`These records are from CDER’s historical file of information
`previously disclosed under the Freedom of Information Act (FOIA)
`for this drug approval and are being posted as is. They have not
`been previously posted on Drugs@FDA because of the quality
`(e.g., readability) of some of the records. The documents were
`redacted before amendments to FOIA required that the volume of
`redacted information be identified and/or the FOIA exemption be
`cited. These are the best available copies.
`
`

`

`NOR-828450
`NDA-8284!58
`
`F!RH:PBRKE DFWIS
`FIR" :PARKE DAVIS
`TRHDE NRHEICEREBVX INJ 75HB/HL
`TRADE NA"E : CEREBYM INJ 7S"G/"L
`GENERIC NHHE:FOSPHENVTOIN SODIUM
`GENERIC NA"E :FOSPHENYTOIN SODIU"
`
`1 OF 5
`1 OF S
`
`

`

`Summary Basis of Approval
`cover Form
`
`Appl • : 0204St:r
`
`Firm t PARKS DAVt•
`Reviewing Div: 120
`Trade Namer CEREBYX (FOSPHBNYTOIN SODIUM)INJ 7SMQ/ML
`Oeneric Namer
`FOSPHBNYTOIN SODIUM
`
`Approval Letter: y
`
`Statistician Rt~vi~w: N
`
`SBA Form: N
`
`Bio/DiNHnlut inn R~vl~w: y
`
`Final Printed lJabel ing: N
`
`M:i.crobiologiot ftt!V 1 a!JW : y
`
`Medical ot f lcet· Re'!View: y
`
`NAS/NRC l<@Vi@W: N
`
`Chemist Review: y
`
`Pharmac0logiaL Review: y
`
`Federal Register Notice: N
`
`Completion Date: ll~APR~97
`
`

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`--=-=--=-=---=-=-;==--=--=--=-=-=--=-=--=---=-===---=-c:---~----=~-c-~-=~-§-~---~---~--~-~--§ ___ § __ §_~_~ __ § ___ §_ -~ __ §_§_~~§--_§_-_§ __ ~::_~-:-_~--~=--§-~~--~-~-~--;_~-=--~~---~---~-=---~:_:_¥.-=-~~-~~
`
`
`

`

`Approval Letter
`_ d Related
`Correspondence
`
`

`

`DIPAITMINT Of KIAL TH t. HUMAN lllVICll
`
`,.... Ind DNe ...... Idun
`ftaci\ltttt MO JOll?
`
`NOA 20-.450
`
`P•rt.-Davil Ph1rmac.uttcal A-•rch
`otvtston of Warner .. Lambert ComP9nY
`Att•nteon: Ma. Janeth L Turner
`2100 Plymouth Road. P. 0. Box 104 7
`Ann Arbor, Ml •1108·1CM'7
`
`De•r M1 Turner:
`
`PlelH ,.,., to your July 141 1984 new drug appttcat,on 1nd your retubml11t0n d1tld
`FebNlty 22. 1118 1ubmftted under Hctton 505(b) of the Fedet1I Food, Dfug, It'd
`Coemetio Aot for Cerebp9 (foaphenytotn IOdtum) tnjec\'°n 76 rnglmL (90 mglml PE).
`
`W. 111a acknowtedg• recetpt of your lddltionlt oorreepondenoe 1nd 1mendmant1 datta:
`
`Pebruary 27. 1888
`March 13, 1111
`March 14. 1111
`
`April 12. 1189
`May 1. 1118
`May 2. 1911 (2)
`
`Maya, 1118
`Juty 12, 1HI
`Juty 30, 1898
`
`Thtl naw drug appHcat,on provld• for the '°"Owing;
`
`Cerebyx9 ii 'ndte1ted for ahott-term partnteral ldmtnfttr9tton wnen other
`me1n1 of phlnytoln lldnatnittration are un1v1ltable. tntppropf'ilte or dMmed
`1t111dv1rageou1. Tht uflty Ind effeottven•11 of Ctr•byX- ln thil ut• h••
`not bffn 1yettmattally 1v1lu1ttd for more than I d1y1.
`
`C•rebVX- c.n be uHd for th• oontroa of gener1H1td eonvullive 1t1tu1
`epll1ptfeu1 ind prevent•on •nd prevention and trtatment of Hlzur•
`occurring dunng neuroaurgery. tt can 1ho be 1ub1tttuttd, ahort·tenn, for oral
`phenytoln.
`
`WI hlV• completed the teYteW of thil •PPllOltlon lnc!uding th• IUbmlttld drift labeH"g •nd
`hive oonctuded th8t •dequate Information hu o.-.n PtaMnted to deman1tr1te lh•t the
`dNg product ii 11fe and 1ff8ottv1 for UH'' rr omm•ndld In th• draft tlNHnl in the
`1Ybml111on dated July 12. 1881 with the , .. 1i1ion1 tilted below.
`Aaoording~, the
`apptlcltion i11ppro~td 1fflcltv1 on the d•t•., thll letter. The rtvie&fon1art11 foflow•:
`Ple111 correct th1 legend to 'kc·~" ~ to tt1d " ... 1 zoo mg PE Cerebyx lnfuMd .. ,"
`1 .
`rather than ..... 1200 mo C•ntbr~ ;"fu~~ .... "
`WARNINGS; Uu91 In P,.gm.,.1cy. Cllnie•t· 1eotion
`
`2.
`
`

