Guidelines for practical usage of botulinum toxin type A (BoNTA) for refractory

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RECOMMENDATION

Guidelines for practical usage of botulinum toxin type A (BoNTA) for refractory

idiopathic overactive bladder management:

Translation of French recommendations ^夽

Recommandations pour l’utilisation de la toxine botulinique de type A (Botox ® ) dans l’hyperactivité vésicale réfractaire

idiopathique

J.-F. Hermieu

, P. Ballanger

, G. Amarenco

, É. Chartier-Kastler

, M. Cosson

, P. Costa

, B. Fatton

, C. Saussine

, P. Denys

, X. Gamé

,

F. Haab

, G. Karsenty

, L. Le Normand

, A. Ruffion

, X. Deffieux

aServiced’urologie,hôpitalBichat,46,rueHenri-Huchard,75018Paris,France

bServiced’urologie,hôpitalPellegrin,placeAmélie-Raba-Léon,33076Bordeauxcedex, France

cServicederééducationneuro-urologique,hôpitalTenon,4,ruedelaChine,75020Paris, France

dServiced’urologie,hôpitaldelaPitié-Salpétrière,47—83,boulevarddel’Hôpital,75013 Paris,France

eServicedegynécologie,CHRUdeLille,rueEugène-Avinée,59037Lillecedex,France

fServiced’urologie,CHRUCarémeau,rueduProfesseur-Debré,30029Nîmescedex9,France

gServicedegynécologie,CHRUCarémeau,rueduProfesseur-Debré,30029Nîmescedex9, France

DOIoforiginalarticle:http://dx.doi.org/10.1016/j.purol.2013.10.006.

夽 ThisarticleisanEnglishtranslationofFrenchguidelinesconcerningpracticalusageofbotulinumtoxintypeA(BoNTA)forrefractory idiopathicoveractivebladdermanagement(J.-F.Hermieu,P.Ballanger,G.Amarenco,É.Chartier-Kastler,M.Cosson,P.Costa,B.Fatton, X.Deffieux,P.Denys,X.Gamé,F.Haab,G.Karsenty,L.LeNormand,A.Ruffion,C.Saussine).Recommandationspourl’utilisationdela toxinebotuliniquedetypeA(Botox^®)dansl’hyperactivitévésicaleréfractaireidiopathique.ProgUrol2013;23:1457—63.

∗Correspondingauthor.

E-mailaddress:[email protected](J.-F.Hermieu).

http://dx.doi.org/10.1016/j.purol.2014.06.005

1166-7087/©2014ElsevierMassonSAS.Open access under CC BY-NC-ND license.

hServiced’urologie,CHU,1,placedel’Hôpital,67000Strasbourg,France

iServicedemédecinephysiqueetderéadaptation,hôpitalRaymond-Poincaré,104, boulevardRaymond-Poincaré,92380Garches,France

jServiced’urologie,hôpitaldeRangueil,1,avenueduProfesseur-Jean-Poulhès,TSA50032, 31059Toulousecedex9,France

kServiced’urologie,hôpitalTenon,4,ruedelaChine,75020Paris,France

lServiced’urologie,hôpitaldelaconception,147,boulevardBaille,13005Marseille,France

mServiced’urologie,Hôtel-Dieu,CHUdeNantes,1,placeAlexis-Ricordeau,44093Nantes cedex1,France

nServiced’urologie,centrehospitalierLyonSud,165,cheminduGrand-Revoyet,69495 Pierre-Bénite,France

oServicedegynécologie-obstétrique,hôpitalAntoine-Béclère,157,ruedelaPorte-Trivaux, 92140Clamart,France

Received4June2014;accepted12June2014 Availableonline9July2014

KEYWORDS Botulinumtoxin;

Refractoryidiopathic overactivebladder;

Urodynamic;

Botox^®

Summary

Objective.—ProvideguidelinesforpracticalusageofbotulinumtoxintypeA(BoNTA)forrefrac- toryidiopathicoveractivebladdermanagement.

Patients and methods.—Guidelines using formalized consensus guidelines method. These guidelines have been validated by a group of 13 experts quoting proposals, subsequently reviewedbyanindependentgroupofexperts.

