CENTER FOR DRUG
`EVALUATION AND RESEARCH
`
`Approval Packagefor:
`
`APPLICATION NUMBER:
`
`75-383
`
`Generic name:_CytarabineInjection, 2 g/20 mL
`
`Sponsor:
`
`Faulding Pharmaceutical Co.
`
`Approval Date:|November 22, 1999
`
`(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)(cid:3)(cid:21)(cid:20)(cid:22)(cid:26)
`CELGENE 2137
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:89)(cid:17)(cid:3)(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)
`APOTEX v. CELGENE
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:22)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:21)
`IPR2023-00512
`
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`

`

`CENTER FOR DRUG EVALUATION
`AND RESEARCH
`
`APPLICATION NUMBER:
`75-383
`
`CONTENTS
`
`Reviews/ Information Included in this ANDA Review.
`
`x
`
`Approval Letter
`Tentative Approval Letter
`ANDAs
`Approvable Letter
`Final Printed Labeling
`Medical Review(s)
`Chemistry Review(s)
`EA/FONSI
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology & Biopharmaceutics Reviews
`Bioequivalence Review(s)
`Administrative Document(s)
`Correspondenceeeee
`
`x
`
`Ps
`
`Ms
`
`2/77
`
`2/77
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`

`

`CENTER FOR DRUG
`EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`75-383
`
`APPROVAL LETTER
`
`3/77
`
`3/77
`
`

`

`ANDA 75-383
`
`Faulding Pharmaceutical Co.
`Attention: Heike Maaser
`11 Commerce Drive
`Cranford, NJ
`07016
`
`Dear Madam:
`
`NOV 22 |gg9
`
`This is in reference to your abbreviated new drug application
`dated May 15, 1998, submitted pursuant to Section 505(j) of the
`Federal Food, Drug, and Cosmetic Act,
`for Cytarabine Injection,
`2 g/20 mL,
`(100 mg/mL), packaged in a Single-Dose Vial.
`
`Reference is also made to your amendments dated November 24,
`1998, and July 6, August 4, September 28, and October 8, 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 drug product, Cytarabine Injection,
`2 9/20 mL,
`(100 mg/mL), can be expected to have the same
`therapeutic effect as that of the listed drug product upon which
`the Agency relied as the basis of safety and effectiveness.
`
`=:
`
`Under 21 CFR 314.70, 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 314.80-81 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
`
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`

`We call your attention to 21 CFR 314.81(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.
`
`Please note that as of April 1, 1999, unless this requirement is
`waived or deferred, all applications for new active ingredients,
`new dosage forms, new indications, new routes of administration,
`and new dosing regimens are required to contain an assessment of
`the safety and effectiveness of the product in pediatric patients
`(63 FR 66632). We note that you have not fulfilled the
`requirements of 21 CFR 314.55 (or 601.27). We are deferring
`submission of your pediatric studies until December 2, 2000.
`However,
`in the interim, please submit your pediatric drug
`development plans within 120 days from the date of this letter
`unless you believe that a waiver is appropriate.
`
`If you believe that this drug qualifies for a waiver of the
`pediatric study requirement, you should submit a request for a
`waiver with supporting information and documentation in
`accordance with the provisions of 21 CFR 314.55 within 60 days
`from the date of this letter. We will notify you within 120 days
`of receipt of your response whether a waiver is granted.
`If a
`waiver is not granted, we will ask you to submit your pediatric
`drug development plans within 120 days from the date of denial of
`the waiver.
`
`Pediatric studies conducted under the terms of section 505A of
`the Federal Food, Drug, and Cosmetic Act may result in additional
`marketing exclusivity for certain products (pediatric
`exclusivity).
`You should refer to the Guidance for Industry on
`Qualifying for Pediatric Exclusivity (available on our web site
`at www.fda.gov.cder/pediatric)
`for details.
`If you wish to qualify. for
`pediatric exclusivity you should submit a “Proposed Pediatric
`Study Request” in addition to your plans for pediatric drug
`development described above.
`If you do not submit a Proposed
`Pediatric Study Request within 120 days from the date of this
`letter, we will presume that you are not interested in obtaining
`pediatric exclusivity [NOTE: You should still submit a pediatric
`drug development plan.] and will notify you of the pediatric
`
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`

`

`studies that are required under section 21 CFR 314.55. Please
`note that satisfaction of the requirements in 21 CFR 314.55 alone
`may not qualify you for pediatric exclusivity.
`
`SinigexelyMED.
`Douglas ‘Be Sporn!
`
`i /a2/99
`
`Director
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`6/77
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`
`

`

`CENTER FOR DRUG
`EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`75-383
`
`Final Printed Labeling
`
`7/77
`
`7/77
`
`