`

`10:MJ
`
`NDA20""450
`
`8. Rl1k1 to ttt. Fetui.
`
`Pege2
`
`Parmgreph 1, t11t Hnttnae:
`
`pie- cnenge "contribution" to 11oontribution1".
`
`3.
`
`WARNINGS: Uaag• in Preon•ncy: pt9G/lnJc•I: section
`
`Th• wording of dOH oomparilona end plaama tevel d1t9 1hauld be m1d1 conMtent
`•• fotlowl:
`
`P•f'I 1, aentence 2: ... (1pproximltely 30,. of tht mulmum human lo8dlng dote
`or htgh1r on 1 mg/m1 baaia), whtch produced pe1k maa.mat
`pt1am1 phenytotn concentr1tton1 of 1pproxtmltely 20 ~g/mL
`or greater.
`
`P•ra 1 Mntence •: ... (•ppro>etrnatety 10~ of th• maximum human loading fjot•
`on• mg/ml baala) ....
`
`Par12, Hntence 1:
`.. (1ppr0Jelm1tely 50'4 ... .
`P•r• 2. umenctt 2: ... (1pproxtm1tety 120'K ... .
`
`4.
`
`PRECAUTIONI; Carainog1ne1la, Mutqennta, tmpainMnt of Pertutty; MGtiOn
`
`Para 3, lilt Hntence.
`
`. .. at doan of 10 mg PE/kg or higher (approxlmltely
`40 ~ of the maximum hurn1n I01ding dOM or ~lgher on
`a mglm1 b1at1).
`
`Thne r1vflton1 are t•lml of the NOA approval. Markettng the product befor• m•klng th•
`requeat.d, an the produof• ftn.1 printed labtNng (l'PL) may render the
`revtlionl, n.atty •
`product mtlbranded and an unapprovld n9W dNg.
`
`Pt11u 1ubmlt 1ixt .. n oopie1 of the FPL 11 toon H lt l1 •v1ifable. in no GIH mOf9 than
`30 dllYI .ttet It ii printed. PfHH individually mount ten of the copln on heavy wetght
`papar or 1imH1r m1t1rta1. For 1drnint1trlttve purp0111 thlt 1ubmtal6on thoutd be
`d11i9n1ted "FINAL PRINTED LAB!LINO" for 1pprovtld NOA 20-450. Approval of thtl
`aub'""8ion by FDA ti not NqUlred before thl t1bellng ta Ultd.
`
`Should additional '"formatton rttating to the ufety ind 1ffectivena11 of the drug become
`•vadablt. reviaton of that labe.ling may be required.
`
`'h••• IV Commitment
`
`

`

`10:50
`
`FOA/f'£~0l.OG1C~ -+ 94430200
`•
`
`NOA 20-450
`
`Page3
`
`We remind you of your Ph•• 4 commitment 1pecifled in your eubmiaaion dated Apnt 12.
`1888 and *'1ended on July 12, & 30, 1999. Thia commitment ia Hated below. Protocols,
`datll, and ftnw~ rwporta should be •ubmitted to your IND for th'• product and a copy of the
`cover tatt•r Mnt to thta NOA. For 1dmlnl1tr1tlve purpou1, all 1ubmla1ton•. 'ncludh1g
`labeling aupp'9ment•, rel•ting to th" Ph•M • commttment mu1t be cte•rty de1ton•tad
`"Ph• .. 4 Commttmant." Yo\lbommitment ta 11 foUowt:
`
`In lddition, plll1u 1ubmtt thrH copte1 of the lntroduotory promotlonaf mlterial th1V ~ou
`propo•• to uu for thta produot. AH propOHd m1t•rf•I• 1hould be aubmmed In draft or
`modc·up form, not ftn1I prtnt. Pie••• aubmjt one copv
`to thtt DtvMn of
`Neuropharmaoologtcat Drug Producte 1nd two coplu or both the promotiOnal mlterilf and
`the package tn11rt dtreotly to:
`
`Food and Drug Admtnlatration
`Dlvi1lon of DNQ Markettng, Adve..Uing and Communlcatlont,
`HFD-40
`5800 Fi1her1 Lane
`Aockvilltl, Maryland 20857
`
`We remd you that you mu1t r.omp~ With the requirementa for an approved NOA Mt forth
`und9r 21 CFR 314.80 and 314.81.
`
`tf you have any que1tion1, pleaH eonlaot:
`
`"obbtn N1gn1wenmr, R.f'h.
`Regutatory M1nagement Officer
`(301) 894-2171
`
`Sincerely youra.
`
`Obert Im::~
`
`Dtractor
`Office of Drug Evalu1tion I
`Center for Drug Evaluation 1nd ReMaroh
`
`

