CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number 75-492
`
`Approval Letter
`
`_
`
`----
`
`

`
`ANDA 75-492
`
`_
`FEB II 2660
`
`Keller & Heckman
`.
`Attention: John Dubeck
`U.S. Agent for: Biovail Laboratories Incorporated
`1001 G Street N.W., Suite 500 West
`Washington D.C. 20001
`
`Dear Sir:
`
`This is in reference to your-abbreviated new drug application
`dated October 30, 1998, submitted pursuant to Section 505(j)
`of the Federal Food, Drug, and Cosmetic Act, for Diclofenac
`Sodium Extended—Release Tablets, 100 mg.
`
`Reference is alsoimade to-your amendment dated November 19, 1999.
`
`We have completed the review of this abbreviated application and
`have concluded that the drug is safe and effective for use as
`recommended in the submitted labeling. Accordingly,
`the
`application is approved.
`The Division of Bioequivalence has
`determined your Diclofenac Sodium.Extended-Release Tablets,
`100 mg,
`to be bioequivalent and,
`therefore,
`therapeutically
`equivalent to the listed drug (Voltaren®-XR Tablets, 100 mg of
`Novartis Pharmaceutical Corporation).
`
`We acknowledge that the following “interim” dissolution testing
`has been incorporated into your manufacturing controls and
`stability program.
`The "interim" dissolution test and tolerances
`are:
`
`The dissolution testing should be conducted in 900 mL of
`phosphate buffer, pH 7.5, at 37°C using USP Apparatus
`II(paddle) at 50 rpm. The test product should meet the
`following interim specifications:
`
`
`% Dissolved
`
`Time(hours)
`
`1 4 8 1
`
`6
`
`

`
`The "interim" dissolution test and tolerances should be finalized
`by submitting dissolution data for the first three production
`size batches in a supplemental application.
`The supplemental
`application should be submitted as “Supplement-Changes Being
`Effected” when there are no revisions to the interim
`specifications or when the final specifications are tighter than
`the interim specifications.
`In all other instances the supplement
`should be submitted as a “Prior Approval Supplement”.
`
`Under section 506 A of the Act, certain changes in the conditions
`described in this abbreviated application require an approved
`supplemental application before the change may be made.
`
`Post-marketing reporting requirements for this abbreviated
`The
`application are set forth in 21 CFR 3l4.80—8l and 314.98.
`Office of Generic Drugs should be advised of any change in the
`marketing status of this drug.
`
`in duplicate, any proposed
`We request that you submit,
`advertising or promotional copy that you intend to use in your
`initial advertising or promotional campaigns. Please submit all
`proposed materials in draft or mock—up form, not final print.
`Submit both copies together with a copy of the proposed or final
`printed labeling to the Division of Drug Marketing, Advertising,
`and Communications
`{HFD—40).
`Please do not use Form FD-2253
`(Transmittal of Advertisements and Promotional Labeling for Drugs
`for Human Use)
`for this initial submission.
`
`We call your attention to 21 CFR 3l4.8l(b)(3) which requires that
`materials for any subsequent advertising or promotional campaign
`be submitted to our Division of Drug Marketing, Advertising, and
`Communications
`(HFD—40) with a completed Form FD—2253 at the time
`of their initial use.
`
`Sincerely yours,
`
`/63»...
`Janetxfidodcock, M.D.
`FEB ll amn
`Director
`
`Center for Drug Evaluation and Research
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number 75-492
`
`FINAL PRINTED LABELING
`
`

`
`Biovail Laboratories Incorporated
`Diclofenac Sodium Extended-release, I 00 mg
`
`Amendment to Abbreviated New Drug Application
`
`Diclofenac Sodium Extended-release Tablets, 100 mg in Bottles of 1000
`
`ca_.n$oTnSon
`____________.
`
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`on.3.«.2...£33853.3.
`
`NBC 0093-1041-10
`
`DICLOFENAC
`SODIUM
`Extended—re|ease
`Tablets
`100 mg
`
`} 1-n “
`
`D33.
`
`
`
`
`

`
`Biovail Laboratories Incorporated
`Diclofenac Sodium Extended-release, 100 mg
`
`Amendment to Abbreviated New Drug Application
`
`Diclofenac Sodium Extended-release Tablets, 100 mg in Bottles of 500
`
`30093-1041-cs”
`
`'V'S'flU!D9|U!1d
`
`
`
`I3oo93-1ot.1-o5‘’
`
`'V'S'|'lU!P31"!-‘d
`
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`$33?
`3
`
`§
`Eigiésg
`
`s 3-
`§
`
`HDC D093-1041~05
`
`DICLOFENAC
`SODIUM
`Extended-release
`Tablets
`10!) mg
`Each tabla! contains:
`Dlclotenac Sodium
`
`IOOITIQ
`
`GEE
`B only
`'I||IIIil"I'I".‘k
`
`Tenn
`
`§§§§§ 9
`
`§§§§§§§$
`§§§E§§§EE253
`E
`gg 3‘
`ggsggii
`;g‘2Es
`gag 3% *§
`2%-g
`s 3-
`§
`
`IIDC 0093-1041-05
`
`DICLOFENAC
`SODIUM
`Extended-release
`Tablets
`100 mg
`Each tibial cornllns‘.
`Dlclnianac Sodium
`
`100 mp
`
`B only
`
`'r'%»'J.~V=.¥t-.‘-
`
`'IiEEIlII
`
`()2£5
`
`