`

`Cytarabine Injection
`Forintrevesons,Intrwihece!sadSehevtnegsesUseOnly
`
`SAMPLE R aed
`e
`
`/
`
`Cytaratina Injection,anantinsopiastic, is.astaniasolution ofcytarabine forintravenous, intrathecal
`
`SuOCUIaMeOUS admwnatration. Each mL contains 20 mg Cytarabine in 4
`}
`ai dod
`100 mg Gytarabing en 2g (106 mg/mL} cingle dose val,
`
`Cytarabine injection 100mg/SimL is
`lwile solution tor intravenous,
`Sera Each m\contain20nqOya, USPad the pllowing A
`|
`water
`\njection 9.5. When necessary the pH is adjusted
`
`hydroxide ta a pH of 7.4, Each vial contains appronmatety 0.58meq oni
`
`
`Cytarabine Injection 2g/20mL Is a stanta sotutton for intravenous,intrathecal
`mL contains 20 mg Cytarabine, USP, and the lollowong inactive ingrecuarts,
`tor
`thapH is agjusted wilh hydrochloric acidand/or SOdIUMhydtamida10a OH ofTA,
`‘(Cytarabine is chamicany 1-8-D-Arabinofuranpsyleytosing. Thestructural formula ‘*
`
`
`> @
`
`-
`
`:
`
`* ~ .
`in alepho! and in chion
`I.
`Cytarabien in an odociess, wie to wlf-white crpstaline powerwhich in treaty soluble in waterina
`coli: %
`"
`2 eo
`CLINICAL PHARMACOLOGY
`
`{5 cytotametox wide variety of proltfenstirig maryraan in CUTE. IT exhibits onl .
`
`Orimanty lilting celle undergoing DMA syrtivesis (5-phasa| and under cera conditions blocking the pression of
`calls trom the Gyphase totte S-prame,
`rechantam a schon s acme
`SS
`Tha
`, appears
`Thal cytarabine acts througn the infilivtibon of
`Dolyerierase, A trited, Dut significant, incorporation of cytarabine
`Into both DNA and AINA has ao Deen reported. Extensive chromosomal damage, including chramuinid breaks.
`ave Deen produced by cytarabine and malignant trangtormation of rodent calls in culture has been reqocted.
`Decaeycyticine prevents oF Gatays (out dows not revarss)the cyiotoxi: activtty.
`Sarai crenata
`Cyterabine ts mecnbolinsl by
`hoina
`innase and other Nuclotioe kinases to the nucieotide trighnephaws, an
`
`come
`
`to
`
`lube
`
`dome
`of the
`hese Weary
`metahovined and is
`4a
`‘idmunistered
`20 percent
`Hot effsctive
`napisy
`‘Cytirabires
`‘i
`—
`om
`absorbed Inn the gastrointestina tract.
`Following fipid lirevenous injection of cytarabine labeled with trmum, the disappearance from plasma i biphasic.
`‘There fganinitialdistributive phase with4 Hast-tfeofabout 10 minuizs, owedby & sacanda@rination Phasewita
`hatt-life of about 1 103 hours. Aftw tha distributive
`|. more than 60 perce
`Sccolunted for iny the inactivw matabosts 1
`Yare-U). Wither 24 hours about 80 percent ofthe
`administered radioactivity can be recovered in tw uring, approximately $0 parcant af whic is wxerated ax ara-U
`Fislatively constant plasma levels can be achieved Oy Cominuces «travenous infusion.
`After subcutanacus or inframuscular adminietration of cytarabine labeled with Irttivm, peak-pissina lyveds of
`Intravenous administration.
`‘aGloactivty ara achieved about 20 to 60 minutes after injaction and ara conskserably lowar than those after
`
`
`
`-
`
`reseed (he developmentofcell-mediated immunerespories suchas delayed
`Cytarabine injectionaiso
`‘
`typesetsn reactiona Sntrochorobenrwe. Rewer had Moet taeeeaeyoeope
`Indeediors ponentsmae artinacon btenueraponsa wassopreae. 3
`following parameters: macrophage ingress
`weindowa:
`circulating antiboudy raaponee
`{ollawing primary antigenic stimulation: lymphocyte Blaxtoganesis with pbrytohamagoutloin A lrwdayater
`termination of therapy there was a rapid return 10 normal.
`
`oe
`
`ws
`
`yesaing to pulmonary ema and radiographicadly
`Asyndroma of sudden respiratory distress, rapitty
`Dronoxineadcardiomagaly has beenrebertedfolowingwaperineesta
`Goad Inerapy withcytarabine used for the
`Ireatmnent of retageid loukarnda Irom one institution in 16/72 patients,
`outcome of inl syndrome can be fatal
`Two patients weit childhood acate
`iaiskarrea who recetved intrathecal and intravenous cytarabing
`inpection at Conventional doses in
`fo a hombder ofother concomitantly administered drugs) developed
`Onlayed progressive ascending paralysis resulting in death in one af the Two patlants,
`hem ha Preqesacy (Category 0)
`Cytarabene
`an cauce fetal harm when adminestered toa pregnant woman. Cytarabine causes abnormal
`cermbeliar Onewtonmert in thn neonatal hamster and Is teratogenic to the (al fetus. There arn no acequate and wrel-
`Dregnart.
`‘Comtroved setudhes In pregnant women, Women of chidbearing potential should fe advesed to avoid becomwng
`A review of the titenmure has Shown 32 reported cases where cytarabine injection Wes Qivén during pregnancy,
`seihar glone of in combination with other cytotoutic agents
`Eighteen normal untants vaca dedivered. Four of thease had first trimestar sxposure, Five infants were preeratiore a
`Of tow Olrth weight. Twwiva of the 18 normal infants ware followed Up @f ages ranging from six weades fo sinven
`VRAIS, and showed no abnormalities. One apparantly normal intant died a 90 days of pastroententis,
`‘Two cages of congenital aboormalities nave bean reported, ona with UPPAT and lower divtel limb detects, and the
`ottver with eactramay and ear deformities, Both of these cases had lirst trimesien exposure,
`Thert sae seven infants with various problarres in the neonatal pariad, including pancytopenia, transienl depression
`of WBC, hamatoerit or plutelets: tlectrolyts abnormalities transant eosinophilia; and one case ot incraased IgM
`vets and Pryparpyrinia poseibly dua to sepsis, Six of the seven stants ware also premature. The child with
`Pancylopenia diad at 21 cays of sepsis.
`Therapeutic abortions were dorw in Wve cases. Four fwluses wars grossly normal. but one had an eniarped spisen
`and another showed Troy C chromosome abnormality in tha chorionic frssue
`Because of tha patecitial tor abnormalities with cyintwke therapy, particulary during tne frst trimester, a panent
`wit Is or who may bacamne pregnant while on cytarabine Should be apprised of the potential risk Io the fete and
`(ha advisabality of pregnancy continuation, There is a definite, Sul considerably reduced rai it (fearapy it invttinted
`Suring the Second of third trimester.
`mal intants have bean delivered (0 patients traated in all threw
`HmeStare nf nraqrana.
`tallnearg >
`
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`
`