`

`( ; ; / - DEPARTMENT or HW.m :_HUMAN-SIRVICIS
`
`NOA 20-450
`
`food Ind ONG Admlnllntion
`Aor.kvtlle MD 208&7
`
`Parke-Davis Pharmaceutical R•aearch
`Division of Warner-Lambert Company
`Attention: Ms. Janeth L. Turner
`2800 Plymouth Ro•d, P.O. Box 1CM7
`Ann Arbor, Ml 48106-1047
`
`Dear Ms. Turner:
`
`FEB 23 la
`
`Pl•••• refer to your July 14, 1984 new drug application (and your re1ubmi11ion dated
`February 22, 1995) 1ubmitted under aectlon 505(b) of th• Federal Food; Drug, and
`Co1m1tlc Act for Cer1byx9 (fo1phenytoin aodium) Injection 76 mg/ml.
`
`Wa acknowledge the following additional correapondence and 1mendment1:
`
`September 2, 1994
`September 14, 1 994
`October 6. 1994
`Daeamber 1 e. 1994
`March 29, 1Q95
`June e, 1995
`June 22, 1 995
`
`July 21, 1995
`September 5, 1995
`September 14, 1995
`Saptambar 27, 1995
`October 19, 1995
`October 27, 1995
`(2 1ubm111ion1)
`
`October 31, 1995
`November 3, i 995
`November 20, 1995
`January 4, 1996
`January 8, 1996
`February 9, 1996
`
`W• have completed the review of this 1pplle1Uon •• 1ubmitttd with draft libeling, and It
`111pprov1ble. Before the application may b• approved, however, It will b• nece111ry for
`you to adopt aa labeling for CerebyX-1 the draft p1ck1g1 tn••rt attached to tht1 letter,
`modified as requested (I.e., aa per thla letter and th• not•• tmbedd•d within the text of
`the attached package inaart).
`
`

`

`NOA 20"'450
`
`Ph••• IV Commitment
`
`We also ask that you submit the following Information:
`
`1.
`
`L.lb•llng:
`
`Insert: Should addltlonel inform•tlon relating to
`Pack.age
`the safety and
`effectlv•n••• of Cerebyx• become available prior to our receipt of the final printed
`labeling, revision of th1t libeling may be required.
`
`Product and Container L•b•ling: Ple11e rev11e •II product and cont1iner l1b11ing
`to approprl1tely convey th•t do1•g• conv1r1ion calcul1tlon1 do not need to be
`performed when converting p1ti1nt1 between foaphenytoln and phenytoln (I.e., all
`labeling should clearly convey that 50 mg/ml of phenytoin ii being delivered and
`that NO do11g1 converalon factor need be 1ppll1d).
`
`2.
`
`MJcroblology;
`
`The following mlcroblologlcal l11ue1 concemlng aterlllty a11ur1nce and other l11ue1
`have not been completely addr1111d:
`
`a.
`
`b.
`
`Bulk 1olutlon bioburden llmlta (prior to filtration) 1hould be apectfled end the
`method• to teat thla, Including 11mple points, 1hould be deacrlbed.
`Hl1torical data may be provided tn aupport Of the e1t1bll1h1d llmlt. We
`prefer th• 11mpl1 collection point b• Identified In the menuf 1cturlng
`ln1truction1.
`
`The frequency of requalifying 1terilizer1 (autoclaves and tunneta) waa
`1pectfted 11 every 2 yeara. We generally recommend more frequent
`evaluation of the lnatrument and proc•••.
`
`

`

`NOA 20'"450
`
`page 3
`
`c.
`
`d.
`
`e.
`
`The operating parameters for 1tenllzatlon Of fitters and filling o~uipment were
`not provided end their validatlon was not discussed.
`
`Validation of the integrity of the container and clo1ure 1y1tem1' barrier to
`microbial ingr••• was not di1cu11ed. Pl•••• provide • 1umm1ry of the
`methods 1nd results demonstrating the Integrity of this system.
`
`Your amendment dated October 27, 1995 daaalbes 1peclflcatlon1 for med'ia
`fills (Tab 5. App•ndix 1, page 19). Th• 1tated Alert Limit permits no
`Investigation Of any kind when aa many 11 2 container• ire cont1minated In
`a batch of 5000. We encourage aome investigation of any evidence of
`contamination In product (1tmulated or otherwise) manufactured by a
`process for sterile product.
`
`3.
`
`M1nYf1ctydnq and Cgntrol1:
`
`S1fety Update
`
`Submit• safety update report 11 provided for under 21 CFR 314.50(d)(o)(vi)(b). Thia may
`be limited to deaths, 11riou1 adverse •vents\ other adverse event• that t•d to
`discontinuation of the drug, and any information 1uggeating a aubatantial dlfferanC9 in the
`rate Of occurrence of common but le11 serious adverse event•. The upd•t• 1hould cover
`all studies and u111 of the drug tndudtng: ( 1) tho•• involving indlcationa not being sought
`In the present 1ubmi11ion, (2) other doAg• forma, and (3) other dose level•. Pl•••• 1110
`lnciude 1ny 1arlou1 adver1e event• reported elnr.e your la1t ••fety upd1te In the final draft
`version of product labeling you 1ubmit In re1pon1e to thl• approvabl• action.
`
`In addttion, plaaae submit three copies of the Introductory promotional material that you
`propose to u11 for thl1 product. All proposed mat1rl1l1 should be submitted In draft or
`mock..up form, not final print. Plea1e submit one copy to thl• Diviaion and two copl11 of
`both th• promotional material and the package Insert dir•ctty to:
`
`