`
`IDC 0083-104.1-01
`5.? DICLOFENAC
`SODIUM
`Extended-release
`Tablets
`
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`
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`_..a..A.a..
`
`-rl"
`
`~90-<0
`
`e.
`
`rl'|l]¢5IlU(1 OI -Jlclllleflac -‘luv nI..'ea:.e sewn
`ul zerialn Jluqs
`concen1ralIans nl drgorun am mulrolrulrale mu Increase
`I.1cIosnnnna's nlohrnlnzlcny. Palllnts vmn baqln llI.JI1|]
`dlclolonac or Mm lncraasa thulr mclulrnar: nose or any other
`NSAIO vrllnla mung olgaxln. matrlnlruaa. or cyolosoonna may
`amlop toxmy cnaractcllstlcs for lllau drugs may should be
`olmrvod closely. pamcularly rl nnnl lIIrIr.-nun I: omnarrod. In lhe
`case 01 fllODlIrl,!-II’1.lI'I'| mm slloulcl In monltorad.
`Lilnlarn:
`Drcknenac accrual: Ilnnmm canal cuaranoo and
`IIICYBCSBS lltnlum plasma lwals. In plllflls lalrang Illclolenac and
`lnnlum concomnantfy. lmllum toxlcrty may fllvllon.
`Dnl llrnnlnollla: Dlclolanac um: um Illur ulucou manna-
`llsrn In normal subpccts nor arm ll allar ma Iflccls M oral Hypn-
`glycemlc agents. Then If! rare rlpofls, ham-wlr. lrorn maflmlnq
`uparlencns. n1 cnanoes ll'| allocts In Insulrn or oral llyooglyumlc
`agents In the presence Ill dlclofnnac mat naomrlalad changes ll'l
`me dons ol such agents Bum lIypII- and rryporurycemrc mums
`have nun reportnd, A mrocl causal rnlatrunallrp has not been
`eslabllshad. Dul ptlwclans alwulrl cnnslclar the possrbriny that
`dlcluranac may am I olahulsc naulnrs muons: In Insulrn or oral
`hvlloulvoemlc auants.
`nlultlfiz Dlclolanac and Inner NSNDI can Inlnbrt mu actnnty nl
`uIuraIII:. Concornllant lraallnont wrll-I notnalunl-spanno mural-
`Ics may on aaaoclltoa wlttl Inmasoo serum ootassrum lwuis
`Ollor map: In small groups nl palrenls [7-lclnntoraclnun slum.
`1113 cnnconlulanl admrnrslraliun o1 azalnionrlno. cold. cllloroquml.
`D-penlcrllamlno. nraanrsolona. I1orycycIInI_ or druilolnn Iltd nnl
`srgnilioanlry amct Inc paak lawns and Auc valuaa of dlclofanac
`Plounobamrlal torrlcrty has been ronnrlad to have occurred In I
`Inllonl on crllolllc phlnobatonal lraalmam lollowrng the Innmron
`o1 dlclofonac Iharaoy.
`Pnuia lladlng
`.
`In Irllrn.dIclolanar.III1¢rlarn mrnirnaw or not at all mm the nio-
`taln blndina nl saflcwc and 20% uterus: in ulndlng),
`lIIIbu-
`lamina, pndnlaolona (10%
`run In blndlnal. nr wanann.
`Banzylpanlcillin. amolclllin. oncilln. cnlrotatracydine, downy-
`cllne. coIIIIalotIIin.mIrlrornl1-Iycln. and aultarnelnnnzole have no
`lnlluancu In mm on Illa orotun running In ulclolanac In human
`scrum.
`Iltlllfy III Uhrltllln
`Eflln II Iland cupllthlz Dflolanu Incraasea platalat aggre-
`uatlon tulle llul dun: not amcl blaonlng lil1'lI.
`lama Illromurn
`mrw Ilunilllarn
`ngnln pm: omlnnandnlflla l rom-
`glultlng tima. plasma
`III 'lwI¢1ntI
`and VIII I: III
`borllawn IllI'|I$ have bun reported In normal volurllurs
`The
`mean cllanon warn olmrvod to be has man 1 saoond In both
`I290fIl|E'Ba
`IIIH M. DVWILI
`Ilr'Istanon.
`llowovlr. and are un|IIwly to Ilq'N§:lllnlI':‘aIly Impogrgl
`drug: ml inllibn ornmglanfiln aynthoala Imnaru vn'1h nlaulal
`lunolion In aonla doom; Inmlon. natlcms who may In annua-
`ly afllclndby aucll anactionshulldnuoarmllyohuwod.
`I
`caruuganala. Iutqqalula.
`_
`_ al Earflllly
`Leno-lorlllnrc
`atullaslrrralsonnn nlclolanac andlutn
`up no 2 Inollloloay (or 1
`May. aonrolnnlalaly ma human
`dual Mn maabd no slorl
`loanuncraanu Inlrrmor IIII-.ldaIII-.9.
`1'llmvm a alinlruncruaaa in lumen rrlumlllary flbroamnnmu ‘In
`mid-don-{mud (0.5 Inwllnmy or 3
`nfloayl lamala rats
`(nloh-oou lomalu nad maaaiva mortality .hu1 Illa lncraau was
`"°‘ :.“‘»."»”"“‘...".‘.&m $"n‘r?'e.°“.%.'r"o';‘."'
`...§'..’r'.'.£.?='“.“.?I°.‘.’r’n"'i;
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`nounlul.
`andllllll Iflld nu mow rnulauonlc activlly in
`In vlrrn noonl rrluullun assay: In rnarnmallan (menu lymphoma)
`and rmoroblal mast. Arms ml
`Induaa non
`nu:
`
`lllity.
`Han. Mull! DIIIQII1 I
`human. 1
`‘II! have bun namrmad In rllloo union
`Ra roductlon II
`dicgmnac sodium (no to 20 MMWIV or so
`fdI1)I|'|di"
`or
`.
`.
`3'3’ W rloay I ""r:§°'a°on all raw ‘"l:3r‘°rau?:vt":?‘-‘I‘I‘a
`"3
`......r° -v-.".:'I;-Ll'-°-".,¢...,r:".5.°.?"~".......*"'.:".:£:..."°'
`12.. meg” um: dyatuou. urblonotdouunmr. ruduold man
`3 5
`E
`SHOW WW "
`,
`.
`-
`Ina anlma raproliuclm
`woman.
`,
`an. no anaquaiia and waII¢cnl'l\rollaIl atudlns In vrnmnl
`dlctlva oi nurnan mourn. this drug should nm on used dun,
`praonancy urlou Ina bumllla II: Inc mnlnor nlnlly Illa potanlla
`nslllollrofma. Baewa-oHlIInalI_IaIlII1ctuaraauItlnu Iluifr
`malura clouura In Illa ductua amrroaus. dlcluhrlac sum as
`avoldad III M! Dflmall-‘Jr
`
`araurlunclvrn. BaIausaolllI¢lIIIovInaflnI:nnIw°It¢lI'lI‘|5|"-
`inhlbilmqnruql
`Inlauloarulumpxlarmtalnldlmnol
`ductlri Imnoual. ualotdlolallnacnurw Ian l>|'|I_||||'N-"I should
`be lvclklnd and. II Mm ollllr llulllwoflll Iml-I1|U'|'||||I10|'Y
`mugs. II I: oosailrlu rm Illclolmc may mlllllfl «MN MW-
`tlnnurldthflfllflllrllon.
`
`salatymoullaclivnnaaaolulclalmchruotli-Iricntllimsflm
`nolbaunamhlbluu.
`
`Iulaaaa an-In mar 19:. - canal Ilalallan-III! PIIIIIIOI
`{_Nl darmd Ironl cllnrlzallroaln
`_
`IIIolnaIIcI.3%mH-tuloumeoolulmulradrucnorls Is 1'1.-3%).
`uonnllnran; Iuruumnal nun onnrnna ‘I-urlame. -rlurn
`rmnlromllaorrnlamrnlorr.
`, D
`I
`.
`mu mu
`mun us-ulna
`
`I mum‘nun’loam.
`-mu“.
`ulmr. mm or
`i.a..
`or Illanolnu vlillloul ulc-r
`
`such! laws: 1'lnnIn.Is,
`lnclaum Less than 1% - canal
`
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`
`ll allonhll Pmhbllr
`
`