`

`facamatyon Gt rrarapy ete mia ae + Sh
`Dytaracine inpection incomoinathonwih athec apprevedanti-canoae rugs (x tndicated for raeresanonin@uction
`ute Ton-WnphAcyECMulia of adultsand padiaiecpatrents iV hagalaoQeen (ound uselulwy thw trearment of
`Ceeeae ieukemaa andthe Dlast phase of chronic Myelneyic WurarT intrathecal admenirstration mt
`xa OTEare rues ny) Raa epropsan emer MEM
`CONTRAINDICATIONS
`(Cytarabinainpection iecontraindicated in those patients who areMypersercetive{0tne drug.
`WaARWiNGS (S68 baxed WARKING)
`WARWUNGS (Ses rena marc vagresaie.Tassould besaad East8 PG Sop
`Drug-induced bonemarrcws
`prasadracewving tndrug mustba underclosa radical supervision an
`duringanduction
`shold navewucocyta and platelet countsperformeddaly ‘Bone marrow
`ghould be performed(requanttyafter blasts ‘avi
`trom tha peripheral blood. Facilities
`be
`
`injechon.Thess remecticnres,ireclucht reversiblecomeal toxicity,and haenerrhagicconjunctive, which rary bet
`prevented or dlrmiesteec byofophytaxiswithaiocalcorticaistercsc eyedog;carabraland carebatlar gystunction,
`preventedotracemes commieendear, usual revrnle:hvaryGRSOSTECS wloeration,
`ny prawns cystoses tetasadiYOPATRONSSSHec, abacess; pulmonarysaeiver
`
`assed tor the
`osetherapy wit
`hasbeen reported
`pronounced
`putcomeofthls syndrome can Oefatal.
`of relagyeed bnckarraarom ocinstitution wn V7 patents
`TakarawharecetvedIntrathecaland intravencuscytarabine
`Twopatients with chilghood acute
`injection atconventionalGoses [1A
`roemia of cher conewotanttyadraisiared drugs) GAVSIoO#
`a ogress ascandlngDaralysis restingi deat ane ofthe Fwopater
`Usa bs Pregeasey (
`0)
`Cyiarabiew injectioncancausa fetal harm eranadenistered
`woman.
`cereballarcarveloprment inthe nwonatalhamster andistersloganc 19
`ral telus. Thereare ro adequate and well
`controtled ctudles unpregnant wiiTelN
`otf chldbearng
`be actvtaedToavold
`pregnant.
`
`Egnteen
`,
`of low triteweegirt.ureeg 1normal fartswerfxlowed wp atapesrangingfromsixwanes to Sveotaw cessnorris,apres wat nd a90cayofeto
`raeercomputa sortsava bow repetadone wth upp and owerCaih SWsk2708
`Twocae SATB aid Otc oh of eau Cazes bad ist Uriyesser expo%Ty
`irs wth varoux probs ne mera parod. elude panocoela eee aan
`Taareworeavnaprove abnovrases, vansoaoRMa andoneCet eee OM
`bevels aed)Pryparpyresia
`duetoseoses. Bix oftha seven infantswerealso prerrumure Thechild eh
`pancytopenia died af 27 days
`segsrt
`Baneyepw noms wredoneve casesFou ae wareor normal bv oneNad a ara28
`Thera showed Trisomy ©chromosorre abnormaaty inthechorionic sssanae ne ponata fornboxalts wh erro arapy.paaty GuiaNTTNSa
`Seca of he poi fam wr acrarabie SOU be wooed of he StanWO oe
`wewa TaDmuna,vasais Ou cesT Guin AfMa
`duringthasecond orthird trirrestir Tan ncrimal varityRave bana dale to patentstreated 1m au three
`Aaasers of pregnancy. tollaw-up ot such jars woul! be aavisa0l,
`1, General Precewiless
`PatientsrecatvengCytarabina injection mustbe monitoredclosety. Frequentplateatand laucocyté countsaint
`PatentsrecengCare sy anes. conadetseapandng axtng Eby wenSod
`aervrow depression hacresultedin a platelet count under 50,
`oFapolymorphonucisargranulocytecourt
`i
`(ha peripheral blood
`stopped and reach lowes! values afterdrug-ren intarvaisof 12 To24days, Whenindicated, restart therapy
`senan definitesignsof TrarTowrecoveryappaat (on SICARECEDOCMANTOW studies), Pailents whosedruglt
`watriterid until
`peripheral blood values are aftained mary escape fOr
`When lange intravenous doses are given too quickly.
`‘aretrequantlynauiasatadand may vorndl for
`severalhours
`Tatsqroblam tendsIabeWesssevere whenthadrug is used
`‘The human liver
`gtoninas a substantial tractionélan administered dose. in particular,pagent
`
`wath renal o#teapatlcsraent may has a highesViahhood of CNStoxacityafer high-dosewibininjection tealmant. Usa ths drug with caution anépossialy dose in patientswhassver
`ov hidnany function 1 DO0F-
`penceweesot boramar; ive ane ney faction shoud performed in pans CANA
`cytarapine injection.
`
`wha ematcyttoterus, Cyrincon may nse hyperacon 2a YtLuneamare re ou roo pee=Cas UTEafr mm Pere oUt EN
`reced Barna raasures 2I MACASEATY 16 CORSODA.
`Acute
`ft
`vues been repostedTooccurina patient receiving Cytaranine Injection Dy conteNous
`havi pancreasOa esd wthCarabie nacion wnhaveNa rir ran WAP
`
`
`
`8,
`
`Leberatery trots
`
`5
`
`inbipetion OfMts uptake,
`coftarabine injection, Tis maybw dua topotential
`Carsinaganeals, martoyensaie,Impairment of fortify
`reais havebean produced bycytarabwea and
`Extensrve criremoeomal
`inalignant transformation of rodent cals in caifure hes bees
`-
`. eee
`Pregnancy Category 0. Sea WARNINGS.
`Laker wed delivery
`Not applicable
`
`7.
`
`MOVERTE REACTIONS
`Reactors
`ma
`anemia, MukOpeTia,
`cytarabinaina bonemarrow
`ThacoverttyofTse
`Baca Celcytes can beexpacied 23 resiofadmlnstraion wi
`‘of boremartoe and
`reactions aradows and
`_ Catalachanges in the
`amaant can ta expected,
`vrrtng5-yeonaant infusions of acu ojacons ot 50 mai1400 MT whitecall dapression follows @
`#5noticaacieat 5 cayswith @ peal
`betwen days 12-18. Maraupon, a raped rise 0
`above basalina occurs in tha rect 10 days
`-
`lobes
`aijoetioat: Virw, bacterial Ma. yarasicor aprophtciacons.nary ocala nth Dod muyRSS
`latte usofcytarabine jntionalee of eycomirnation wi Soe
`agents [olbiretng
`nmuncsupe! Aa Uo mary, ass econay Ded. eC O8RE
`ard at treme tanta,
`
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`