Results.—In thecaseofpatientswithurinarytractinfection,itmustbetreatedandinjec- tionpostponed.Beforeproposinganinjection,itisrecommendedtoensurethefeasibilityand acceptabilityofself-catheterisation bypatient. Theinjection canbeperformed afterlocal anesthesiaofthebladderandurethra(lidocaine),supplementedwherenecessarybynitrous oxideinhalationandsometimesundergeneralanesthesia.Injectionisperformedintheoperat- ingroomorendoscopysuite.Thebladdershouldnotbetoofilled(increasedriskofperforation).

Treatmentshouldbeappliedin10to20injectionsof0.5to1mLhomogeneouslydistributedin thebladderatadistancefromtheurethralorifices.Itisnotrecommendedtoleaveaurinary catheterinplaceexceptincasesofseverehematuria.Thepatientshouldbemonitoreduntil resumptionofmicturition.Afterthefirstinjection,anappointmentmustbescheduledwithin 3months(micturitiondiary,uroflowmetry,measurementofresidualurineandurineculture).

Performanceofself-catheterisationshouldbequestionedinthecaseofasymptomaticpost- voidresidualand/oraresidue>200mL.Anewinjectionmaybeconsideredwhentheclinical benefitofthepreviousinjectiondiminishes(between6and9months).Aperiodofthreemonths mustelapsebetweeneachinjection.

Conclusions.—ImplementationoftheseguidelinesmaypromotebestpracticeusageofBoNTA withoptimalrisk/benefitratio.

©2014ElsevierMassonSAS.Allrightsreserved.

MOTSCLÉS Toxinebotulinique; Hyperactivité vésicaleidiopathique réfractaire;

Urodynamique; Botox^®

Résumé

Objectifs.—Définirdesrecommandationspourl’utilisationpratiquedela toxinebotulinique detypeA(BoNTA)dansl’hyperactivitévésicaleréfractaireidiopathique(HAVRI).

Méthode.—Élaboration de recommandations de bonne pratique par consensus formalisé, validéesparungroupede13expertspuisparungroupedelectureindépendant.

Résultats.—Encasd’infectionurinaire,celle-cidoitêtretraitéeetl’injectionreportée.Avant l’injection,ilest recommandédes’assurerdela faisabilitéetdel’acceptabilité del’auto- sondage.L’injectionpeutêtreréaliséeaprèsuneanesthésielocaleurétro-vésicale(lidocaïne), éventuellementcomplétée parl’inhalationde protoxyde d’azoteet parfoissousanesthésie générale.L’injectionseraréaliséeaublocopératoireouensalled’endoscopie.Lavessiene doitpasêtretropremplie(risque deperforation).Letraitementdoitêtreappliqué en10à 20injectionsde0,5à1mLrépartidemanièrehomogènedanslavessieenrestantàdistance desméats urétéraux. Il n’estpas recommandéde laisseren placeune sondevésicalesauf encasd’hématurieimportante.Lepatientdoitêtresurveilléjusqu’àlareprisemictionnelle.

Unenoted’information surleseffets indésirableséventuelsdoitlui êtreremiseàsasortie.

Une consultation doit être prévue 3mois après la première injection (calendrier miction- nel, débit-métrie, résidu post-mictionnel et examen cytobactériologique des urines). Un résidu>200mLet/ousymptomatiquedoitfairediscuterdesauto-sondages.Unenouvelleinjec- tionpourraêtreenvisagéelorsquelebénéficecliniquedelaprécédentes’estompe(entre6et 9mois).

Conclusions.—Lerespectdecesrecommandationsdevraitpermettreuneutilisationoptimale delaBoNTA.

©2014ElsevierMassonSAS.Tousdroitsréservés.

Introduction

SincethefirsttimethebotulinumtoxinAwasused,almost 25yearsago,onthestriatedsphincteroftheurethratotreat detrusor-sphincter dyssynergia [1], the use of botulinum toxin has been progressively extended tonumerous areas ofurology.

Severalmajorpublicationshave alloweditsapplication in neurogenic detrusor overactivityto be validated [2,3], andthis toxin has nowbecome acomponent of thether- apeuticalgorithmusedinthemanagementofneurological bladders[4].