`
`

`
`'2:
`
`Diclofanac Sodium
`Extended-release Tablets
`R: onoy
`
`PrmnhInul
`
`I
`
`IIEICIIPTIII:
`Diclutanac sodium Is a honzanaaeatic acm darmtwa. desiunatnd
`monnsodlum an . Tha slmctural lormula is shown an hour! 1
`n
`chamlcllfy an 2—|£(2.B11ich|oro|1hany|):mIrrn! banzamaomc ICH1.
`...J». a
`
`rum 1?‘
`:11 name unnu-
`Dociolanac sodium is a I'am11y yailuwiah Mull lo
`r, Tha malac-
`Illy odorless, slluhl hygrnscapu:
`llina
`ular
`‘mum:
`anacsodiumna 13,14. Illalraayaoluhiain
`. aolubla in aflunol. and uranmafly imolubia in chloro-
`fonn and Ill dame am. Dbcloianac sodium up
`‘
`P; soluhla in
`«am The n-ocnnowatar pam'1ion‘cualhcn_ant Is! .4 :1 pH 7.4
`11111545 I
`5.2. This all has I dusudatmn eonshrn IDKIJ (II
`4.0 2 02 I1
`‘C In wI10f.
`Didotanac soaium us availabla as Dldulanu: sodium E:rIandau-
`taiaaaa Tablas of 100 mg for ml anrnims1ra1Ion.
`Diclafanac Soduum'EtIanoa\1-ralnsa Tablets Inacma Ingredients:
`hyutoxyanry! nalluloaa.
`iaoor
`I aleoltoc. anluyamus lactoaa.
`'um
`nnaary II pink). noadry (char), povidona
`(K
`1, caloul sahmna duutlda. talc.
`BUIGII. PIIIIIIGULDGV‘.
`
`Emnnarl-r
`mum.
`is I norutannml anti-umammatory
`Plavnaaamlar Didnhnac. ma amon_ in Dldolanac Sodium
`drug (NSAID),
`in pharrnamloml: s1udI_as. uipialanac has shown
`arlmrrflammatory. analoaalc.‘ and amlmratac actmly. Aa_ vtfilll
`omarNsAIDa.itsmnuaalac1nonanotInomI:IuabmlyInvnmh-
`flfnI1flIflH|11IYflIfIl'|l.h0VRVOf.lI|I¥flIil1VflNflmflIIflIi-
`inf€amgnawyacIMly.nwal|aanoInrI:_\lIahoflsa0hcacyinn|iav-
`mg nun rahm to infhmmalion and urinary msmanorrhaa. wnn
`raganl In as analuaaic aflac1.dIuolInar. ba run a natcotic.
`Plamaamauhaz Didoianac Sodium Extarldachalana Tauata
`cumin ma
`‘ mcuaw. cllclotanac. Diciatanac Sodium
`Eaelandau-ralaaaa ablats an tonnulatau to ralaau drug war a
`prololpoad uariod, Tha pallam _u1 onau ralaaaa and aowation :5
`daaonhad haonwand Is shown m Table 1.
`mm
`IaIa('!-tilraavnacaalaallualfllalaluac
`Failaulaallaalaou-alnaaaadllflalaaaalaalaniataaaafi
`nhaaaTaNaIa
`
`Drug
`
`Dldollnaa: Sodium
`
`‘ Tm
`Gnu
`MIC
`(WML)
`[M
`iW"'fl'|"|LJ
`423.5!»
`3.96
`2750.19
`£26.59‘/o]
`[7D.4."M)
`(202156)
`—
`: Unoar tasting commons. dnclofanac is cmnolataly
`tlomlhauaalruInlaIflna|1IIc1.Hawavar.dua1u1ir:t-
`naa§rrIalam|i:m.nnIyabnut5lJ!soIthaauuorhaddoaauaaya-
`Iarrnaalyandabh.
`llhihnlllllilinlniai-III-IITDIIH: Thaamntol
`dicluhnacabaurntionitolnlllarlavldld-rat-Iallblalianolsiw
`ni1I:an11yaHactadwIIaMhadn|gaalam1wflhlood.I~nwnar.iond
`‘nfliumiyallar-dlhaabaomlnon
`aaindiualad
`away
`1to2aoura‘1nT......arIauwn-f
`imraaaain
`w uaama
`uasInaptn1IIaoftnaa:nzandad—raiaaaat.au|al.unda_r
`condi-
`!sona.vnsnrnaac1ar1zaglllymu|upIapad:sandmohnnI_zatauh|acI
`nrmal
`In mod pruhlua In cnnIna1.ma_pIaama prnhla tor Ina
`a
`rahaaavablataundartad oondmunaanouaaamqro
`conaistnmaosotmionpammwnhaainqiaoaakuauallvouulmnu
`batwaansandfimuraamtmamaai,
`
`Dos:
`(I119)
`IN
`
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`
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`ma
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`
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`mum unuuuuaaaluofanmaummlforsx-Iofimtm
`uugumo
`_
`uncormnaaurugsumm.
`
`'
`Plum with Ram‘ anew: flaparic lmpumant
`Iaranccs In the nhar1'I'Iacnl‘me1Ics of mclolenac hm bean amn-
`
`