`

`Most Freqesn Advise Aneaibpes
`Onward anv inane
`Anoreria
`thrombopebitie
`of ulceration
`Niue
`Cnecirig (it ttre)
`heretic dyehunction —
`Vomiting
`fever
`Olurrhaa
`Agus and vorniing ere most frequent following rapid intrawenceus injection
`Lowa Freqereat Autversa Aaectheas
`tore thromt
`Conjunctivitis (rmimy occur with rasan)
`Poeumonia
`eeophages! ulceration
`dizi
`esophagitis
`wopecta
`callytttta at injection site
`shin ulceration
`cheat pain
`ruphylnxts (see Warning}
`urinary retention
`pericarnaitis
`allergic edema
`renal Oyshunction
`bowel necrosis
`prurttia
`Pema
`abdominal pain
`shortness of breath
`nanan Does
`‘papcreatitia
`urticaria
`trveking
`ob
`‘jones
`
`Copeman! Taaag
`(offtarent from that meen with comnrtional thanagy
`Severe and af thermeg tata! CRS, Gl and pulmonary
`figlmans Of cytarabins injection) has bean reported fotlowing some mqerimental done achedules of cytarabine
`ingecthon.
`Include reversible comes! toceity and hemorrhagic conjunctivitis, which may fe
`Onevented or diminisived by prophylaxty with a ical coricosterokd aye grog; cersbral and cernéella cystunetion,
`bnechectinng
`Changes. LOMmOMNCS End come, usually reversible; Revers DERITONTTERDNAl ulceration,
`iancoeae
`Dane neaaaacne SeemaStirs bir
`(o Gepquarmetion huss been reported. Complete Hopecia ts more commonly saan wt axglrimsead high dae
`
`A Byndrome of sudden reapiratory dtetrana, rapidly progressing fo pulmonary edema and radiographically
`treatment of relagreed hrukeméa from oom institution in 14/72 patients.Theoutcomeofthis myndrome can De fatal
`a
`Teportad followingE=perrenty Mandost
`withcytarmbingused forthe
`consolkdation with high-dose cytarabine, daunorubicin, and asparagine. Patents tresied wth higi-tos
`cytarabine should be observed for neuropathy since coe Echecule afterxtions may be needed to evold irrevernibke
`Omrologic discordant.
`Ten patients treated with expertrmrra intermacias doses of cytarabine (1
`with and without ather
`chamesarageuiie agents (etaAMSA. CaUNorvb, mOpowian)atreoous raplnnescoro ctuas
`interstitial prevents without clear comme Chast may Rave Deen rataded fo tte cytarabine.
`Two cases of pencreatfilt fare been ranoried following experiments! doses Of cytarnbing injection and numerous
`ole drugs. Cytaraiine injection could heve bean the causative agent,
`‘There ts no anticots for overdosage of Cytarsbine Injection. Doses of 4.5 g/m? by intravenous infusion over 1 hove
`avery 12 hours for 12 domed hve caused an unacceptabh (ncrames in Itrevermibie CMS toxichy and deat.
`Single doses es high a2 3 g/m? have been administered by rapid Uvtrvenoes infusion without apparent toxicity.
`eeeeee eenny Thascheduleand methodofadministration varias withthe program
`net
`a
`therapy to ba used. Cyturabine Injection may 8 given by intravenous infusion or injection, subcutenegucsty, or
`(ntrathvecally (preservative tree prageration evty)
`Theembophvetitis has occurred at tha sfta of drug injector or infusion in some patients, and
`packers hae
`Noted pain andInflanenestion ateubcutanscis Mijectionsites. in remhatanne wavetherahRas hens
`
`
`
`‘a th Induction therapy of acuta noe-ymphacytie leukemia. Ine wie! cytarabine cos ie combination with other sti
`Cancer drags ta 100 mayday by Comtinucum IV infusion (Capa 1-7) oF 100 mayneIV every 12 hours (aya 1-7).
