IPSSquestion8,andPatientPerceptionofStudyMedication(PPSM)questionnaire.RESULTS: CombinationtherapyresultedinsignificantlysuperiorimprovementsfrombaselineinBIIandIPSSquestion8thaneithermonotherapy.ThePPSM questionnaireshowedthatasignificantlyhigherproportionofpatientsweresatisfiedandrequestedthecombinationtherapyfortreatment comparedtoeithermonotherapy.conclusion:combinatiointherapyprovidessignificantlysuperiorimprovementsinpatient reportedqoland treatmentsatisfactionthaneithermonotherapyat4yearsinmenwithmoderate to severebphsymptoms. 11. NaY,YeZ,ZhangS.EfficacyandsafetyofdutasterideinChineseadultswithsymptomaticbenignprostatichyperplasia:arandomized,doubleblind,parallel group,placebo controlledstudywithanopen labelextension.clindruginvestig.2012;32(1): OBJECTIVE:ToevaluatetheefficacyandsafetyofdutasterideinChineseadultswithsymptomaticBPH.METHODS:Thiswasarandomized,doubleblind,parallel group,placebo controlledstudywhichtookplaceover6monthsandwasfollowedbyanopen labelextensionof12months.patients wererandomizedtoreceiveeitherdutasteride0.5mg/dayorallyormatchingplacebotreatment.after6months,eligibleparticipantsentertheopenlabelextensionallreceivingdutasterdie0.5mg/dayorally.thechangesintotalprostatevolume(tpv),qmax,andamericanurologyassociation SymptomIndex(AUA SI)wereevaluated.RESULTS:DutasteridesignificantlyreducedmeanTPVcomparedwithplaceboat3and6months(P<0.05). HigherimprovementsinQmaxandAUA SIwereobservedinthedutasteridegroup,butnostatisticalsignificancebetweengroupswasfound. CONCLUSION:DutasteridewaseffectivecomparedwithplacebointhetreatmentofsymptomaticBPHamongChinesemen. 12. ShinTJ,KimCI,ParkCH,KimBH,KwonYK.α BlockerMonotherapyandα BlockerPlus5 Alpha ReductaseInhibitorCombinationTreatmentin BenignProstaticHyperplasia;10Years Long TermResults.KoreanJUrol.2012;53(4):

16 OBJECTIVE:Tocomparetheeffectsofalphablockermonotherapywithcombinationtherapycontaininganalphablockerand5 alphareductase inhibitoronbphprogressionforover10years.methods:atotalof520patientsreceivedalphablockermonotherapyorcombinationtherapyas theirinitialtreatment.theincidencesofacuteurinaryretention(aur)andbph relatedsurgerywerecomparedbetweengroups.results:the incidenceofaurwas13.6%inthealphablockergroupand2.8%inthecombinationgroup(p<0.001).atotalof8.4%and3.2%ofpatientsunderwent BPH relatedsurgeryinthealphablockerandcombinationgroups,respectively(p=0.008).conclusion:long termcombinationtherapywithalpha blockerand5 alphareductaseinhibitorcansuppresstheprogressionofbphmoreefficientlythanalphablockermonotherapy(whichshowedthe bettereffectsinpatientswithpsa>2ng/mlorpv>35ml). 