`
`

`
`

`
`

`
`/
`
`tolerate aaverse reactions >355 men men
`
`-ill JIM to
`Eiliifllr
`vounofl Dltlerrts.
`IDUEBSE REIEHDIS
`MING! lflflllofl l|'|l0l’l'|'lll|Dl'| IS dtflvld Pr0l'I'I bltflddd. controlled
`lfld ODOH-llhll
`fllllllflll lfllll. I5 U!" B Wflffiflfll marketing
`elvclllnlll
`In tho dllcflmlon other. ram M More common
`events represent clinical etiidy reeults. rarer event: are derived
`princioally lrom marlretuno eitoarielioa and publications. and accu~
`rate rate estimates are oenerellg not IIOIIING.
`The tollciwinu adverse reactrom werl rename In patients treated
`with iticlotanac
`Iiieleaaee Brealer The 1% - caaul lalatleaeale Pnaaaia:
`(all oanveo lrorn ruinical trials.)
`'1ni:ii1eni:e. 3% lo 91- (inuoenoe ol iinrnaniao reaction: is 1%-3%:
`led] an I Whole: Ahdolnunal pain or cramps. ‘headache.
`'t|uid
`retention. abdominal itiatention.
`ulanol. liver lest almomiaitaaa. ‘PUB.
`i.a.. Dllfllt ulcer. emli or
`lllaailaa: Diarrhea.
`'ino‘?estion. ‘nausea. ‘constipation.
`'tlai~
`without hleeoirio Irldltll perloretion. or bleeding without ulcer
`[see above and also WARNINGS].
`lei-eaealyleat: Dizziiins.
`we no aaaeaaaeee: Rash. nruntus.
`Slaelal Iaaaae: Tinnnus.
`llletlanallu Pmlollaz
`Iacldlnol Ln: ‘I'll: 1% - taaall
`(Adverse reaction: reported only Il'| worldwide rnarlrelino expen-
`ll'lCI Of II1 Ihl Ilflfllllfl. fII'.|l Sllll Ill C|I|1lCI|»IHl.|S. are cflllilfllfld
`rare and are italicizern.
`lady la a Whale: Malaise. swelling at line and tongue. photo-
`sanaithnty. arlaphylaara arianliylactold reactions.
`Berlleeanelr: l-tynerterision, congestive heart lallure.
`Illaeulea: Vomiting. iaunoroa. nielana. esophageal lesions. aphi-
`houe erorriatltie. dry mouth ano rnucoue rriernorenee. bloody diar-
`rhaa. lIl‘|lI1fllS. hepatic rrecrriss. crrrhoers. nepalormal syndrome,
`ie. oollria.
`aopetna cllifllfl. Dlrlcrlatrtia earth or without concomitant hOIIIII'
`llanle all Lifnplale: I-lemoolohin decrease. leuliooenia. throm-
`hecytooenla. eosinomllla.
`.llaniolyti'r: anemia. aplastic anemia.
`agrarriilocyrass. ouroura. ¢Wll'BlC purpura.
`latabella and Ilatlllaeel learlara:
`Azotemia,
`Insomnia, oroiigsinaes. dapreeaion. oioiooia.
`Iereaae Iyaleia:
`arunety. irrrlabltlty. aseptic nlanulolfls. oorrvulalaru.
`llnpli-may: Eolataina uthnia. laryrioael aoama,
`Bela eel Maaalaeaaz illonaoia. urtioeria. eczema. dermatitis.
`hullous eruption, eryrliema rnirrtrrorme mayor. engioaoema.
`Srnwiwoirrrsansyridruna
`Iaaelal Iaaaea: Blurred vlelrin. tam dlaoroar. ravarxrbla and
`irraillmble hearing Ion. Icotnrna.
`:
`llephrullcsynwoirie. prolaunurra. olrouna. rim-rarrrnr
`
`_
`laelIeaeaLaaeThaa1!i-ceeeellalallauelpllfluauez
`(Thetollwi
`reacilonahavetieenrepnrtedinpatlentstekino
`oiclolenaiu
`oircurrietaneee tlietoo not oarmltaclear attribu-
`tion at the reaction to olelotenac. These reactions are being
`included ae alerting intonnalion to physicians. Meets: mentions
`reported only in wrii'lt‘.lwit'le martmirln aimerianlle or ln the litera-
`
`-VI‘
`
`.
`
`rt'.1ion. nypolallslon.
`laehycaroia. pralnaturl
`
`eaen Ill rglinnoal triela. are oonaioereo rare and are itali-
`Iadalaaflldaz-Cllutpein.
`vlritrI¢ularcuI'ittIr:horra,lIIyounfial'
`Blilenaealarz Pelonations.
