DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 50-475/S-046
`
`Pedinol Pharmacal, Inc.
`Attention:
`Harry Gordon, Ph.D.
`Regulatory Consultant
`30 Banfi Plaza North
`Farmingdale, NY 11735
`
`Dear Dr. Gordon:
`
`Please refer to your supplemental new drug application dated August 13, 1996, submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for Gris-PEG® (griseofulvin
`ultramicrosize) Tablets, 125 mg and 250 mg.
`
`This special supplemental new drug application changes being effected provides for the addition of
`“erythema multiforme – like drug reactions” to the ADVERSE REACTIONS section.
`
`We completed our review of this supplemental new drug application, and have concluded that
`adequate information has been presented to demonstrate that the drug is safe and effective for use as
`recommended in the final printed labeling submitted on August 13, 1996. Accordingly, the
`supplemental new drug application is approved effective on the date of this letter.
`
`In the DESCRIPTION section, please harmonize the listings in both dosage form descriptions, using
`“povidone” as the appropriate USAN name for polyvinylpyrrolidone at the next printing of the
`package insert and report the change in the Annual Report.
`
`If a letter communicating important information about this drug product (i.e. a “Dear Health Care
`Practitioner” letter) is issued to physicians and others responsible for patient care, we request that you
`submit a copy of the letter to this NDA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`If additional information relating to the safety or effectiveness of this drug becomes available, revision
`of the labeling may be necessary.
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2076 - 1/4
`
`

`
`NDA 50-475/SLR-046
`Page 2
`
`If you have any questions, call Frank Cross, Regulatory Project Manager, at (301) 827-2020.
`
`Sincerely,
`
`{See appended electronic signature page}
`Jonathan K. Wilkin, M.D.
`Director
`Division of Dermatologic & Dental Drug Products
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2076 - 2/4
`
`

`
`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Jonathan Wilkin
`nulldate
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2076 - 3/4
`
`

`
`Gris—PEG‘
`(griseofulvin ultramicrosize) E
`Tablets
`%“"
`USP 2
`125 mg; 250 mg
`
`OR
`
`AcfivekigredientgdseotuIvi1uttra'nicrusiae...25dnrg
`
` : rrIeii1yiparaben;poIyethyleriegIyooI4O0ar1dBD0{I;
`povidone:sodiurnlauryIsuttate;andtitaniurn rfioxide.
`
`A£:11DN:Nfir:'obioIogy—GriseoiLrivin isfungistaticwith in vitro activi-
`ty against various siesta of Microsporum, Epidermophyton and
`Trk:hophytor1.Ithasrioeifer:toniJactenaorothergeneraotfui1gi.
`Human Pharmacology — Following oral administration, griseofulvin is
`deposited in the keratin precursor cells and has a greater affinity for
`diseased tissueflliedruglstighhy bound tnthenewkeratin which
`becomes highly resistantto fungat invasions.
`
`the elficienq of gastrointestinal absorption of ullramicrocrystalline
`griseotutvin is approxiniatelyone and orrehatftirnes tbatofthe con-
`ventional microsize griseofuIvin.1'liistactorperrnits menial intakebf
`two-thirds as much ultramicrocrystatline griseofulvin as the microsize
`forrn.t-Iowever.tbere isourrentlynoevidencethat this Iowerdose con-
`fers any signitirnnt cllnicat differences with regard to safety andlor
`efiicacy.
`
`INDICATIONS: Gris«PEG" (griseofutvin ultrarnicrosize) is indicated for
`the treatment of the fotlowing ringworm infections: tinea oorporis
`{ringworm of the body), tinea pedis (athletes foot], tinea cruris (ring-
`worm oi the groin and thigh). tlnea barbae (barbers itch}, tinea capitis
`(ringworm oi the scalp), and tinea unguium (onychemycosis. ring-
`worm of the nails). when caused by one or more of the foliowing
`genera of
`lungi: Tricbophyton nltirum,
`irichophyton tonsurans,
`Trichophyton mentagroptiytas, Trichophyton
`interdigitatis,
`Trichoptrylnn vemrcosum, Tiichophytnn megnini_ ‘irichopbyton galli-
`nae.Trichophyton cratedform,Tnchophyton sulphureum,Tnchophytnn
`schoenleini, Microsporum auriouini, Mrcmcporurn canis, Microsponim
`gypseum and Epidennophyton floccosr.rm.NOTE:P1'iorio therapy. the
`typeofimgiresprxrsibleforflieinrectionsiroirtd beidettifiedihe use
`oftbednigisnntjrrstifiedin minorort1'ivialirrfeclior1svv‘l1icl1wfll
`respond to topical agents alone. Griseofuivin is not effective in the fol-
`Iowing: bacterial
`r:m1didiasis(rnonilrasis), histoplasmosis,
` , sporotriehosis, chrornoblastomyoosis, coccidioidorny-
`costs. North American blastomycosis, cryptococcosis (torulosist, tinea
`
`OCINTRAINDICATIONS: Two cases oi conjoined twins have been
`reported since 1977 in patients taking griseofutvin during the tirst
`tiimesterof pregnancy. Griseofutvin should not be prescribed to pneg—
`nantpatientsiithe palierittiecornes pregnantwtirletakingthis dmg,
`the patient should be apprised ofthe potential hazard to the fetus.
