Nf>A No.2I..tl.Cipre OtictLde SaMt

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~ 01eiprGfloxaein ust4 at .... recommcndtd dosaps. Then~ no rvonsof~nofe.bIti.mcttbolita ofciplOt1oxacift. 11Ine results arcGOllSistenlwi1h..-liAioaI ascssments ofciprotloxaein altsorption inaai~ asdi_" in Module2.6oftftg"ission. Ciprofloxacm Otic Solution 0.2% is not likely to haye Ill)'disGomiblc~Iogie effect whon used in accol'daaa with the~ labeldinecions for tra&ment ofOE.

~",.""" ...........The Applicant pl'Ovida flO explanation ofprimary pharmMo4ynamiGs in Soetion 4.2.1.1.In this section... ApplieMt J'I'Ovidos one refe:renee from the lit.... (31). TheA....__ that primuy phamulcodynamies is SU}'JIJOItC4 by literature and by theApney's liM"" StqJpOrtiIlS the dev......ofciprofloxaein for llpPftWedformulations aM indications ......~ in ciprot1oMcia pmcIuGt ..lint(Ci~ He Otic PrcscribinaI~ TIIh 4.3.2. Module 4. Vohne 1, tIHssublftisJion).

~,..,.....--A:J...by 11M Applicant in Section 4.2.1.2 o'1his submissien; no~~)'IIMtics studies w-. conchlGted. This sectioIl ..f........to theApncy's findHIp suppottina th« development ofciprofJoxaem for IfPIIOVMf0l'lltUfatioM·_ indications'" aN SUIIIIftarized in ciproftoueia's,,",* ........

,. 1.."".,.A:J by the Applicant in Sedion 4.2.1.4 ofdtis submissioa, Dei)~

dNa inleracIien studies were~ This section mtnncts hack te" ApftGy'srmdia tit. developmatt ofciproftoxaein fOl...-ve4~ ancIilKlicatiou SUJRIIIIrized in cipleftoxacia's product 1aH1iq.

PnHctDtftlep Ratio••n. It the ...... fer tile development0'............ s.e1ioa 2.S.10' .The Ao is iavtsti.....1he UN o'Ciprefloxacin Otic Solulieft •.2%.........for bilIttria otiUs atiIIM (0£). Ciproflouciais.~.....widl spec;trUIII ..........MtiYity. It is a MIkhuIc COIIIJIOUftd... is..in1raYCllOUlly. orally, _tepiull)' to..avlricty ofinfldi Topial........._contaiIt...c~inia~wilh~(HC)_widl................ lppIOYedia..USfortu..s..... oIOE. Ode ........~.i..~ ............. .,provcdoulSidl- us......A"n..·selillial••,........... forC~ Otic Wutioa 0.2%indudIS -1IIUItieentG' seucty (with IIUtI)' aaten iA the US ....~)of"'"....., ia.................c.....(1Iw Pivotal Study~ CIPJtOT nW3 IA 62),

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NDA No.21-9ttC......Otic~s.Mt..~....._...6iIk..,.,........notappliGaWe,a......Qaa)iIyCoabol--'w submit l'tIpft1infaewIy..,. MlCtestiIJI.

........,.,......... '1beAp..........pnMcleMlCiDteqJNIiwcritaiafIDrS. ......atP.~~to~ Howevw. tbefulJowiDc MlCifttapNtive criteria....·....·ffoatlleCSpM LV. CkYw),...........maybe a)ll'JliedtotlaecliaialmiclroDioloIY.....perbmed ia the appIicatioa.

For di1tUion ......,..-. the followina Wl'bilpwu takeD from tbepM....fer Cipftl I.V.C....)~ '

Qualitative ......... used to detcmsine lIItimicIobial minimum~COncentntiORl (MICs). These MlCs provide ......oCtile susccptiWlity ofbacteria toantimicrobial compounds. The MlCs shcNId .. determined usm,.~procedure.S~ proeedwa arc __on a dilution method (Moth or apr) orequivalent witll~ inoculum concentrations and~GMCentrations ofcipreflouein~.The MlC val.,. sIlo&tlel be intcrpNtcd aceordin. to the followinlcriteria:

For-ftl__iG IftiGroorpmsms etMr· thaaJlaemop1liltu i1t.fIwnz-. ancIl1MmopIUlru.....i.

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.... . .. , . . ..•.• ....., MCI' • ., ..........,······UIinIU.lll nl:.li....' ......u.~ ....

~.....ily tat",. the use oflaboratory control~·to COfttIOI the ·..,..01. laboratory procedura. Standudc......,..,.,should.."We'" follow" MIC values:

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PIL\OJDPlVOfALCUNlCAl.TRIALCIPitOT nJiOJ IA 02. is a .......iJWs~·"iadId com,.ison of" dIiaoy.....,ofciJn"'•• sohaIiM 0.%% with MOIIt)'Cia and pllymyxinB and~ ia"__E_o'ac..dim. otitis cIJi.......-......, ................• "....,. tJ1J}«tIN is te........ wIIIther the~ofpllic. wiCh .liitiGalCUN......"'oE~".......wia CiplefloxHiIIOk SoIuCioIt·••• is...iaftriat'to" ,..,....WillI chicaJ;an'" smmclays of .,tie with rMH iltdliWrcA; _1 _ wich 01iIiI .C etIlcacy ( ), .