Newindications,suchasthenon-neurologicalrefractory overactivebladder,havebeenstudied[5].

This pathology representsadiagnostic andtherapeutic challenge. It is a functional pathology which is non life- threatening and has no influence on renal prognosis, but whichcan leadtoprofound changesinthepatient’s qual- ityoflife.Currently,thetherapeuticmethodsusedforits treatmentdonotallowthisconditiontobefullymanaged.

Theefficacyofdrugtreatmentsisinconsistent,andthese can lead to side effects, which hinder observanceof the treatment [6]. Behaviouraltherapy and rehabilitation are alsofirst line treatments, whose efficacy is unfortunately inconsistent.Amongpossiblesecondlinetreatments,percu- taneousposteriortibialnervestimulationcanbeasuitable choiceinterms ofbenefit-riskratio[7].Sacralneuromod- ulation, which is more invasive, is a validated form of treatment. It callsfor theuse of a preliminaryeffective- nesstest,priortopermanentimplantation.Goodlong-term resultshavebeendemonstrated,althoughthisisanexpen- sivetreatmentandcanhaveundesirableeffects,sometimes requiring reoperation. The use of more complex surgical techniques(enterocystoplasty)iscurrentlyrare,inthecase ofnon-neurologicaldetrusoroveractivity,asaconsequence ofthemorbidityandinconsistentlong-termoutcomeasso- ciatedwithitsuse.

Currently, numerous publicationshave reportedon the usefulnessandefficacyofBoNTAforthisindication[8—10].

Contrarytoneurologicalpatients,treatmentsinvolvingthe intradetrusor injection of BoNTA are confronted by the difficulty of ensuring voiding which is reliable, efficient, spontaneous,andnon-deleterious(renalprotectionandrisk ofinfection).

Although the efficacy and safety of botulinum toxin A havebeenvalidatedbymajorevidence-basedpublications (randomizedplacebocontrolstudies),practicalinformation for its use cannotbe based ona strong consensus.More- over, these studies are often disparate, in terms of their inclusionorexclusioncriteria(menand/orwomen,different

definitions for the clinical criteria of OAB, presence or absence of detrusor overactivity, different definitions for therefractorynatureofthesymptoms)andintheinjection technique(highdosage—200to300IU—orlowdosage—100 to150IU,numberofinjections,injectionsites,dilutionof the toxin, submucosal or detrusor injections). In France, drugmarketingapproval for BoNTAis currentlylimited to casesofneurogenicdetrusoroveractivity.Theencouraging resultsdescribedintheliteraturehaveledBoNTAtobeused byexpertcentresinthescopeofaresearchprotocol,asa lastresorttherapyfor non-neurologicalbladderoveractiv- ity.ArequestforanextensionoftheFrenchdrugmarketing approval(AMM)hasbeensubmitted,andanexpertgrouphas prepareda setofrecommendations forthe useofBoNTA, inordertogovernmedicalpracticesshouldthisrequestbe granted.

Patients and method

Asaresultof theabsenceortheinadequacy ofliterature withahighlevelofevidence,dealingspecificallywithques- tions related to the practical use of botulinum toxin for thisindication, it wasnot possible toprepare good prac- ticerecommendationsusingthemethodforclinicalpractice recommendations(CPR). It wasthus necessary touse the methodfor formalisedconsensusrecommendations(FCR).

Thismethodhastheadvantageofidentifyingthedegreeof agreement,disagreement,or indecision betweenexperts, onseveralindependentlysubmittedpropositions.Thecor- responding procedure was that published in 2010 by the FrenchNational Authority for Health (HAS) [11].The first step was to draft a list of proposed recommendations, basedon the criticalanalysis of a summary of accessible bibliographicdataandthediscussionofcurrentpractices.

A systematic review of the literature wascarried out on Pubmedusingthe followingkeywords: ‘‘botulinumtoxin’’

and‘‘bladderoveractivity’’, or‘‘idiopathicdetrusorover- activity’’,or‘‘non-neurological’’.Twenty-fivepaperswere retained outofatotalof417 papersrevealedbythebib- liographicsearch,whichwaslimitedtopaperspublishedin EnglishorFrench.