`‘The Iargtere should be consufted for the Current recommendations tor une in marie hyphocytic heukernia_
`ranging
`Soiree Upmsunbas bootneedHemaneraylosciota bySom
`from 5 mgm?to 75 aginof
`
`
`Furlanares. Thefrequencyofadministrationvariedfromone for 4daystoonce every4 The
`Troedequi uoed deen wea Mgrevery 4 days uel
`ol
`fotHachoga wera herrea,lokowndby
`‘one additional trestmamt. Tha dosage schedule is vsumlly poverned by the type and severity of central nerves
`
`(Cytanebing injection intrathecadymyClaiee eysterntc: toxichy and careful manstoring of the hamatopokric
`
`
`Yeceanet, gttemsonofhurtnetochapesey nesee eeCE
`mild anvmarta Parelogabas been ported
`SnglnuoencaphaoparyoccurredstCRAG'onBoe
`|
`patios had atao heentreaded wiltintrativecedsouonbyorecorioon 2e0llaa byCITE!nerves
`AT7EIT radiation. |solaund newrotoxichy hes been reported. Bindnaas occurred in Tec pathente in remission whose
`Innretneca cy aceceinationaystemiccheectherapy, propirfactc Carta Nervous Ryetamracistion and
`When cyturabing injection ts idminsstered both intrethecally and intrvenousty
`wer
`inern ia
`incremeedral of espinalcordtoxesty, however, intievesiaring denn,concisrenosof Pereventon
`
`by ultnviokgsmoon Cyarabing inmerion in infusion solutions, Than
`Sudha showed thal when Cytarabine injection was sdded to Water far Injection, $% Dextrose in Water or Sodium
`Choride Injection, 2M to Ol percent of thw cytarabine wae Oreset after 182 hours eiorage al room Iemperature.
`Parwmters! drugs should bo inepected vieusily for particulsts matter and discolorzDon, prior to adminieiration,
`‘eharrret EDIUION and Comtainer perry.
`HANHWedCL
`Procedures for proper haniling and dimpomel of anti-cancer Grugs ahoukd he corsidnnd. Severa! guidelines on this
`subject hava bean publianed.“' There it no general apreamecd (Tet all of ihe Groceduren recommended in the
`Quitelings are necemuary Of sppropriane,
`
`2/20 mL ina wingla dose Wp Top vial (green cap) packaged individually. WOC Wo.: 61 700-219-22
`TTOAABE
`Protect Irom Hight, Retaky in carton until tre of una,
`Store the Ofoduc! at COMtroliad room temperature 15" to SC (8 to Be" Fp.
`
`flecommendations tortha Sut Handing of Purentens Aniinowpiastic Drags, WIM Pubiiortions Wo, 64-2021.
`For male by the Superintendent of Gocuments. U.S. Government Printing offic, Washington, 0.6, 20402.
`AMA Councdl Report, Guiding: for Handling Purertimral Ameinecpumeicn, JAMA 11004; 2.83 (11): 1590-1902,
`‘Manon Study Commission ov
`ExposureRecommendations for Mandling Cytotac Agents,
`Available trom Louis P. Jatiray,
`ScO., Crusirman, Matkons! Study Commission on Cytotoxic Exposure,
`MRC
`Of Pharnacy ard ABled Health Eclences, 170 Longwood Avenue, Boston,
`Mammachusets 02115.
`of Aumtratie. Guidatinas ant Reccwwrundations tar Sete Harniling of Artirwenpinstic
`Clinical
`Agente. Med Jaea,eae
`
`5, :ARspart from the Mount Sinad beeen! Carter,Jones Fil, of at: Sate Handing of Chemotherapeutic
`
`CAA Cancer Journal of Canictars, 183: (DapyOct)
`256-263.
`Amancan Society of Hospital Pharmackts Technical Amistencs Bulletin on Handling Cytotoric and Mamerdous
`Dregs. Amt. Hosp. Prune, 19 47'1053-1049,
`Controting Occupations Exposure to Hamintous Droge. (OSHA Work Practios Guidelines), Arn, Hamith: Syet
`Pharm, 1990; 53:7000-1088,
`
`oe
`
`7.
`
`10/77
`
`10/77
`
`