`
`This drug iscontraindicated in patients with porphyria or hepatoceilu—
`lar failure and in incfividuals with a history of
`to grise-
`ofutvin.
`
`WARNINGS: Prophylactic Usage — Safety and efficacy of griseofutvin
`for prophylaxis of fungal infections have not been estabtished. Animal
`Toxicology - Ctmonic feeding of griseotulvin. at Ievets ranging from
`ll5%—2.5% of the diet resulted in the development of tiver tumors in
`several strains of mice, particutarly in males Smaller particle sizes
`result in an enhanced eflect Lower oral dosage levels have not been
`testedsubcuraneousadministrationofrelaiiveiy srnafldosesotgrise
`ofulvin oncea week duringthefirstthree weeksoitifehas alsobeen
`reported to induce hepatomata in mice.Tl1yroicl tumors. mostly ade-
`rrom$butsomccan’cin0mas,l'rave been reportedinmaieratsreceiv-
`ing griseofulvin at levels at 2.0%. 1.0% and 0.2% of the diet, and in
`female rats rewiving the two higher dose levels. Although studies in
`other animal species have not yielded evidence of tumorigenicity,
`thesestodieswere nototadequatedesign tofonna basistorconclu-
`sion in this regard. In subacute toxicity studies, oratty administered
`griseofulvin produced hepatocetlu|m' necrosis in mice, but this has not
`been seen in other species. Disturbances in porphyrin metabolism
`have been reported in griseofulvin-treated laboratory animals
`Gfiseotutvinhasbeenrepodedvariaveapplpmcine-rikeenecrmmnc»
`Sis and
`withm in cutaneous tumor
`inductiorri1laboratoryarrirnalsUsap,einPregr1ancy-SeeC0N-
`TRAINDICATIONS section. Animal Fteproduction Studies - It has been
`reported in the literature that griseofulvin was found to be embryotox-
`ir: and teratogenic on oral administation in pregnant rats. Pups with
`abnormalities have been reported in the littersofa iew bitches treat-
`911 WW1‘! Qttseofuivin. Suppresion of spermatogenesis has been
`reported to occur in rats, but investigation in man faiied tnoonfinn this.
`
`PRECAUHONS: Patients on prolonged therapy with any potent med-
`icationshoutdbeundercloseobservation.Periodicmonitoringoi
`organ system function, including renal, hepatic and tiematopoielic.
`should be done. Since griseofulvin is derived from species of
`Penicillium, the possibility of
`with penicillin exists;
`however, known penicilfin-sensitive patients have been treated with-
`out difficrllty. Since a phutosensitivity reaction is occasiorlalty associ-
`atedwllfliaiseofismntherapypotientsshoutdbewarnedbnavoid
`exposure to intense natural or artificial sunlight lupus erythematosus
`07 ‘UPI-IS-iI'ke syndromes have been reported in patienk receiving
`Qrlseofulvin. Griseofulvin decreases the activity of wartarin-type anti-
`Wagulaflls 50 ma‘ patients receiving these dnzgs ooncomilarrlty may
`
`require dosageadirrsln1erdcffl:ea|1fiooag1Jlantduringandaftergr‘ise-
`oiuhiin therapy. Barbiturates usually depress griseofulvin activity aid
`concomitant administration may require a dosage adjustmentof the
`arttihmgalagerttihereiiavebeertreportsinflrelfleratureofpomble
`irrteracbonsbebveengriseofLdrdnandm$cont:acepfives.1heefl‘ectof
`aIcoholmaybepotenfiatedbygnseoiulvin,produoings3cf1effectsas
`Iachycardiaandflush.
`
`ABVERSEItEAi:rl0NS:Wfier1adlrersereacliorisooerrnfl1eyaremost
`oomn1ontyofthehyperse1sitivitytypeeichassldr1ra§res,urficaria.