`

`NOA 20-450
`
`page 4
`
`Food and Drug Administration
`Division of (Jrug Marketing, Adverti1ing and Communications,
`HF0-40
`5800 Fishers lane
`Rockville, Maryland 20857
`
`Within 1 o days after the date of thia letter, you are required to amend the application,
`notify us of your intent to file an amendment, or follow one of your other options under 21
`In the abaence of auch •ctlon FDA may take actlor. to withdraw the
`CFR 314.110.
`application.
`
`The drug may not be legally marketed until you have been notified in writing that the
`application ii approved.
`
`Should you hr.we 1ny questions, pl1a11 contact:
`
`Robbin Nighswander, R. Ph., M. S.
`Regulatory M1nagement Officer
`Telephone: (301) S94·2850
`
`Sincerely youra,
`
`Robert Temple,~
`
`Director
`Office of Drug Evaluation I
`C•nter for Drug Evaluation and Research
`
`attachment ( 1 )
`
`

`

`...
`
`Memorandum
`
`Department of Health and Human Service•
`Publlc Health Service
`Paod and Drug Admlnlatratlon
`Center
`for Drug
`l!valuatlon and Research
`·-------------------------------__ .... _____ ...,. ______________ .,_.~-..----~'-
`Febru•ry
`DATE:
`ii, 1111
`
`PROM:
`
`P•ul Leber, M.D.
`Director,
`Dlvlelon of N•uroph1rm1cologlo11 Drug Praduot•
`HFD·120
`
`IUBJICT: Cerebyx~ l'fo•pheytoln
`
`lnJeotlon] NDA 20·460 Approv1ble Action
`
`TO:
`
`Robert Tempi•. MD, Dlreotor, ODI 1
`
`' I'll• NOA 20·410
`-------------------··--------------------------------------------
`This memorandum provides a diacuaaion of several factors affecting the
`regulatory action that might be taken In regard to P1rke·D1vl1' pending
`NOA 20-450 for Cerebyx• [fosphenytoln).
`
`Several options, ranging from approval to disapproval are defensible. Aa a
`matter uf tactics, how•tvar, the action latter being forwarded declares the
`NOA approvabl1, albeit under a number of condition• that are enumerated
`both within the text of the letter and within a veraton of product labeling
`"Jveloped by the dh''tlon (I.e., In 'not•• to the firm' embedded within the
`text) that would be attached to the letter, If Issued.
`If tt. :t Office were to
`choose an alternative notion, the draft approvable letter may be modified
`accordingly.
`
`tb1 1dmlnl1tr•tlv1
`tntrpduotorv Camm1nt1 and not11 about
`111:1ttgy 1ppll1d In tbt 1v1ly1tlqn pf tbla . NDA
`
`Iba atruotura of thl 1rgym1nt1 1upogrttng 1pgrov1t
`
`Although Cerebyx• [fo1phanytoln] 11 a new chemical entity, an approval of
`the NOA tor Cerabyx• le only po11lble, given the type of the Information
`provided In the NOA, becau•• ouantln•, Park• Davit' Innovator brand of
`phenytoin, is an approved anti-eplleptlc drug product (AEDJ.
`
`