`

`Chienee ingechon 24 "0 a6 pacers 3 (ne judi eae te ee
`CHa Ae oman tho arc ra ana create, 9010 AINA
`aranment sohalion and Container PETA
`HANDLING AND CIEPORAL
`KANOLIMG0OUPandepowancaadcnneaete
`subject hurvm Daan piste 4adeoeerpararal wgroamertht al of TM procadura recommend 9
`quidelines are necessary OF
`HOW BUPPLIED
`Cytarabin Injection is avaviable ax follows:
`Pep mgr mwa wg doelop val(coerencae) actagninten: NW a1703-904-008
`2 gat minangcounfi op vi (gr cap) packaged India, HOG WO: 64709-31022
`STORAGE CONDITIONS
`Protect {rom ight. Ratiln bn carton atl tina ot wae.
`storea product atcontroied room rempareure 18° 90"(8H"10 66" F
`REFEREMCES
`4
`Recommendations for theSafe Hancting of Parenteral AntinospineticDregs.Wil}PubtexSors Mo. 62-2621.
`for sale bythe Superintendent.ofDocu, Te covernmam Prineing office.Washington,0 (20402
`2 FScaningPereanclAMA,TA:2591500-1592
`1 vata uy Gamma on Cpt meteDMSO ayoone
`Avaltapiefrom Louia P. Jetirey.
`Chairmen,Natiorad StudyCommission on Gyvatzic Espowurt
`SuccesCmotPacesHauBaresLnewingWs
`Masaachueetts 0211
`Racommendanors
`4 Gincane torSatuHandling.ofAntineopkestc
`; ata.
`Jones FA,at al: SeteHandling ot
`A Report fromtheMountSinal MedicalCerne’.
`5
`eeaout)
`CAA CancerJournal of Celnicsans, 1283; (S#euOct) 1.
`6, Be arecaHapa Paracas Tecnica! Anuanes ub on anco/sadsane H#BFS
`Orogs. Amd. Hosp. Pharm, Vira a7T-1083-1048.
`Pharm,1900;53:1880-1685.
`‘
`a
`7.
`GontrenngerspeonalposefoHeaoo¥sDe OSHAWorkPracticaGuidesnes),AmJ. Health
`panutactured in Auetraia by:
`rn
`1bGoLimited
`
`
`
`11/77
`
`11/77
`
`

`

` A World of Hoalth
`CYTARABINE INJECTION
`ANDA75-383
`100 mg/mL, 20 mL vial
`
`REVISED CARTON LABEL
`
`
`
`
`
` Varo ee MOC 3700-31027 Preservative free,
`Discard unused Ssohylion.
`Each mi. contains:
`100 mg Cylarabine USP and
`water for wyection qs.
`Sodwim hydrosde andlor
`hydrechionc acid may be used lo
`adjust pH to a Largel of 7.7.
`Usual Dosage: See package insert
`for complete product informanon.
`Protect from bight.
`Retam in carton until ime of Use,
`Store af conirolied room
`lemperature, 15°-20°C (59'-G6'F).
`
`Slenie
`Cytarabine--
`Injection
`
`
`
`Foe intravenous,
`intrathecal and
`SUbCULANEOLS
`use only
`ingle
`dose vial
`
`Manutactured by
`PH Faulding & Co Lerubect
`123 lems Pace
`Mulgrave Victoria 2170 Austral
`
`ot Faulig . Bi
`200 Elnora Avenue
`Bhizaberh 6107207 LS
`
`FeeTi
`
`
`
`
`aS,
`
`| =
`
`e
`
`uonsafiy
`auger |
`
`‘
`3
`
`61703-319-22 7
`aR,
`
`=
`
`azure, | artwork
`
`Customer: Faulding Pharmaceutical Co.
`Container(s): 1 x 20 mL tallvial
`Size: 32.5 x 32.5 x 80.5 mm
`Colours: 295 C (dark blue), 575 C (olive)
`Drafted: 30 October 1998 mf
`
`12/77
`
`12/77
`
`

`

`
`
`‘Suerike
`
`EleMitel
`
`NOV22Ke 8,4 ‘}‘|
`Nov22IOGE)
`
`VE
`
`
`
`
`70m val
`
`Serie
`.
`
`NOC BY POV22
`
`.
`
`2]
`
`ii q 3
`Bic § i
`
`Be onty
`(ited.
`tow
`Faulding
`Eliabeth A 07207 USA
`
`KXARKK
`
`q
`3
`-
`
`Mae 61700-11922 |
`
`{20mm wt
`Sterile
`TELE em ul eaten
`
`
`MWRageercompeterou
`acidToorlerapecagure
`ydrochiene
`3
`
`faghtRetaininconeunlumeofuse
`3
`15-MC i
`g
`. 5 aE
`rah
`a APH 2
`4
`aeons
`Frit
`Soon fel |
`ElzabetnM107207USA
`fiein i lll
`
`MEE
`
`13/77
`
`