`Dlaaetleaz lntosflrllf pertbrahui.
`iie-in aee Lynaeeria: snmia,
`Iahlelhaaellaullaealllleerdare: try-poqlyeeri1la.iien‘gi'irloea
`ll:-eeae ennui: Pmniina. memory dixlurherloe, nlohtmam.
`tremor. tic. drlmrlfl morlfirllht, mum nartfllaflcraullui,
`naaaii-shy: Dyepnea. hyoerienillation, eoarna ol pharynx.
`Ila aal Ineaheuz Eiioaae DI'IPl'l‘l|\‘ll'I. axtamlva dennaririu.
`speelal Ieeeea: Vltreoos lloaters, night blindness. amtilyooie.
`Ilnaeelal: _Uririery Ireoiiaircy, nocturie. liarnatuna. impotence.
`iraqiml bleeding.
`I
`IJVEIIIOIIIE:
`Mth dlcldllrlc cover lficues.
`Worlthuidl ieportsorova
`reports of overaoeeoe. con-
`In aoproirtrnately one-hall of
`oornhant
`rriarlicationa were also Ialian. The hluhur dose at
`dlclnteriac was 5.!) o in a _1'Heer—o_lo male who suffered loas o1
`noriecioiisnaaa, inonaaarl l1IlICI'Il1l.| prenure. aentmloll oneti-
`l1'll'.IlliIl|,Irl'IflfllII12flI!|lNlfflUIl'flNl.T|'|Il'|II.1|'l
`Iiastooeee
`ol olelotenec wereto oand 3.75 o.1'lia2I-year-old ernale who
`looli 4.0
`aridthe28—andl2-year-old lernal_ae.__eaeh olwliom
`aymntnnie. Huweeeulienneereoon
`a
`-year-old erriale
`looli3.‘:‘ uolonotoevalooatyclinial
`a
`|'li'l|€Il1'ISl?fllDl'
`whoaiqieriereiedvornhtrioaiiooroiialriaaaalteranevarooaaol
`2.31 g ml dlclclerial‘.
`Min-ial L059 nliiae a
`a and: range or atieceotlliilltlaa to acute
`ovarooaaoa. with
`‘
`ti-‘ho more reeierant to acute toxicity
`than rodents [
`in rliollqr
`. 55: done. 500‘. monkaw.
`
`niendedltiatlliaiitomacli
`Ini:aeeofeeuteoveritoaaoe.lt‘ie
`. Forced itlumie may theoreti-
`be emptied
`won-iitlnq nr lav
`oiae:u.'reteolnttieurlia.TlIa
`rally-he
`lclalhaeaiaeettie
`effect at dlalyus or lleniopertuaion in the elimltletlon of dlolotenat:
`(99% protein-liourio: eee cLlllICA_L Pl-ll.lllaW.'.OLOGY) rarliairia
`unproven.
`In aodltinri in nipoortiye meaauree. the use or oral
`activated charcoal may hell:
`to reduce Ilia absorption at
`
`Will! All allllllrnlllll
`Diclelenar: may lie aoininlatered a memo Dlclotenac Sodium
`Exiiarioerl-rinse Talilere. Dlcloteiiac Sodium Emnoed-release
`oitioneaaioeliou
`bauaedaeehqonietheeeoyin oatlentevnth
`Taliletaianotindl|?lenlorttiemanaoemantolacutaoa_intulun_n-
`osteoarthritis and rheumatoid arthritla.
`The
`at dlelelenac ehoulo he iiidlvlouellaed to the lowest
`ettecthie
`one to nirriarilae aoveraa allecu {lea Ill0lVlDlJALIZA-
`non OF DOSAGE).
`
`lor chronic lltlllw
`Duaaarlrlhz The reoorlirrianoeo
`Doeaoee ot Dlclolenac Sodium £irleridegt-releaea Tablets
`with Diclolanac Sodium Extended-r-Ieaae atileis is too ha
`mg oally are not recommended tar patients with oeteoarlhrhle.
`D5 ID!
`I
`.
`Dl.'llIIDI"IhlfiI2mfl1fl"fli5'hIVIfl01bOIflItUdlO¢lflDI1'Il|IIII1h
`flhaeiaaleld Arlrllaz Tha racmnrnanded dosage for chronic
`there
`with Dlclolenac Sodium Extended-releasertablets ‘is 1m
`rn
`erg.
`In the rare patient where Dlclolanac Sodium Emman-
`reloeaee Tatilete Ill) moldey ie iinaatlelactory. the dose may be
`. Doaaoa: above
`moloay are
`recorrimenoeo in
`irgaaled to 160 mu b.i%5ll the Dandltantgflliull the C||l1|fl_l
`patient: with rheumatoid
`
`Diclnt-inc sacrum Extended-releeae Tetileta
`Ill] m - iinacored. plrilt. round tilrn coated laolats. engraved
`with “ 1” no rm! -:ir1r and “I011” nn Ilia rilhnr «Id».
`
`