`

`Leber: Cerebyx~ [phosphenytoln Injection] approvable action
`
`...
`
`page 2
`
`The conclusion that Cerebyx• is effective In use, in particular, tuma not
`on reports of adequate and well controlled clinical inve1tlgatlon1, but
`upon 1) the knowledge that phenytoin Is an effeotlvft AED, 2) that
`fosphanytoln ls completely converted within minute• of Injection to
`phenytotn and 3) evidence adduced by the sponsor In blopharmacoklnetlc
`and clinical trials showing that when Cerebyx• is administered under the
`directions provided Ir, the proposed Cerebyx• product labeflng, the
`resulting plasma levttla of phenytoln approximate thoae that are obtained
`when Dllantln Injection ts administered under Its recommended conditions
`of uae for the same claimed use.
`
`Although the agency's earlier determination that the benefits of DUanUn•
`Injection outweigh the rlake of lta u11 11 a nece11ary element In the chain
`of argument and evidence that can be used to support a conclualon that
`Cerebyx• wllt be safe for us• under lta proposed labeling, the
`determination
`Involving Dtlanttn• ta, In and of lt11lf, Insufficient to
`support the ooncluslon about Certbyx•·a safety. Not only le fosphenytoln
`a different molecular 1p1cl11 than phenytoln (and, therefore, may poae an
`entirely distinct panoply of risks unrelated to lte oonverelon to
`phenytoln). but foaphenytoln Injection yields two/three molecular
`species, ph<•aphate and formaldehydt/f ormate that are not produced when
`Ollantln la administered.
`How theae difference• affect the regulatory
`dectston, and how well I belteve they have been addressed by the ft rm. are
`dl1cu1sed tn a later section of thle memor1ndum.
`
`- -
`
`-
`
`- -
`
`- - -
`
`- - - -
`
`- -
`
`-
`
`- - - - - -
`
`- -
`
`An 1dmlnl1tr1t1v1 l••u• afftqtlng
`DJ11nt1na.
`
`l•tJ•llng oJ bath Ctrtbyxa 1gd
`
`Cerebyx• labeling can be viewed 11 addr111lng both toaphenytoln specific
`(e.g., toephenytoln, formate, phosphate) and ph1nytoln related l11ue1. The
`latter, to the extent that they repreaent Inf ormatlon not currently
`included In Ollantln• labeling poae a problem In that, with the marketing
`of Carebyx•, there would be In exlatance dlff erent, arguably
`contradictory, statements about the same drug 1ub1tance (phenyt,,tn) In
`the labeling of two different approved drug products (Dllantln• anj
`Cerebyx•).
`
`While we do not propose to r1101ve the problem by linking the approval of
`
`

`

`Leber: Cerebyxtt [phosphenytoin injection] approvable action
`
`...
`
`page 3
`
`the Cerebyx• NOA to full revision of Dliantln• product labeUng, we do
`recommend, If the Cerebyxe NOA Is declared approvable, asking the firm
`to revise the content of those sections of Dllanttns product laboUng (both
`oral ard Injectable) that differ substantively from Cerebyx• product
`labeling (e.g., phenytoin specific matters via a vis pregnancy,
`taratogenlclty, etc.) and to submit labeHng supplements to an1 their
`Dllantln product NDAs at the same time as they make a response to a
`Cerabyx• approvable action letter.
`
`1ll1,atly10111
`
`ID U••·
`
`As noted in the preceding section, although the Cerebyx• NOA contain• no
`reports of adequate and well controlled cllnloal lnve1tlgatlon1 that
`document fosphenytoln Injection's capacity to 1uppre11 seizures, the
`offacUveneaa of the product •• an anti-epileptic drug [AEOJ can be deemed
`established on the ground• that 1 ) fo1ph1nytoin ta a prodrug for phenytolnl
`and 2) under the conditions of use recommended in the labeling propo11d
`by the Dlvlalon, Cerebyx• Injection will yield plaam& levels of tree
`pnenytotn that are aufflclently cloae3 to those that would be produced
`
`' The firm might not choose to revise DUantin• injection becauH they
`intend that it be replaced by Cerebyxe; I would recommend that we insist that they
`do, however, in part to ensure that generic labelirag for injectable phenytoin is
`consistent with Cerebyx•.
`
`2 Each molar unit of administered fospheytoin is converted to an equimolar
`qu.,.ntity of phenytoin.
`
`3 It is acknowledged that 'close' haa no clinically defined or generally
`rtcognized meaning. The woid is intended to convey a judgment by the review
`team that the rate and extent of free phenytoin delivery to the 1y1temic circulation
`that follows the admini1tration of Cerebyx® do not differ from the rate and extent of
`tree phenytoin delivery that follow• the administration of Ollantin® injection to a
`degree that will a cau1e a clinically significant difference in treatment response. This
`judgment, admittedly, cannot be supported by reference to tmpiriral findings; there
`is no e1tabli1hed quantitative relationahip between chana•• ln the rate and extent of
`phenytoin delivery and change• in the percent of patients exptrienclns a aatiafactory
`anti-epileptic response in any of the clinical 11tting1 in which parenteral phenytoin
`is recommended. While auch a judgment ia, therefore, undeniably arbitrary, it is
`
`