`

`CENTER FOR DRUG
`EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`75-383
`
`CHEMISTRY REVIEW(S)
`
`14/77
`
`14/77
`
`

`

`Office of Generic Drugs
`Chemistry, Manufacturing and Controls Review
`
`CHEMIST'S REVIEW NO.: No. 1
`
`ANDA #: 75383
`
`NAME AND ADDRESS OF APPLICANT:
`Faulding Pharmaceutical Co.
`Attention: Heike Maaser
`200 Elmora Avenue
`Elizabeth, NJ 07207
`
`LEGAL BASIS FOR ANDA SUBMISSION:
`505 j
`
`PROPRIETARY NAME:
`N/A
`
`NONPROPRIETARY NAME: Cytarabine Injection
`
`SUPPLEMENT (S) PROVIDE(S) FOR:
`N/A
`
`°
`
`AMENDMENTS AND OTHER DATES:
`Faulding:
`05/15/98
`
`Submission of ANDA (received on 05/18/98)
`
`FDA:
`06/10/98
`07/14/98
`08/26/98
`
`Acknowledgment letter
`Labeling review completed (Deficiencies) .
`bioequivalent WAI Granted.
`
`10.
`
`PHARMACOLOGICAL CATEGORY:
`Acute non-lymphocytic leukemia
`
`Li:
`
`Rx _or OTC:
`
`Rx
`
`12.
`
`RELATED IND/NDA/DMF(s) :
`Innovator: Pharmacia & Upjohn (NDA 16793)
`100 mg/vial, 500 mg/vial,
`1 g/vial and 2 g/vial
`
`5 mL, (single dose)
`ANDA 71868(Faulding)-Cytarabine USP, 20 mg/ML,
`ANDA 72168(Faulding)-Cytarabine USP, 20 mg/ML, 50 mL (bulk package)
`ANDA 72945(Faulding)-Cytarabine USP, 20 mg/mL, 25 mL(multi- dose)
`
`oMEOO
`
`15/77
`
`15/77
`
`

`

`DMF ——
`
`RM:
`DOSAGE
`Solution for Injection
`
`POTENCY:
`2 g/20 mL (100mg/mL)
`
`CHEMICAL NAME AND STRUCTURE:
`4-amino-1-B-D-arabinofuranosyl-2 (1H)-pyrimidinone
`
`13.
`
`14.
`
`La
`
`16.
`
`RECORDS AND REPORTS:
`
`N/A
`
`17.
`
`COMMENTS :
`
`|
`
`|\
`
`3
`
`18.
`
`CONCLUSIONS AND RECOMMENDATIONS:
`Not approvable (Major Amendment).
`
`19.
`
`REVIEWER:
`Bing Cai, Ph. D.
`
`DATE COMPLETED :
`10/08/98
`
`DATE Revised:
`10/19/98
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`16/77
`
`16/77
`
`

`

`Redacted a ‘
`
`pagesof trade secret and/or
`
`confidential
`
`commercial
`
`information
`
`17/77
`
`17/77
`
`

`

`Office of Generic Drugs
`Chemistry, Manufacturing and Controls Review
`
`CHEMIST'S REVIEW NO.: No. 2
`
`ANDA #: 75-383
`
`NAME AND ADDRESS OF APPLICANT:
`Faulding Pharmaceutical Co.
`Attention: Heike Maaser
`200 Elmora Avenue
`Elizabeth, NJ 07207
`
`LEGAL BASIS FOR ANDA SUBMISSION:
`505 3
`
`PROPRIETARY NAME:
`N/A
`
`NONPROPRIETARY NAME: Cytarabine Injection
`
`SUPPLEMENT(S) PROVIDE(S) FOR:
`N/A
`
`AMENDMENTS AND OTHER DATES:
`Faulding:
`05/15/98
`11/24/98
`11/25/98
`
`Submission of ANDA (received on 05/18/98)
`Major Amendment.
`Petition to change Major to minor amend.
`
`FDA:
`06/10/98
`07/14/98
`08/26/98
`12/03/99
`11/24/98
`
`Acknowledgment letter
`Labeling review completed (Deficiencies).
`bioequivalent WAI Granted.
`Telecon-Petition denied-
`Labeling review (2™ round) completed with
`Deficiencies.
`
`‘
`
`10.
`
`PHARMACOLOGICAL CATEGORY:
`Acute non-lymphocytic leukemia
`
`ll.
`
`Rx or OTC:
`
`RX
`
`18/77
`
`18/77
`
`

`

`12.
`
`RELATED IND/NDA/DMF(s):
`Tnnovator: Pharmacia & Upjohn (NDA 16793)
`100 mg/vial, 500 mg/vial,
`1 g/vial and 2 g/vial
`
`ANDA 71868(Faulding)-Cytarabine USP, 20 mg/ML, 5 mL, (single dose)
`ANDA 72168(Faulding)-Cytarabine USP, 20 mg/ML, 50 mL (bulk package)
`25 mL(multi- dose)
`BANDA 72945(Faulding)-Cytarabine USP, 20 mg/mL,
`
`DMF ~ pO
`DMFee—__—r—r"
`
`13.
`
`14.
`
`15.
`
`DOSAGE FORM:
`Solution for Injection
`
`POTENCY:
`2 g/20 mL (100mg/mL)
`
`CHEMICAL NAME AND STRUCTURE:
`4-amino-1-f-D-arabinofuranosyl-2 (1H) -pyrimidinone
`
`16.
`
`RECORDS AND REPORTS: N/A
`
`17. COMMENTS:
`—_
`
`\4
`
`—
`
`18. CONCLUSIONS AND RECOMMENDATIONS:
`Not approvable (FAX Amendment) .«
`
`19. REVIEWER:
`Bing Cai, Ph.D.
`
`DATE COMPLETED:
`05/20/98
`
`DATE Revised:
`05/21/99
`
`19/77
`
`19/77
`
`