`
`lffiflfll I055
`IUIIIIIIIIC llll llflflllfllll UIIIIIIHZ rlypoolycnmlal
`Iowan haul: Parasthesla. rnamorv dlsturoahcel ruohrmaras.
`trl'l'|Dl'. hr. aomrrrlal axaurlaoarl dworrarlum psycmoc mcmn
`Iqhton: Dysrlllca. llynarvunulatlon. mm: o! pharynx
`I! d upulaun: Eaooaa Detspflllon, mnhalm aorrrlanns
`Initial luau: vitreous floaters‘ nlohl hllnonass. amhlyupra
`Urogenital: urlnary fraouoncy. Oflfllfllr homatuna lmpolerlce.
`nglnal hllodiho
`DVEHOSME:
`wodowrde raports o1 nnrllosaoa vntth olctotanac com 66 cans
`in aoproaurnatalv one-halt at than towns o1 onrdosaoel con—
`cornrlanl
`rnoolcatlons were also lakoh
`The mohasl dost o1
`dlclofonac was 50 ll m . l7-yoar-ola mate who sullmd loss or
`monms. and and 2 days amr uucrdou. Thu ml h‘ hut dons
`ot alclotanac worn 4.0 u and 3.15 or The 24-year-old male who
`look to 9 and the 23- and I2-yaar-olo Inmates‘ oach ol whom
`loot 3.75 a old not dcvulorl any cllnloal
`slanlfrcanl
`I'll or
`symptoms Howivcr, more was a rooorl u a 11-year-old arnalc
`who elloamncad vomrting and drmmnoss aflor an lmruoso ol
`2.37 9 of fllcloflnal:
`Animal L054; nlllas show a wad: range ot $|.EvG9fllbi|lIlO.'n to acute
`auerdoaaga. wlth primates bolno rnnru rllslslant In acute loxlclty
`lgaorlmrooenls lLD5a In mglko-rats. 55: does‘ 500: monaleys.
`In case of acute ovorlrrosaoc. II as lICflt11l'|'|Il‘ldGfl that the stomach
`bu arnptloo I: vommng or lav
`u Forced dlumlo may mentall-
`ully ho hum lclal beans: The
`rug ls ucrotoa rn tho unna. The
`effect at dlalysls or llornoporfuslon rn tho atlmlhatloh oi dlclotarlac
`(99% proluln-hound: an CLINICAL PHARMACOLOGY} romalns
`unproven.
`in addition to supoortlva musuras. tho use ol oral
`acllvatod charcoal may hlllp lo roducu tho atlsnrpllon of
`dlclofanac
`
`DQIMIE Ill} AOIHHTMTTOI
`Dlclofanac may DI admlnlalerud as lwmu Dlclolanac Sodlurn
`Extended-raluau Tahlats. Dlclolanac Sodium Exlalload-ralaasc
`Tablets la nol mdlagloo lor the rrlanaoorrlonl ol acula oalnlul con-
`dltlono and should he one as chronlc therapy In patlonla wnh
`oslaoanhmin and rflluhlalnld. arthrma
`TM
`ot dlolofonal: should no indwldualiud to the lowest
`cttoclm on to mlnlrmza advam uttacts (no |NDlV1DUALlZlt-
`
`for chroolc "Ion?
`Tho ruoolhmanoad do
`ndlurthrilll
`wlth Dicloiarlal: Sodium Extended-raloau ahlats la 1m try
`our oi Dlcllmnal: Sodlurh Emhdad-raluu Tahlals
`_
`rho
`the an no! rocornrnohdnd tor patlams um: osmarthrllls.
`ulllolnh '
`.
`Dosaonarflvazmmway havonnl boon ltudlatlin polilnts wnh
`ltoilnllnll Mlhllh: TM roooltlrnarldao oouou tor chronic
`thonpy wlth Dlclolonac Sodium Exlandad-ulna tablet: is 100
`ad In the tar: pallam when Diclolcrlal: Sodlurn intended-
`rlmaoa Tahlata 100
`la unaalisiaaoryl tho dose may he
`irlcruud to 1m mo V ltlaglldtlls 0l.'IMIJflfl lhln§l:‘|]|cIJ
`lists. Dosages alum
`III on rocomml
`In
`nlllohts wrlh rhourrlanord arIhn"t;|“.[
`MI IWPI.I1_I
`Dlololinac Sodlllrh Exlandod-man Tabla:
`lull
`unsound. pink. round tllm cooled raulota. ohoravao
`with
`'oIIol'lc:looand '1tM1'onlhI mhorsdc
`BOIIIII I11 100
`N06 M93-1041-01
`Bottles D1500
`NDC C093-IO-"415
`lmllu of1£lJD
`NDC G393-T0-I1-10
`Do not store ahova are com. Protect lrom morahlro. Dial:-rm
`ln um oomarmr (USP).
`Marlutlcturld by:
`Blallall Corporltlorl lntlmatlollal
`Manlflliwrilln Dlvhilan
`Slllllblch, Ilarldoha
`Canada and 2T3
`Marlullcturod ton
`TEVA PHARMACEUTICALS USA
`Salloravllll. PA 15960
`
`LB-N07-0Jl'lss. {W9
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number 75-492
`
`CHEMISTRY REVIEW(S)
`
`