`

`Leber: Cerebyx• [phosgt)enytoln Injection] approvabla action
`
`page 4
`
`when Dllflntln• Injection is administered for the same lndlcation4 under
`Dllantln• Injection's recommended conditions for use to allow Cerebyx•
`Injection to be uaed tn place of Dilantin.• injection.
`
`As noted, the bloequlvalence of Cerabyx• and DUantin• Injection have not
`been demonstrated under every possible aet of doses and routes of
`administration being recommended In Carebyx• labeling.
`It Is our
`judgment, however, that the products are 1funglble 1 when given In
`equimolar doses In settings where the extent, but not the rate, of
`phanytc,ln delivery controls Its affectlven•ss.
`
`In thft one situation in which rate of phanytoln availability is deemed of
`crltlcal cllnlcal Importance, that la, Intravenous loading for the treatment
`of 1tatu11 aplleptlcua, the firm has been able to develop a regimen of use
`under which the pharmacoklnatlc parfonnanca of Carabyx• and Ollantln•
`injection are bloequlvalent by ordinary agency criteria (I.e., the 90% CL
`llmlta on the ratio of the realized values of the estimates for the usual PK
`parameters of the new to the old product are ~ 0.8 and s 1.2S).
`
`A digression concerning the doses of phenytoin and fosphenytoin studied
`may be helpful at this point. The molecular weight of fo1phenytoin is
`approximately 1.5 times that of phenytoin; accordingly a dose of phenytoin
`only 0.67 that of fosphenytoin is equimolar to the latter. Unfortunately, it is
`sometimes difficult to be certain whether or not the dose of fosphenytoin
`
`every bit as reasonable a1 the one that allows the agency to declare products that
`differ in their biopharmacokinetic performance 'bioequivalent' as long as the
`difference in their performance falls within some arbitrary tolerance limits (e.g., the
`90% confidence limita on the ratio of realized estimates for a particular
`pharmacokinetic parameter, say Cmax or AUC, for two products, falls between 0.8
`and 1.25). Having aaid all this, however, it should be noted that the firm did show
`that fosphenytoin and phenytoin can deliver free phenytoin to the same rate and
`extent under ontt specific set conditions of dose and rate of administration. (see
`discuuion of atudy 982-240).
`
`4
`1. IV loading in status epilepticus
`2. IM or IV loadin~ for treatment or prophylaxis
`3. IM or IV uae for maintenance therapy
`4. IM or IV use for temporary substitution for oral Dilantin
`
`

`

`Leber: Cerebyx• [phosphenytoln Injection] approvable action
`.a I
`
`page 5
`
`identified in file documents (e.g., in both FDA review document• and
`sponsor's reports), is intended to repreaent the actual weight of fo1phenytoin
`or the weight exprened in ph•nftoin 1quiva1•nt1 (PE). that 11, tbt w1i1htaf
`pbell);t0in that wguld. yi1ld an aquimotar amgµpt pf phln)'toln •1 tb1
`fg1ph1nytgin dpae actu1Uy 1dminJ1tercd. There ia not much that can be
`done about those ambiguitlea ln uaage other than to be aware of them.
`
`The table that follows prl"videa a concrete example: it enumeratea the actual
`ma11 do1t1 for both foaphenytoin and phenytoin that would generate the
`same molar amount of phenytoin in 1tatua epi11pticu1. Note that the rate of
`phenytoin specified in the table ia not actually deliverable with DUanttne
`injection becauM the maximum rate of intravenous administration for that
`product la SO mg/min.
`
`dose
`rate
`Drua
`22.S to 30 mg/kg
`foaphenytoin
`150 to 225 m1/ min
`••too to 150 mg/min
`1! to 20 mg/kg
`phenytoln
`.. theoretical: phenytoin caMot 11fely be delivered at thia rate; 50
`mg/ min ii the maximum recommended rate.
`
`Study 98224 1how1 Carebyx• and Dllanttn• btoequtvalent under th• Iv
`loading infu1ion regimen employed (l.1., ••• the table above).
`It beara
`repetition that this regimen 11 lnt1nd1d tor u11 when phtnytoln la being
`administered intravenoualy to a patient In 1tatu1 epll1ptlou1: thl1 la the
`only cllnlcal aettlng, In our Judgment, In which a d•cre111 In the rate of
`ayatemlc phanytoln delivery might have an advaraa effect on ottntcal
`In all other 11ttlng1, we 111ume that It ta the extent, not the
`outcome.
`rate, of phenytoln d1Uv1ry that '' oontrolllng.
`
`A dlgreuion about the method UNd to aaaeu the relative rate at which
`Cerebyxtt and Dilantin• infuaiona deliver free phenytoin ia uaeful here.
`When drugs are adminiatertd by coNtant intravenous infusion, the Cmax
`and Tmax occur typically at the end of the infualon and the realized values of
`these parameter 11timat11 are controlled, other variables held constant, by
`both the total dose and tht rate of delivery of that doY.
`
`In ordinary circumatancu, therefore, the administration ol two dru1 productl
`that yield the 1am1 molar amounta of the same dru& 1ub1tanc1 caMot
`po11ibly generate bloequlvalent delivery proftlea if they are 1dmini1t1red at
`
`