The analysis of thesepapers wasfocussed onthe pro- posed indications, the criteria for primary and secondary efficacy,thetechnicalprotocolsusedfortheinjections,and thereportedside effects.Only thosepublicationsdealing withonabotulinumtoxinA(Botox^®)wereretained.

Theratingandevaluationgroupcomprised13members hailing from different specialities (urology, gynaecology- obstetrics,or physical andrehabilitationmedicine), allof

whomdealwiththetreatmentofbladderoveractivity.These expertshadnotparticipatedintheinitialelaborationofthe votedproposals.Theinitialversionoftherecommendations waselectronicallysubmittedforafirstroundofratings.Each memberof the group wasrequired torate each proposal withagraderangingfrom1to9,with1correspondingtoa totallyinappropriateproposal,9correspondingtoatotally appropriateproposal,and5correspondingtoanundecided opinion.

Following the analysis and summary of the responses, thegroup metin ordertovalidatetherecommendations.

Arecommendationwasacceptedinthecaseofstronggroup approval(medianratinggreaterthanorequalto7,andrat- ings lyingin the range between 7 and 9).The group was theninvitedtoprovidedetailsofthereasoningbehindthe inappropriate and uncertain proposals, and following this discussioneachmemberwasgiventheopportunitytomodify his/herrating.

Followingthismeeting,anymodificationstothepropos- als,orthepotentialwithdrawalofsomeproposals,couldbe decidedupon.

Thisquestionnairewasthensubmittedforasecondround ofratingsrequiringacertaindegreeoftolerance,sothatthe systematicrejectionof anyproposalsbyoneexpert could notblocktheproposalselectionprocess.

The rating group then met a second time,in order to establishaconsensusof recommendations,withproposals havingtheoptionofbeingclassedasappropriate,uncertain orinappropriate.

Aninitialversionoftherecommendationswasthusestab- lished.Thiswassubmittedforevaluationtoareadinggroup comprising 30 participating urologists, gynaecologists and specialistsinphysicalandrehabilitationmedicine.Sixteen members(53%)of thereading groupreplied.These mem- bers gave their opinion on the content and form of the initialversion of the recommendations,in particular con- cerning their acceptability, applicability and clarity. An analysisandsynthesis oftheseresponseswascompiledby theprojectleader,whodraftedanynecessarymodifications.

Theseminormodificationsconcernedmainlythecomments added to the recommendations. The final text was then validated.

Results

Indications and contraindications

ABotox^®injectioncanbeusedforidiopathicbladderover- activitywhich hasdeveloped over aperiodof at leastsix months.

As a general rule,Botox^® is not a first line treatment foridiopathicbladderoveractivity,exceptwhenthereisa contraindicationforafirstlinepharmacologicaltreatment.

Thefailureofananticholinergictreatmentisdefinedby the absenceof any significant efficacy, withat least two pharmacologicalagentstakenorallyat thedosage recom- mendedbytheFrenchAMM,foraperiodofthreemonths, orbytheinterruptionoftreatmentduetoadverseeffects.

Botox^® injectionsarecontraindicatedduringpregnancy, breastfeeding,inthecaseofmyastheniagravisoranamino- glycosidetreatment.

Anevaluationperiodofatleast6monthsfor idiopathic bladderoveractivitywasretained,inordertobecertainof dealingwiththecontextofachronic,butnotasubacuteor acutepathology.

Asaconsequence of theinvasivenatureof anintrade- trusor Botox^® injection, and the availability of first line pharmacologicalorrehabilitativetreatments,thebotulinum toxininjectionremainsasecondlinetreatment.

The criteria retained to determine the failure of first line treatmentsvary widely in the literature. Very often, this is relatedto thefailure of one or sometimes several anticholinergics, or sometimesthe failureofanticholiner- gicsandphysicalrehabilitationorbehaviouralmethods.The recommendationadoptsthenotionoffailureofatleasttwo orallyadministeredpharmacologicalagents,inordertotest drugshavingdifferentavailabilitiesormodesofaction.

Inordertoaccountforthepracticalconstraintsofconsul- tations,aperiodofatleastthreemonthsoftreatmentwas required, although periods of onetotwo monthsarefre- quentlyencounteredintheliterature.