13. KruepEJ,HogueSL,EaddyMT,ChandraMD.Clinicalandeconomicimpactofearlyversusdelayed5 alphareductaseinhibitortherapyinmen takingalphablockersforsymptomaticbenignprostatichyperplasia.pt.2011;36(8): OBJECTIVE:Toassesstheclinicalandeconomicimpactofearlyversusdelayed5 alphareductaseinhibitor(5 ARI)therapyinpatientstreatedwith alphablockerforbph.methods:thisisaretrospectivedatabaseanalysisthatincludedmen>50yearsofagewhoweretreatedwithbph.the primaryoutcomewastoevaluatepatientsusing5 ARIearly(within30daysofstartinganalphablocker)comparedwiththoseusingdelayed5 ARI therapy(between30and180daysstartingthealphablocker).acuteurinaryretention(aur)andbph relatedsurgerywereassessed(clinical progression).results:patientswhostarted5 ARIearlywerelesslikelythanthosereceivingdelayedtreatment(12.8%vs.17.4%,p<0.0001)tohave clinicalprogression,aur(10.2%vs.13.8%,p<0.0001),andprostatesurgery(5%vs.7%,p=0.0002).theearlygroupalsoacquiredlowerbph related medicalcosts($572vs.$730,p<0.0001).conclusion:theresultssuggestthatearly5 ARItherapyformenwithsymptomaticBPHwhoarereceiving analphablockermaysignificantlyreducetheriskofclinicalprogressionoverthenext12monthsaswellaslowerbph relatedcosts. 14. MadaniAH,AfsharimoghaddamA,RoushaniA,FarzanA,AsadollahzadeA,ShakibaM.EvaluationofTadalafileffectonlowerurinarytract symptomsofbenignprostatichyperplasiainpatientstreatedwithstandardmedication.intbrazjurol.2012;38(1): OBJECTIVE:Toevaluatesafetyandefficacyoftadalafilonlowerurinarytractsymptomsrelatedtobenignprostatichyperplasia.METHODS:Thisis acase controlledrandomizedclinicaltrial,fromnovember2008toaugust2009.thestudyselected132patientswithobstructiveandirritative urinarytractsymptomsduetobph,ipss>8,noindicationforsurgicalinterventionandthatreachedplateaulevelsofresponsetotreatment.the treatmentgroupreceivedstandardtreatmentofbphandtadalafil10mgnightlyandtheplacebogroupreceivedonlystandardtreatmentofbph. TheprimaryoutcomeassessedIPSS,maximumurinaryflowrate(Qmax)andqualityoflifebeforeandaftera3 monthperiodofstudy.results: Beforetreatment,meanIPSS,QmaxandQoLvaluesinthetreatmentandplacebogroupswere13.06±4.37and13.66±4.25,8.92±2.96mL/sand 9.09±2.91,2.93±0.86and2.66±0.78mL/s,respectively.Aftertreatment,meanIPSS,Qmax,andQoLvaluesintreatmentgroupwere7.66±3.99, 9.99±4.76and1.80±0.98mL/s,respectively.Thesefindingswerecomparedtocorrespondingvaluesoftheplacebogroup(11.37±3.64,8.73±2.22 and2.19±0.53ml/s,respectively).ipssandqualityoflifeweresignificantlydifferentbutqmaxdidn tshowasignificantchange.conclusion: TadalafilimprovesqualityoflifeandurinarysymptomsinpatientswithLUTSsuggestiveofBPH,butdoesn thaveanysignificanteffectonqmax. Therefore,thisdrugmaybeeffectivelyusedincombinationwithstandardmedicaltherapiesforBPH. 16

17 15. OelkeM,GiulianoF,MironeV,XuL,CoxD,ViktrupL.MonotherapywithTadalafilorTamsulosinSimilarlyImprovedLowerUrinaryTract SymptomsSuggestiveofBenignProstaticHyperplasiainanInternational,Randomised,Parallel,Placebo ControlledClinicalTrial.European Urology.2012;61(5): OBJECTIVE:ToassesstadalafilortamsulsoinversusplaceboforLUTS/BPH.METHODS:Thisisarandomized,double blind,international,placebocontrolled,parallel groupstudyassessingmen>45yearsofagewithluts/bph,internationalprostatesymptomscore(ipss)_13,andmaximum urinaryflowrate(qmax)>4to<15ml/s.followingscreeningandwashout,ifneeded,subjectscompleteda4 wkplaceborun inbeforerandomization