`erythema multiiorrne-like drug reactions. and rarely, angioneurotic
`ederrraandmayneoessitatewittidrawalofttrerapyandappropriate
` . Pareslhesias of the hands and teat have been
`reportedrareiyatterexteridedttierapyflltiersideeffectsreported
`oocmimaIIyareoraIttv1nsl1.nausea,vomifirrg,epigasuicdist1-ass,
`diarrhea, headache. fatigue, dizziness, insomnia, mental oonfrsion,
`andimpairrner1tofpertormar1ceotroutineact:vrbes'" .Prtrieu1u‘ziaand
`IeuI<openiabavebeenrepoderlrarety.Adn1inistrationofthedrug
`st1ouldbedisoonflnuedifgrambcytq)erriaocmrrs.Wtrenrare,sena.1s
`
`DOSAGEAIID ADMlNlSTiil\Tl0N:Ac::1rrateclIagrtosisofll1eii'rfectir1g
`organismiseaierltmlderrtificationsmrldbemadeeitiierbvydirecl
`rmcrosoopr''cexaminatimofarnou1br1g' ofinfectedtissueinasutubun’
`ofpotassium hydroxideorbycuitoreonanappropriatemefitrrn.
`Medicalionmrrstber2orttinuedmfitIl1eiratectirlgorganismiscorn-
`ptetelyeradicatedasindiraiiedtfiaflflfflflriateclinicaiorbaboratbry
`eiandnafim.Represerttabvelreannerrtperiodsaretinear:apifis,«¢tn6
`weeI<s;fineacor3)oris.2to4weetrs;tineapedis.4t1o8weeI<s;tir1ea
`unglirrm—deperrdirrgor1rateofgrowth—fingemaiis.a1|east4
`moriths:toenaris,atleast6rnortth&
`
`Gerieralmeasrnesirregardmhygieriestroxddbeobservedtooontrol
`souroesofiifectimorreirrtediortcorrcomitantuseofappmpriate
`b3picalager1sisrsr1a|Iyregr1hed,parfiarIartyirh'eaunernrifirrea
`pedis.'lnsnrrlefnrn3ofathlete‘sfuut.yeastandbactetiamaybe
`imoIvedasweilisfimgi.Gnseohdvirrwr1lr:iteradicatethebacb:rial
`ormonflialinfection.
`
`Addt:Dailyadministratixtot375mg(asasir1gledoseorir1divided
`doees)vrilIglveasatisfactoryresponsei1mristpatientsvvitt1tinea
`
`mmecif£imlittoeradicate,suchasfiI'reapedisaridfil1eaw1guh:m,a
`divideddoseof75l)mg isreoorrrmended.
`
`rediarricuse.-Appm:dmatetv3.3mg rrermundofbodyv-eietflner
`dayofulbamicrosizegriseofritvinisarieilerrfivedoseirxniostpedlr
`abic pafienls. on this basis, the following dosage schedule is sug-
`gesed: Children weighing 3560 pounds -125 mg to 1375 mg daily.
`Pelraarncparienlsweiprirlguversoouunds-137-5muta375mo
`daily. Cluidrenarrdh'rianfs2y83fSlFf3§l93"di‘1fl19Bt*¢‘°5a99m5
`notbeenestabiished.
`
`Clinicat experience with griseormvin in_childrer_l with tinea capitis inch‘;
`cates thata singledaily dose IS efte_ctnre._CtrnIcai relapse wiltoccur
`fliemedicationisnotoorrbruiedLu1tlIIheIntecbr1gort3arIsmaserad—
`cated.
`
`(grisoofulvin ultramicrosize) Tablets,
`now soreuen: Gris-FEG'
`125 mg, wm[e_ 5m.-ad‘ ellipljcd-sha.ped, embossed ‘Gris~PEG'_" Oil
`pnesidearrd "125"onIheother.E5:is-PEG‘ tgriseofulvin ultrarnicro-
`size) Tablets, 250 mg. whim. med. cansde~5tIaPed- M90599“
`«[;fi5_pE(;o~'onom5idea1-|d“25fl”mfl3eofi\er:11IB125fiIgS1TG|1§fl1
`as available in bottles of 100 (NDC 90234753414). The 250 mg
`strength is availablein botties or 100 (NBC 002341733414) and 500
`(NDC 002341773-50}. Both strengths are fitrn-coated
`
`crurnore Federal (USA) tan nmhibits dispensing Wttftottttite-‘WP’
`tion.
`
`sronacesixeoris-Pee-raaiersaicpnuprreqmpmtempemtnre
`15-=.3g=c (5g°.35°r=) in tight, right-re-aim containers.
`
`IrarI.Iia:tr.Iedtnr
`AI.LEI'_fliAN Herbert
`Sr'n[}IeDivisi'.I'rt]AIerg:nkIc
`rrvme,c.armm'a92sizusA
`bySANDOZ
`PHARMACEUTICALS
`CORPORATION
`ln1!hnna.NMfl36
`
`@1996NIagcnInc.
`Revmdlrlelflfi
`
`Pri'IbdkILI.S.A.
`
`Z343-42
`
`70932198
`
`
`
`QEAD Y.;._'°$F‘aE.‘3.“.. .'F’F32015-91.77€>‘. ANACOR EX: 2°76;4’4. .
`
`
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2076 - 4/4