Evaluation prior to injection

Before proposing a Botox^® injection, confirmation of the idiopathicnatureofanoveractivebladderrequiresanypos- sibleurological,gynaecological,neurologicalorpsychogenic cause tobeeliminated bymeans of a full clinical assess- ment,uroflowmetryevaluation,cytobacteriologicaltesting of the urine, andultrasound imagery of the urinarytract combinedwithameasurementofthepost-voidresidualand endoscopyofthebladder.

It is recommended toestablish a voiding diary before initiatingatreatmentinvolvingBotox^®injections.

Full exploration of the bladder-sphincter function by means of a urodynamic evaluation, including exploration ofthevoidingphase,isrecommendedpriortocarryingout Botox^® injections.

The search for the cause of bladder overactivity is an indispensable prerequisite. Indeed, the discovery of a uro-gynaecologicalorneuro-psychogenicaetiologyrequires priortreatmentofthecause,beforeenvisaginganypossible symptomatictreatment.

The purposeof a voiding calendaris to determine the frequencyandvolumeofdaytimeandnight-timeurination, thenumberofepisodesofurgeincontinencewithorwithout leakage,andthedailyvolumeofurine.

Concerning the role of a urodynamic evaluation prior tomakingintradetrusorinjectionsofBotox^®,noconsensus wasreached.Mostexpertsrecommendeditssystematicuse.

Someexpertspreferredtolimitexplorationofthebladder- sphincter function to a urodynamic evaluation, including exploration of the voiding stage in at-risk patients (sub- jectsover 65years inage, males,witha historyof pelvic surgery or sacral neuromodulation failure, mixed urinary incontinence,flowmeterabnormalities,orthepresenceof asignificantpost-voidingresidual).

Urinary tract infection and antibioprophylaxis

Inthecaseofapositivecytobacteriologicalexaminationof theurine,aBotox^® injectionshouldnotbecarriedout.In

thecase ofaurinarytractinfection,thismust betreated andtheinjectionpostponed.

Currentknowledgedoes notallowanyconclusiontobe made concerning the usefulness of an antibioprophylaxis carried out prior to a Botox^® injection. In a neurological patient,thelegaltermsofuserecommendtheadministra- tionofan antibioticfor 1to3dayspriortotreatment(at leasttwodaysinthecaseofasymptomaticbacterialcoloni- sation),onthedayoftreatment,and1to3daysfollowing treatment (atleast twodaysin thecase ofasymptomatic bacterialcolonisation).Theserecommendationscannotbe extendedtothecaseofnon-neurologicalpatients,whohave quitedifferentbacteriologicalurineprofiles.

In published studies, injectionprotocols have, or have notincludedanantibioprophylactictreatment(withdiffer- ingproduct,dosageanddurationmodalities).Althoughthe rateof urinarytractinfections appearstobe significantly higher, following a Botox^® injection, than in the case of aplacebo, thisappears tobemore closelyrelated tothe Botox^® injectiondosage,totheexistenceofapost-voiding residual,or tothe absence of a clear definitionof a uri- narytractinfectioninthestudies,thantotheuseof,orthe modalitiesoftheantibioprophylaxis.However,untilnowno studyhasprovidedaspecificresponsetothisquestion.

Anticoagulants and antiplatelet drugs

It is not recommended to make a Botox^® injection in a patienttreatedwithoralanticoagulants.

The approachtobe takenwithrespect toantiplatelet agentsisdefinedbythegoodpracticerecommendationof theFrenchNationalAuthorityfor Health(HAS),relatedto theimportanceoftakingthromboticandhaemorrhagicrisks intoaccountduringaurologicalendoscopicprocedureina coronarypatient(June2012)[12].

It is always advisable to compare the thrombotic risk associated with the withdrawal or modification of an antiplatelettreatment, withthehaemorrhagic riskassoci- atedwiththeinjection.

The haemorrhagic risk with a Botox^® injection can be likenedtothatofabladderbiopsy.

Inthecaseofamajorthromboticrisk,itisrecommended to delay the procedure, or to maintain the treatment usingacetylsalicylicacidandtostoptheadministrationof clopidogrel5daysbeforehand(orofprasugrel7daysbefore- hand).