`
`Office of Generic Drugs
`
`Chemistry, Manufacturing and Controls Review
`
`CflEMl£Il§_BEMlEfl_NQi 3 [First Generic Drug]
`
`AflDA_£ 75-492 [Diclofanac Sodium Extended-release Tablets]
`
`NAME_BND_ADDEEfi§_QE_A££LlQAHI
`Bioavail Laboratories Inc.
`
`(a wholly owned subsidiary of Bioavil Corp.
`St. Michael, EH1, Barbados, West Indies
`
`International)
`
`fli§i_Agent:
`Keller & Heckman (Attention: John Dubeck)
`1001 G Street N.W., Suite 500 West
`
`Washington D.C. 20001
`Telephone:
`(202) 434-4125
`FAX:
`(202) 434-4654
`
`IEEEflcBA£l§_EQB_ANDA_§DBMlE§lQNI See CR #1
`
`SHERLEMENILSLL N/A
`
`RBQEBlEIAEI_EAME: N/A
`
`NQNEBQBBIEIBBX_flAME
`Diclofenac Sodium Extended-release Tablets
`
`su22LEMEum(a) EBQMIDE(s) E93; N/A
`
`mm
`
`AMENDMENI§_AflD_QIHEB_DAIE&i
`Bioayail:
`
`10/30/98
`01/19/99
`06/01/99
`09/29/99
`11/19/99
`
`EDA:
`
`ll/27/98
`05/04/99
`11/10/99
`
`(via overnight courier)
`ANDA submission
`New Correspondence (bioequivalence issue)
`Response to CMC NA letter (dated 05/04/99)
`Response to labeling deficiencies.
`*Response to CMC NA letter (dated 11/10/99)
`
`(accepted for filing on 11/02/98)
`Acknowledgment
`FAX (CMC and labeling deficiencies, Bio letter)
`FAX (CMC deficiency letter)
`
`EHABMA£QLQGlQAL_QAIEGQEI
`For the treatment of chronic osteoarthritis and rheumatoid
`arthritis.
`
`Bz_QL_QIQ RX
`
`EELBIED_lNDLNDBLDMEl£l See CR #1
`
`flQfiAQE_EQBM Extended-Release oral tablets
`
`10.
`
`ll.
`
`12.
`
`13.
`
`

`
`14.
`
`15.
`
`.1,.5 -
`
`17.
`
`EQIEHQI
`
`100 mg
`
`
`Generic name: Diclofenac Sodium
`Chemical name: Benzeneacetic acid, 2-[(2,6-dichlorophenyl}amino]~. monosodium
`{salt}
`
`Formula: C“HwCl2NNaO2, Molecular wt: 318.13 CAS registry number(s): 15307-86-5
`Chemical structure:
`
`2
`
`CI
`
`Cl
`
`,
`NH
`
`(Ii0Na
`
`BE£QBDfi_AND_BEEQBI§i None
`
`CQMMENIE
`
`The drug substance has a USP monograph (6th Supplement).
`drug product is not listed in the USP 24.
`
`The
`
`Type II DMF of the bulk drug substance was reviewed in
`connection with this ANDA amendment, and was found adequate on
`12/16/99.
`
`to the CMC deficiencies and
`Biovail's responses (dated 11/19/99)
`their addendum to their O6/01/99 amendment were reviewed and
`
`found acceptable. There are no more CMC issues. Method
`validation request was issued on 10/25/99 to Northeast Regional
`Laboratory. NRL's method validation report
`(dated 01/11/00)
`indicated that Biovail's analytical method appears to be
`suitable for regulatory analysis of this product.
`
`Labeling approval summary was signed off on 11/09/99.
`
`The bio
`Bioequivalence review was signed off on 03/04/99.
`letter was faxed to the applicant on 05/04/99. There are no
`bioequivalence deficiencies. Biovail's accelerated stability
`data of the ANDA test batch meet the specifications recommended
`by the Division of Bioequivalence.
`
`Acceptable EER was dated 08/30/99.
`
`18.
`
`QQNQLH5lQN3_AND_EEQQMMENDAIlQNS:
`
`Approvable
`
`19.
`
`BEMIEHEE;
`
`Shing H. Liu, Ph.D.
`
`DAIE_QQMELEIED;
`
`December 23, 1999
`Reviased January 28, 2000
`
`

`
`Page(s)
`
`
`
`V3
`
`‘-
`
`.,-' ~..
`
`Commefqial/Confidential
`
`.,4'
`
`‘Information and are not
`
`releasable.%
`
`7
`Cl£\§Iw.;A3;.m
`
`¢3
`.
`Ngimflmv
`
`C:
`
`fl
`
`1
`
`V
`
`
`.
`
`3
`f9-%*‘2C>"“"f’
`
`21,9:
`_ ;
`
`

`
`NOV
`
`.:,:':
`
`38.
`
`Chemistgx Cements to be Provided to the ggglicant:
`
`ANDA: 75-492
`
`APPLICANT: Biovail Laboratories,
`
`Inc.
`
`DRUG PRODUCT: Diclofenac Sodium Extended—release Tablets,
`
`100 mg
`
`A.
`
`The deficiencies presented below represent MINOR
`deficiencies.
`
`1.
`
`The amendment dated April 28, 1999 submitted by the
`holder of the Drug Master File (DMF)
`for
`Diclofenac Sodium USP was reviewed in connection with
`
`your submission, and was found deficient again.
`holder of the DMF,
`’
`'
`I
`has been notified of the deficiencies.
`
`The
`
`Please do not respond to this MINOR deficiency letter
`until you have been informed by
`A
`irm.
`Co., Ltd.
`that their response to the deficiencies has
`been filed with the Agency.
`
`2.
`
`Please amend your specifications for bulk drug
`substance release to include
`‘est.
`You do not
`
`have to conduct the test if your bulk drug substance
`supplier can provide you with a certification that no
`are used in the manufacturing process.
`
`3.
`
`4.
`
`Please provide specifications and test results for
`residual solvents other than
`Please note that
`
`specifications include tests, analytical procedures
`and acceptance criteria.
`
`Please tighten the range for individual tablets weight
`(p. 8767)
`to i 5%.
`'
`
`B.
`
`In addition to responding to the deficiencies presented
`above, please note and acknowledge the following comment
`your response:
`
`in
`
`We have issued a methods validation request to the
`Northeast Regional Laboratory.
`Please prepare to submit
`samples to the Laboratory upon request.
`
`Sincerely yours,
`
`/gg
`
`_..
`
`£4’ Rashmikant M. Patel, Ph.D.
`Director
`
`Division of Chemistry I
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`