`

`Leber: C1rebyx• (phoapJ\lnytoln Injection] 1pprov1bl1 action
`
`PIQI 8
`
`difNrtnt rate1 of infuaion. The 1ituation ia different where Cartbyx9 and
`Oilantin'I are concerned, however.
`
`A number of events and phenomena, including fosphenytoin protein
`binding, foaphenytoin hydrolyaia, phenytoin protein binding, and phenytoin
`di1placement from protein boW\d 1lte1 affect fhe rate at which CerebyXCS
`infusion d1Uv1r1 frn phtnytoin. Al 1 coauequence, Cereby~ mu1t be
`1dmini1ttr1d at a f11t1r rate than Dilantif\9 injection to deliver free
`phenytoin at an equJvalent rate and extent.
`The parameter employed to compare the pace of tree phenytoin deUvtry b/
`the two productl i1 the ratio of their cumulative AUC1 for fr•• phtnytoln.
`Thi ratio la obtained by dividing the cumulative AUC for frt1 phtnytoln at
`aom1 time, t, followina tht 1t1rt of the inlualon of C1r1by_., by tht
`c:umwative AUC for fr• phenytoin at th• Nmt timt, t, followln9 the 1tart of
`an infualon of DUantin• injection. II the two product• deliver free phenytoln
`at the 11m1 rate, the ratio will b• unity at all tlm11.
`
`..
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`
`l.ft
`
`The Dtvt1ton'1 con1ult1nt btopnarmaceuttcat review team ha• evaluated
`th• firm'• report of Study 88224 and conotud11 that It dooum1nt1 that a
`
`

`

`Leber: Cerebyx• [phoaphenytoin inJ1ction) approvabfe action
`
`...
`
`page 7
`
`doae of 1200 mg PE of f 01ph1nyto1n1 delivered lntravenoualy at a rate of
`1 SO mg ~l!/mln produc11 the 1am1 cumulative free phenytoln AUC over
`ttma 11 • do•• of 1200 mg of pnenytoin .d•llv1red at 50 mg/min.
`
`Even In 1tudy 88224, however, th• performance of thu two product1 11 not
`pr1ol1ely identical throughout the entire po1t·do1lng Interval 11 the plot
`of th• ratio of th• cumulative tree phenytoln AUC demon1trate1 (••• the
`figure on the preceedlng page which 11 rtproduotd from the top panel of
`Flgure 13 on page 12 of th• 12121195 blopharm review).
`In 1hort, even In
`thla atudy, the techntcat declaratton of bto1qutv1t1no1 11 1om1wh1t
`arbitrary 11 tt tum1 on the time after the start of lntualon that 11 cho1en
`tor th• 1valu1tlon of th• cumulMtive AUC ratio.
`
`In this regard, It 11 Important to note th1t th• regimen ••l•ct•d for
`
`C1r1byx• lntualon 1n1ur11 that In comp1rt1on to Dltantln• more, rather
`than I••• free ph1nytotn, 11 g1nerat1d 11rty on In the oour1e of th•
`lnfualon (e.g., from 10 to 30 minute• or 10), th• very pertod In whloh It 11
`deemed crltlcally Important trom a cllntoal per1peotlv1 to 1n1ur1 the
`rapid dellv1ry of blo1v1U1bl1 ph1nytoln.
`
`11t1tr In u11; 1p1olflo
`
`l11y11.
`
`Whether or not toaphenytoln 11 aaf• In u11 cannot r11t on th• knowledge
`lecauH to1phenytoln 11 not onty a
`that ph1nytoln 11 a 1af1 drug, howev•r.
`prod rug for phenytoln but for pho1ph•t1• and f orm1ld1hydelform1t1•, the
`rl1k1 that might be u1ocl1ted with the par1nt1r11 admlnl1tratlon of
`th111 product• under th• oondltlona of uae recommended In Cerabyx
`labeling muat bt con1ld1rld.
`
`Both Dr. Edward Pl1h1r, th• prtmary reviewing phann1oologl1t, and Dr.
`John F11ney, th• neurology group ollnloal reviewer r11pon1lble for the
`
`e 20 ms/kg given to a 60 kg patient r11ult1in1200 mg total dole
`
`• Bach molar unit of foaphenytotn forma equimolat unitl of phoaphatt and
`formaldehyde. Porm1ld1hyd1 i1 then converted to formate whlc:h i1 then converted
`to C~ and Hi() by I folatt d1ptnd1nt 1ttp.
`
`