Inthecaseofaminorthromboticrisk,whenacetylsali- cylicacidmonotherapyisused,thismustbestopped3days beforehand.

Inthecase ofaclopidrogrelmonotherapy,thisistobe stopped5daysbeforehand orpossiblyreplacedby acetyl- salicylicacid.

Intheabsenceofanyactivebleeding,resumptionofan antiplatelet agenttreatment must beinitiated assoon as possible,ifpossiblethesamedayastheinjection.

Feasibility and acceptance of self-catheterisation

Before proposing a Botox^® injection, it is recom- mended to verify the feasibility and acceptability of self-catheterisation.

According tomajor evidence-basedstudy publications, therate at which self-catheterisation is adopted, follow- inganintradetrusorinjectionofBotox^®,decreaseswiththe injecteddose,leadingtoself-catheterisationratesgreater than 40% at 300units (Botox^®), of the order of 30% at 200units(Botox^®),andlyingintherangebetween7%and 11%at100units(Botox^®)[2,9,13].

Thesefindingsmakeitnecessarytocorrectlyinformthe treatedpatients,toconfirmtheacceptabilityofthisriskand toverifytheirabilitytoimplementthisgesture.App-test canbeusedtoverifythepatient’saptitude[14].

Therecommendeddoseisthathavingthebestbenefit- riskratio,i.e.100units(Botox^®).

Anaesthetic procedures

The Botox^® injection can be carried out following local urethrovesicalanaesthesiausinglidocaine,possiblysupple- mentedbytheinhalationofnitrousoxide.

This involves instilling a solution of two vials of 2%

lidocainewithoutadrenalinein30mLof14per1000bicar- bonate, supplemented by the instillation of one vial of lidocainegelintheurethra.

The injection of Botox^® can sometimes be carriedout undergeneralanaesthesia,dependingonthepatient’spain perceptionthreshold.

Most published studies make use of local anaesthesia involving,atvaryingdegrees,intravesicalandintraurethral lidocaine,sometimesassociatedwithsedation. Somepro- tocolsmakeuse ofgeneralanaesthesia,which ishowever difficulttoacceptfor thisfunctionalpathology, whenlow painperceptionthresholdshavebeenreportedunderlocal anaesthesia.

Practical methods for carrying out injections

Immediatelypriorto makingaBotox^® injection, itis rec- ommendedtocarry out an endoscopic explorationof the bladder,toverifyitsnormality.

Theinjectionis carriedoutinan operatingroomor an endoscopyroombyapractitionertrainedinthistechnique, usingarigidoraflexiblecystoscope,whilstrespectingthe usualasepticprecautions.

Therecommendedirrigationfluidisanisotonicsolution ofsodiumchloride.

Theneedlemustbesuitableforthisapplication.

Thebladdermustnotbetoofull,attheriskofmaking itsliningthinner,leadingtoperforation.

Theneedlemustpenetratethedetrusor,withouttrans- fixingit.

The treatment mustbe appliedusingat least 10to20 injectionsof 0.5 to1mL, whichare uniformlydistributed overthebladder,whilstremainingatagooddistancefrom theurethralmeatus.

The last injection must be made with 0.5 or 1mL of physiological saline, to ensure that the foreseen dose is correctlydelivered,despitethedeadspaceoftheneedle.

Theinjectionprotocolsusedinthemainpublishedstudies [8—10,13,15—20]reporttheuseof0.5to1mLunitinjections containing5to10unitsofbotulinumtoxin(Botox^®).

It is not recommended to leave a urinary catheter in place,exceptinthecaseofmajorhematuria.

Studies comparingsubmucosal and intradetrusor injec- tionsdonotappeartoshowanysignificantdifferences,even thoughthis distinctionappearsratherartificial[21,22].In fact,thereisnoaccuratemethodforcontrollingthedepth ofinjection,sincethisdependsonthethicknessoftheblad- derwall, theextent of itsfibrosis, thedegree of bladder filling,thetypeofneedleused,andthepressureappliedby theoperator.

Injections in the region of the trigone do not appear toinduce anyvesicoureteralreflux.However,theydonot appear to be efficient, nor to induce less post-operative residual, than injections uniformly distributed over the mobilepartofthebladder[23,24].