`

`Redacted
`
`\2
`
`pagesof trade secret and/or
`
`confidential
`
`commercial
`
`information
`
`20/77
`
`20/77
`
`

`

`Office of Generic Drugs
`Chemistry, Manufacturing and Controls Review
`
`CHEMIST'S REVIEW NO.: No.
`
`3
`
`ANDA #: 75-383
`
`NAME AND ADDRESS OF APPLICANT:
`Faulding Pharmaceutical Co.
`Attention: Heike Maaser
`200 Elmora Avenue
`Elizabeth, NJ 07207
`
`LEGAL BASIS FOR ANDA SUBMISSION:
`505 j
`
`PROPRIETARY NAME:
`N/A
`
`NONPROPRIETARY NAME: Cytarabine Injection
`
`SUPPLEMENT (S) PROVIDE(S) FOR:
`N/A
`
`AMENDMENTS AND OTHER DATES:
`Faulding:
`05/15/98
`11/24/98
`11/25/98
`07/06/99
`07/14/99
`08/04/99
`
`Submission of ANDA (received on 05/18/98)
`Major Amendment.
`Petition to change Major to minor amend.
`Amendment
`(CMC & Labeling)
`New Correspondence. (labeling)
`Amendment (Labeling)
`
`FDA:
`06/10/98
`07/14/98
`08/26/98
`10/26/98
`12/03/99
`11/24/98
`06/07/99
`08/06/99
`08/10/99
`
`Acknowledgment letter
`Labeling review(15* round) w/ Deficiencies.
`Bioequivalent WAI Granted.
`CMC NA-Major
`Telecon-Petition denied.
`Labeling review (2™? round) w/ Deficiencies.
`CMC NA-FAX
`Labeling review (3°? round)-acceptable.
`Micro review completed w/ Deficiencies.
`
`21/77
`
`21/77
`
`

`

`10.
`
`PHARMACOLOGICAL CATEGORY:
`Acute non-lymphocytic leukemia
`
`11.
`
`Rx or OTC:
`
`Rx
`
`U2.
`
`RELATED IND/NDA/DMF(s) :
`Innovator: Pharmacia & Upjohn (NDA 16793)
`100 mg/vial, 500 mg/vial,
`1 g/vial and 2 g/vial
`
`ANDA 71868(Faulding)-Cytarabine USP, 20 mg/ML,
`ANDA 72168(Faulding)-Cytarabine USP, 20 mg/ML,
`ANDA 72945(Faulding)-Cytarabine USP, 20 mg/mL,
`
`5 mL, (single dose)
`50 mL (bulk package)
`25 mL(multi- dose)
`
`OE aaaeeee
`DMF ~~ argg
`
`13.
`
`14.
`
`15,
`
`DOSAGE FORM:
`Solution for Injection
`
`POTENCY:
`2 g/20 mL (100mg/mL)
`
`CHEMICAL NAME AND STRUCTURE:
`4-amino-1-B-D-arabinofuranosyl-2 (1H)-pyrimidinone
`
`16.
`
`RECORDS AND REPORTS: N/A
`
`17.
`
`COMMENTS:
`
`18.
`
`CONCLUSIONS AND RECOMMENDATIONS:
`NA, MINOR
`
`1S.
`
`REVIEWER:
`Bing Cai, Ph.D.
`
`DATE COMPLETED:
`08/03/99
`
`DATE Revised:
`08/16/99
`
`22/77
`
`22/77
`
`

`

`Redacted
`
`o
`
`pagesof trade secret and/or
`
`confidential
`
`commercial
`
`information
`
`23/77
`
`23/77
`
`

`

`Office of Generic Drugs
`Chemistry, Manufacturing and Controls Review
`
`CHEMIST'S REVIEW NO.: No.
`
`4
`
`ANDA #: 75-383
`
`NAME AND ADDRESS OF APPLICANT:
`Faulding Pharmaceutical Co.
`Attention: Heike Maaser
`200 Elmora Avenue
`Blizabeth, NJ 07207
`
`LEGAL BASIS FOR ANDA SUBMISSION: 505 j
`
`PROPRIETARY NAME: N/A
`
`NONPROPRIETARY NAME: Cytarabine Injection
`
`SUPPLEMENT (S) PROVIDE(S) FOR: N/A
`
`AMENDMENTS AND OTHER DATES:
`Faulding:
`05/15/98
`11/24/98
`11/25/98
`07/06/99
`07/14/99
`08/04/99
`09/28/99
`10/08/99
`FDA:
`06/10/98
`07/14/98
`08/26/98
`10/26/98
`12/03/99
`11/24/98
`06/07/99
`08/06/39
`08/10/99
`08/30/99
`10/04/99
`10/14/99
`
`Submission of ANDA (received on 05/18/98)
`Ma