`

`Leber: Cerebyx• (phoaphanytoln Injection) approvable action
`
`page 8
`
`. . I
`
`appllcatlon, dl1cu11 rt1k1 that might dertve from th• generation of the
`byproduct• of foaphenytoln hydrolyala.
`
`It 11 Important to acknowledge at the outaet that concem1 about the
`potential rlaka poaed by the11 byproduote art11 for theoretical re11on1:
`there are no finding• of 1ertou1 Injury or toxicity in either ollnlcal or
`precllnlcal te1t1 with f oephenytoln that indicate that eith•r f ormat1 or
`pho1phat• dertved from f 01phenytoln admlnlatratlon h11 actually caused
`hann.
`
`On th• other aide of aotn, however, a ay1t1matlc effort to detect toxicity
`that might have been 01u11d by th111 byproduot1 (partloularty formate)
`h11 not been earned out either In 1nlm1t1 or hum1n1. Perh1p1 more
`Important 11 a r1a1on for caution, th• extent of cllnlcal 1xpo1ur1 to
`Cerebyx• at the hlgh11t do111 and r1t11 of d1llv1ry 11 Hmlt1d7 and,
`accordingly, th• warrant provtdet. by th• 1b11na. of 1vld1nc1 of hann ta
`
`I••• than robust.
`
`formate: th• rl1k of gcylar Injury
`
`Although no reports of bUndne11 or dlmlnl1h1d vl1lon have been reported
`In 111oclatlon wtth th• cUnlcal te1tlng of Cerebyx, formate, a known
`mammalian ocular toxin• 11 a by product of fo1ph1nytoln hydroly111. A1
`much 11 ti mmolee of f ormat1 may be delivered within 7 minute• under the
`regimen r1comm1nded for Cerebyx• In th• management of 1tatu1
`1pH1ptiou1 (SE].
`
`Although the firm had been repeatedly 1dvl11d of our concem about th•
`potential rt1k posed by formate 1xpo1ur1, tt h11 yet to provide a
`1y1t1matlc evaluation of the extent of, and varlablllty In, formate
`
`7 Only 128 patientl have bHn t>epoud to dOlll of greater than 15 mg PB/kg
`at an infuaion ratea of~ 150 mg PB/min and only 66 patient& at thll rate and the
`higher doae of 20 mg PB/kg.
`-
`
`• Studi•• in monkey• doeument that formate level• •• low •• 1 MMOL/L can
`cauN optic nerve damage; formate ii preawnably the agent immediately ruponaible
`for the bUndneu that la 11toclattd with methanol lngeation
`
`

`

`Leber: Cerebyx• (phoaphenytoln Injection] approvabte action
`
`...
`
`pagtt 9
`
`In f aot, only
`generation tollowlng Intravenous loading with foaphenytoln.
`4 patients have had formate levels maaaured, and then during lnfu1ion1
`that delivered only one-half the load of .t oaphanytoln recommended for the
`treatment of status eplleptlcua.
`
`Aleo, •inc• the metabollem of formate 11 folate dependent, and a
`substantive proportion of pattenta with 1tatu1 eplleptlcua may be folate
`deficient (1.g., alcohollca), the l11ue 11 not only the extent of monitored
`expertenca, but the collateral condltlona under which exposure has taken
`place.
`
`The rl1k 111111m1nt proce11 11 further complicated by the 1par1ena11 of
`the information available from precllnloal models.
`At present, we
`believe (know) that expoaurea 11 tow 7 MMOUL can cauae ocular damage tn
`monkey•, but do not know whether or not lower expo1ure1 can.
`
`On the other hand, Dr. Fl1h1r point• out that 1u1talned expo1ur11 to
`elevated level• of formate are probably required to cau11 Injury tn humane
`and that the firm did estimate, b111d on data avallable from other
`1ouro11, the likely lncr1m1nt In 11rum formate that would follow an
`Inf u11on of formate equivalent to that deUvered by the maximum
`recommended doae of foaphenytoln, and that 1uch an Input would be
`unlikely to raise formate le vela above backpround, let alone produce tho••
`known to cau1e Injury.
`
`Accordingly, In my view, conc1m1 about formate are not of a oonoem vie a
`via the approvablllty of Cerebyx, although they probably require mention In
`labeling, unleaa the firm can provide either argument or data, or both to
`convince us such mention la unnec111ary.
`
`Bl•kl gt 1 gbo1pb1te load.
`
`Dr. Feeney draws attention to the rt1k1 that might follow rapid IV
`admtntatratton of a pho1phat1 load.
`Both 11rum Ionized calcium l1v111
`and pH may be affected, but neither have been 1y1tematlcally monitored by
`the 1pon1or. Al with the concern• dl1cu111d In regard to formate, I
`believe we ought to require mention of th• po11tblllty of th••• eff1ot1 in
`l1b1llng unl111 the 1pon1or can provide evidence or argument to 1how that
`
`

`

`Labor: Cerebyxt> [phosphenytoin injection) approvabla action
`
`...
`
`page 10
`
`such labeling statement& are unnecessary.
`
`Systemic sensations
`
`In his review, Dr. Feeney discusses a set of 1enaatton1 that are associated
`with Infusion of Cerebyx (burnlng/prurltu1 affecting the extremities, the
`groin and In part-rectal araaao): aince th••• are not observed with
`phenytoln Infusion, it la logical that they are the r11ult of aome unique
`property of fosphenytoln, ite byproducts, or some 1econdary phenomena
`arising from their Introduction Into the 1y1temlc clrculatton.
`
`Phosphate, for example, might act directly or Indirectly through an effect
`on serum Calcium levela.
`The u1ual 1lgns/1ymptom1 of tetany (pert-oral
`dyatheslas, tingling In the distal extremities, etc.), however, do seem
`dl1tlngui1hable from tho•• 111octated with foaphenytoln lnfu1lon;
`nonetheleaa, the pcsslblllty that changes In serum Calcium are 'nvolved
`cannot be dismissed out-of·hand.
`
`The bottom line, however, la that our ability to 111e11 any hypothe1l1
`regarding the cau1e of th••• phenomena 11 limited by the mlnlmal
`monitoring of aerum for