Precautions for use

Assoonasithasbeenpreparedintheneedle,thesolution mustbeusedimmediately.

Disposableequipmentmustbestoredinappropriatecon- tainerspriortoincineration.

Surfacescontaminated bythe botulinum toxin solution mustbecleanedwithanabsorbentclothsoakedinasodium hypochloritesolution(bleach).

Inthecaseofanaccidentalprojectionintotheeye,itis recommendedtorinsetheeyeabundantlywithwater.

Inthecase ofaccidentalprojectionontotheskin, itis recommendedtoapplyasodiumhypochloritesolution,fol- lowedbyabundantrinsingwithwater.

Post-operative follow-up

The patientmust bemonitored until urinaryrecovery.An informationleafletmustbehandedtothepatientafterthe injection,and thismust in particular indicate thatin the caseofburningmicturition,fever,difficultieswithurination, or an abundance of blood in the urine, the patient must consultwithoutdelay.

Afterthefirstinjection,aconsultationmustbeforeseen withinaperiodofthreemonthsfollowingtheinjection,in ordertoevaluatethetreatment’sefficacy.Thisevaluation mustincludeaurinarydiary,flowmeteranalysis,ameasure- ment of the post-void residual, and a cytobacteriological examinationofthepatient’surine.

Apost-voidresidualwhichisgreaterthan200mLand/or symptomaticmustbeaccompaniedbydiscussionoftheuse ofself-catheterisation.

Arenewedinjectioncanbeenvisagedwhentheclinical benefitoftheprecedinginjectionwearsoff(typicallyafter aperiodof6to9months).

Inallcases,adelayofthreemonthsmustberespected betweeneachinjection.

A delay of twoweeks is indicated by majorevidence- basedstudies,untilmaximumefficacyisachieved.

A decision to initiate self-catheterisation should take completeanalysisoftheclinicalsituation,togetherwiththe voidingcatalogueandflowmeteranalysis,intoaccount.

Apartfromtheabsolutevalueofthepost-voidresidual, theratiobetweentheresidualandthebladdercapacity,the possibleneedfor abdominalthrust,andtheclinicaltoler- anceexpressedbythepatientmustbetakenintoaccount.

In the case of a lack of efficacy following injection,a 50 unit stepwise increase in BoNTA (Botox^®) dosage can

be envisaged, by evaluating the benefit-risk ratiofor the patient.

Thenotionofdosageadjustmentduringinjectionisbased ondatafound inthe literature.Dowson etal. proposean increase indosagein thecase ofinsufficientefficacy, and a reductionin dosage inthe case of asignificant residual volume[25].

Conclusion

The literature provides data with a high level of evi- dence in terms of the efficacy/tolerance profile of the botulinum toxin A (onabotulinum toxin A/Botox^®), allow- ing thebotulinumtoxin tobe includedin the therapeutic algorithmfortherefractoryidiopathicoveractivebladder.

These recommendations provide asummary of current datafoundintheliteratureandexpertpracticeconcerning itsmethodsofuse.

Theiraimistoharmonisepractices,toassistthepracti- tionerwithhis/hertherapeuticoptions,toguidediagnostic evaluationsandthetreatmentandmonitoringofpatients, andtolimittherisksassociatedwithincorrectusageofthis medication.

Disclosure of interest

TheauthorsareallconsultantsfortheAllerganlaboratory.

Thelogisticalandfinancialsupportrequiredfortheprepa- rationoftheserecommendations(organisationofmeetings) wasprovidedbytheAllerganlaboratory.

Acknowledgements

Theauthorsextendtheirwarmthankstotheproofreaders (VincentVillefranque,MartineHerry,FranckBruyère,Jean- MarcSoler,BernardJacquetin,ÉvelyneRagni,FlorenceCour, Mireille Damphousse,Vincent Misrai;Philippe Ferry,Émile Darai,JeanPaulBoiteux,AlexiaEven-Schneider,SophieCon- quy, Jacques Kerdraon Xavier Fritel) who evaluated both the content and the form of the initial version of these recommendations, thereby improving their acceptability, applicabilityandclarity.

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