`
`MAY - A I999
`
`38. Chemis
`
`Comments to be Provided to the
`
`licant:
`
`ANDA: 75-492
`
`APPLICANT: Biovail Laboratories,
`
`Inc.
`
`DRUG PRODUCT: Diclofenac Sodium Extended—release Tablets,
`1_Q2_m9
`i
`
`A.
`
`The deficiencies presented below represent MAJOR
`deficiencies.
`
`

`
`Sincerely yours,
`
`L" Rashmikant%. Patel, Ph.D.
`
`Director
`
`Division of Chemistry I
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number 75-492
`
`BIOEQUIVALENCE REV[EW(S)
`
`

`
`BIOEQUIVALENCY COMMENTS TO BE PROVIDED TO THE APPLICANT
`
`ANDA:
`
`75~492
`
`APPLICANT:
`
`BIOAVAIL LABS.
`
`DRUG PRODUCT:
`
`DICLOFENAC SODIUM EXTENDED RELEASE TABLETS l0OMG
`
`The Division of Bioequivalence has completed its review and has no
`further questions at this time.
`
`The following dissolution testing will need to be incorporated into
`your stability and quality control programs:
`
`The dissolution testing should be conducted in 900 mL of phosphate
`buffer, pH 7.5, at 37°C using USP Apparatus II(paddle)
`at 50 rpm.
`The test product should meet the following interim specifications:
`Timefhours)
`3 Dissolved
`
`The firm should also note the following comments for future
`submissions:
`
`1.
`
`The elimination rate constant(Kel) should be calculated using
`
`a minimum of 3—time points.
`
`2.
`
`The data in firm's diskette should read exactly the same as
`provided in hard copy.
`For instance,
`the AUCum on the
`diskette was over 8 hours whereas the actual period was up to
`24 hours.
`
`Please note that the bioequivalency comments provided in this
`communication are preliminary. These comments are subject to
`revision after review of the entire application, upon consideration
`of the chemistry, manufacturing and controls, microbiology,
`labeling, or other scientific or regulatory issues. Please be
`advised that these reviews may result in the need for additional
`bioequivalency information and/or studies, or may result in a
`conclusion that the proposed formulation is not approvable.
`
`Sincerel/vsyfurs ,
`Dale P. ConHer?’§h2;m. D.
`Director
`
`Division of Bioequivalence
`Office of Generic Drugs
`
`Center for Drug Evaluation and Research
`
`

`
`OFFICE OF GENERIC DRUGS
`
`Division of Bioequivalence
`
`ANDA#: 75-492
`
`—-
`
`SPONSOR: Biovail Labs Inc.
`
`DOSAGE FORM:
`
`Diclofenac Sodium KR
`
`100 mg Tablet
`STRENGTH:
`TYPE OF STUDY: Fasting, Non-fasting and Steady—State Studies
`STUDY SITE:
`Biovail Contract Research
`
`/
`
`STUDY SUMARY:
`The 90% confidence intervals (in the Fasting and
`Steady-state studies) and the Test/Reference ratio (in the non-
`fasting study)
`fire within acceptable limits. All three studies are
`complete.
`
`
`The dissolution testing" was done by an acceptable
`DISSOLUTION:
`Interim specifications have been recommended by
`non-USP method.
`the Division of Bioequivalence.
`
`WAIVER:
`
`N A
`
`
`
`PRIMARY REVIEWER:
`
`Patrick E. Nwakama, Pharm.D.
`
`ERANCH: II
`
`7'(’7[ I2
`DATE:
`S
`-
`INITIAL:
`
`BRANCH CHIEF: Shriniwas G. N rurkaf, Ph.D.
`BRANCH: II
`A
`
`DATE: °*I'3'''q‘Ifl
`
`INITIAL:__
`:
`
`_
`\_/'’‘1 '7' 7‘
`
`DIRECTOR, DIVISION OF BIOEQUIVALENCE:
`
`Dale P. Conner, Pharm.D.
`
`INI'rIA_L;/$/
`
`.—
`
`DIRECTOR. OFFICE OF GENERIC DRUGS
`INITIAL:
`
`DATE:
`
`DATE:
`
`

`
`BIOVAIL
`
`BIOVAIL
`
`BIOVAIL
`
`3
`
`E
`
`C
`
`‘J
`
`.A
`
`L
`
`BIOEQUIVALENCY TELEPHONE AMENDMENT
`
`OVERNIGHT COURIER
`
`January 19, 1999
`
`Douglas Sporn
`Director, Office of Generic Drugs (I-[FD-600)
`FOOD AND DRUG ADMINISTRATION
`Metro Park North II
`
`7500 Standish Place, Room 150
`
`Rockville, MD 20855-2773
`
`Re:
`
`Abbreviated New Drug Application, 75-492
`Diclofenac Sodium Extended-release Tablets, 100 mg
`
`Dear Mr. Spom,
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`
`On January 12, we fielded a telephone call from Nassar Muhrnud and Dr.Patrick Nwakama
`concerning certain BE elements of our file. We are pleased to forward a solicited written
`confinnation of our conversation.
`
`The substance of the Agency question revolved around the media used to perform dissolution
`testing for our product. Indeed, the Agency was interested to solicit Biovail’s opinion why it
`used phosphate buffer for an acidic media as opposed to 0. lN I-ICl.
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`'
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`It should be noted that Biovail’s product is not enterically coated and therefore does not fall
`within the BE guideline for diclofenac dissolution. Our product is an extended release matrix
`tablet, therefore we have selected a media that permits us to best demonstrate the dissolution
`profile of our product.
`
`If you have any questions or comments, please contact me directly at telephone number (416)
`285-6000 extension 213 or at fax number (905) 608-1616.
`
`Yours respectfiilly,
`BIOVAIL CORPORATION INTERNATIONAL
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`.Sc., FBIRA
`Martin Levy,
`Manager, Corporate Regulatory Affairs
`(on behalf of Biovail Lab