toplacebo(n=172),tadalafil5mg(n=171),ortamsulosin0.4mg(n=168)oncedailyfor12wk.theprimaryoutcomeassessedefficacybasedon IPSSandBPHImpactIndex(BII).RESULTS:IPSSsignificantlyimprovedversusplacebothrough12wkwithtadalafil( 2.1;p=0.001;primaryefficacy outcome)andtamsulosin( 1.5;p=0.023)andasearlyas1wk(tadalafilandtamsulosinboth 1.5;p<0.01).BPHImpactIndexsignificantlyimproved versusplaceboatfirstassessment(week4)withtadalafil( 0.8;p<0.001)andtamsulosin( 0.9;p<0.001)andthrough12wk(tadalafil 0.8,p=0.003; tamsulosin 0.6,p=0.026).Qmaxincreasedsignificantlyversusplacebowithbothtadalafil(2.4ml/s;p=0.009)andtamsulosin(2.2ml/s;p=0.014). CONCLUSION:MonotherapywithtadalafilortamsulosinresultedinsignificantandnumericallysimilarimprovementsversusplaceboinLUTS/BPHand Qmax. Appendix3:Abstractsofsystematicreviews 1. LiuL,ZhengS,HanP,WeiQ.Phosphodiesterase 5inhibitorsforlowerurinarytractsymptomssecondarytobenignprostatichyperplasia:a systematicreviewandmeta analysis.urology.2011;77(1): OBJECTIVE:Toevaluatetheefficacyandsafetyofphosphodiesterase 5(PDE 5)inhibitorsfortreatinglowerurinarytractsymptomssecondaryto benignprostatichyperplasia.methods:randomizedcontrolledtrialswereidentifiedandextractedfrommedline,embase,cochranecentral,and relevantreferencelists.thedatabasesearch,qualityassessment,anddataextractionwereindependentlyperformedby2reviewers.heterogeneity wasanalyzedusingthechi squaretestandi 2 test.iflackingofheterogeneity,fixed effectsmodelswereusedforthemeta analysis,otherwise random effectsmodelswereused.results:fivestudieswereidentified.pde 5inhibitorsshowedsignificantimprovementintheIPSS(P< ) whencomparedwithplacebo.nostatisticallysignificantdifferencewasfoundinmaximalurinaryflowrateandpostvoidresidualurinevolume.no statisticallysignificantdifferencewasfoundbetweenthe2groupsintheincidenceofseriousadverseevents.conclusion:pde 5inhibitorsare effectiveandsafeforluts/bph.itcouldbeconsideredfirstlinetreatmentinthefutureaswellasforpatientwithcomorbidbphanderectile dysfunction. 2. GacciM,CoronaG,SalviM,etal.ASystematicReviewandMeta analysisontheuseofphosphodiesterase5inhibitorsaloneorin Combinationwithα BlockersforLowerUrinaryTractSymptomsDuetoBenignProstaticHyperplasia.EuropeanUrology.2012;61(5): OBJECTIVE:ToanalyzetheavailablestudiesontheuseofPDE 5inhibitorsaloneorincombinationwithalphaadrenergicblockersinLUT/BPH patients.methods:asystematicsearchwasperformedusingthemedline,embase,andcochranelibrarydatabasesthroughseptember2011 includingthecombinationofthefollowingterms:luts,bph,pde5 Is,sildenafil,tadalafil,vardenafil,udenafil,α blockers,andα1 adrenergicblocker. Themeta analysiswasconductedaccordingtotheguidelinesforobservationalstudiesinepidemiology.results:theuseofpde 5inhibitorsalone 17

18 wasassociatedwithasignificantimprovementoftheipss( 2.8,p<0.0001),butnotQmaxcomparedtoplaceboattheendofthestudy.CONCLUSION: ThedatasuggeststhatPDE 5inhibitorscansignificantlyimproveLUTS/BPHinmenwithorwithouterectiledysfunction. 18