NDA No.1}-t}ICi".ftuElcia 0Iic~s.Mt

Uot!}CIWcIt~Review

S«tJItf1My obj«:tiYa: To dctermillo whedtet the proportion ofpatients--inaeach ofthe followiftJ endpoints after seven days oftwicc daily tra1malt with the .... product isnon-W" to the proportion after sev...ysof~lytratIMftt with PNH inchiWftrJ. IdoIcscIhtl, and adults with..diR'ue otitis ntcma:• Clinical cure at Visit 3,• Clinical improvement at Visit 3 and at Visit 4,• Resolution ofotalaia at Visit 3 _ at Visit 47

• Improvement in otaIaia at Visit 3 and at Visit 47

• Clinieal and micrebioloaical cure at Visit 3 and at Visit 4, and• ctift.. and miclohioloaical imprev'" at Visit 3 and at Visit -t.

Pa"Pop".".The....... five POPUlations defined for thia stud)': Clinial Per~ (CPP), CliniealIntent-To-Treat (Crrn, MierobioJoaicai Intent-To-Trat (MITI),MiGrobioJoaical PerProtocol (MPP),,, Safety.

The empopulation inclu4ed all pMientI who arc randomiad ......ive.y studymc4icatioa. 11Ic CPP population is the primary population for cftiGacy aaalysa which isdefine4 8$ these patients who:• SatisfY all inelusion and CMlusiorten_a;• Do not reeeive any pIOhibitcd coneomitaM JMdieations;• Do not have any other major pIOtOGol violatjons; Complete Visit 3 ...Visit 4 (Mias

....~ is deemed • clirrieal faihn at.. eadier visit than Visit 4); an4• Have compl" rates bctwoenlO%..110% as.fined under Study McdieationC~ (p8tierats who aN.....CliaicaJ failures arc to be included if'they hadcom, rates tJctwceB 10% IIl4 121%..... the r. tbnc days ofstud)'tN ).

1tIcMnTpopulation iJJeludts all em,...·whose Visit 1 miGlotrie••cultureYioWtd 9M or patho.... 1'bc MPft,.. win iJJeJude aU CPP"....whoseVisit 1miCrobioJoaical cuJtuN yiekts one or pIIIhoaens and who havemio_ioJoaical...(Eradielltion, I'rcsunted ieatioa,""e,.Superinr.tioo) from Visit 3 and/or Visit 4. .

CIiIdcal &fllcacyCIPROT 111/03 IA 02 COIftPI"S tile.,..".ianl's,....~..ciprofloucin Olio solution'" product with ..8JIfIOYcdode"'~ J'NH lorclirrical cure .. Visit -t. TIne iniaI....,,....n inc _......w (0+).ntiN(I ), (2+);_stY (J+). Atotal.,.. score isohtUtld h)' Theoverall eliaical MN _ ItcliRial ~ inIpIoVCJMJlt, eli'"fai Clinical ·is ulllOlutioll of........., IIIdoteJrhoa. A cJiJlical..it iI. GliaicII CUR is SCCII at boIh Visit 3 andVisit 4. At cJillicll ewe is"ifa..impov_ is... at Visit 3 andcliaical CUR: is NGOnllId II Visit.... TIle,......, cftiGaq CIICIpoint for this stu4y is

NDA Ne.21·'llCi......-.Otie~SaIvat

26eUlCliltial~am.w

cliJtial aue at Visit 4 for thc total population. For puIJ)OSeS of the primIJy IR8Iysis,.eicmts who had a cliDicalout~ recorded as clinical improvement at Visit 4 arec;ombiftOd with 1M".u.nts who have a cl.... outcome ncOldcd as eli'" faituro (atVisit 3 or Visit 4) to fOAl' an overall clinical failure 1fOUP.

MIcrob......KtIIacyMicromolosieal- cultures ofCil disc.... are taken at Visits 1. 3. and 4 txccpl when ItOdisehIrp is,... After proccssinl at the ecmtra1laboratory. spec. identification andblcteMl ..... is ISSCSSCd. BIetctiaI ahuradanec is assessed on ..... of J+ to 4+per scancfIrd llberaaory plldin.. To be considered • pMhopn. the cuIturect....ismmust have ....presont. at a level 0(2+ or h.....

ldetUIcatIoa0'........... til. a.ae.tS.., CIPROT JIll OJ JA 81In1hc pivotal ClPIWT IIV 03 IA 02 study. the MiaobioloJieal Per-Protocol (MPP)population, 174...... in each~ IfOUP (70% and 72% ofthe CliaialPer-Protocol lctP] popuI8tions for eiproflo_iA..polymyxin BllIIOtftyewh~ [PNH] aroups resptetivcly) Md at last one pethopn a&~.Table 9 Ustsall0fthe ",-therapy~ i4entificd in the MP' population.h~~II was isolated from a majority ofthese ...... (17% ift thec~.-._ 19% in the PNH 1fOUP). StiIpIry/oe«au mnw" isolatedftont 1mof"" in the ciprofJo_in areup and 17% in the PHH 1fCMIP. TMM..ie.allRteftMO-Treat (MITT) popWatieR includod 232 ,..i••iII_c~ ...(73% ofthe Cliftieal .....Treat [empopu....) _211,.eiaICs illdlo PHD IJOUP (1C)OA. ofthe ernpopulation). The pcrceIltapS 01""'"infeGted with P.~ and So IIIIMU in1Itc MITT popuilltioa ..... ·siatiIIr to thosein die Mr,po,...... Table 10 lists"~ idcfttifacd in ..MITt' popWatieR.

WhcII,..,.,.. WIN ideIItified by GOUIdfy. P.~ and So .,..,Wile apin tIw1110I&.prev." ise..~iatodwith OE. TaWes 9 and 10 show ....com,'"betvJ_..US..st-ish MPP..Ml'M' populllions from whidt·.. feast one,......wu klc¥JdW at ,..-thmpy in..C)PROT study.

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