.
`
`'1. of control
`
`1200 7
`
`._
`
`
`.CLO‘IOOpM
`
`I Comm _
`
`I Modunawm
`
`.Modainiioom
`D‘Alodainfliooow
`IS-Mcsw
`
`EPBaooouM
`
`.RFSOyM
`
`J'MC ”WW
`PB
`-Pb¢noba.rbiul
`RIF
`ifibmpicin
`CLO clofibn‘ctdd
`
`
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

` .
`
`$6 oféomml
`400 -
`
`350 +
`
`250 -
`2m T
`150 -
`'°° -'
`-
`$0
`o
`
`1‘.
`
`*-
`
`n
`
`,S
`if.
`§
`ESE
`i-l-f
`1‘ 2:4
`‘23.
`fig-z." »
`5
`
`'5’:
`‘
`_
`£15:
`
`
`H97
`H100
`Hanan donor
`
`.
`
`H94
`
`
`
`
`
`
`
`J-MC :J-mahyicbolznthm
`PB
`:prnotnrbiul
`REF
`:fifampidn
`CLO :clofibn‘c and
`
`8.9 - Launc aad hydroxylasc acnvny.
`a 72 hour Incubation penod m the presence of modafiml (Mod:
`
`mduccrs
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

` .
`
`
`
`Gélincau’s 5y
`
`Observation
`
` .
`
`
`
` .
`
`, rgsidual Hood level ofCsA tail 10 :30 ng/ml (SYVA
`'
`n latencies. and
`
` WMum 8
`
`«WM
` .
` .
`
`
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`BESTPOSF
` .
`BEST POSSIBLE COPY
`
`
`

`

` .
`
`
`
`Table I
`Evolution of cyddsperine (CsA) blood levels
`'
`u a function of time
`
`Time
`
`‘
`
`‘
`
`to
`t1
`12
`M
`t6
`t8
`
`'
`
`_
`
`CIA
`(”8"”)
`80
`>1000
`385
`185
`10!
`84
`
`\
`
`These figures confirm that the reduction in the t. - and the necessuy increase in posoiogy
`which followed - is definitely linked to an acceleration of the metabolism and not to reduced
`bioavailability. This obscrution serves as a reminder, should such a reminder still be necessary,
`that any modification in treatment in a transplant recipient must be £13110ch by systematic testing
`of ihe kidney function and of the blood lcvelof CaA.
`
`[Illeg]. Clinical evaluation ofdrug interactions ofcyclosporino. Pres: Med i988:
`
`l. Eilleud EM.
`17:2293-[mog].
`2. 130th DE. Montpleisir J, Pctit D, Lemben C. Rubin 8. Effects ofmodnfinil on syniptometelegy of
`human narcolepsy. Clm Neurapharmacol 1992: 16: 46.53.
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
` .
`
`

`

`_..._ -._._A..‘-..-_4‘_:-A _@_ma-w_3.;. .:a.,,.z_a,_..-
`
`‘
`
`.
`
`.e
`
`.
`
`.V a
`
`Objectives“. This study was designed to first ascertain whether or nbt the tablet treatments
`_ A, B, and C‘ofmodafinil were bioequivalent. The second objective ofthe study was to
`determine the relative bioavailabilities ofthe modafinil tablet treatments A. B. and C
`versus an aqueous suspension, treatment D.
`
`
`
`-FKl; used in clinical
`
`Test Treatment
`
`Methods: This study used a single-center. open. randomized, 4 x 4 Latin Square
`crossover design in healthy male volunteers. All volunteers were dosed with 200 mg of
`modafinil on 4 occasions during 4 treatment periods, which were:
`I
`
`Reference Treatment
`
`
`reatment A
`'
`-
`(mart. Fem/c6.
`‘
`
`
`2 x 100 mg modafinil tablets (Lot No. l538-FL5; commercial
`Test Treatment
`
`
`
`1 x 200 mg modafinil caplets (Lot No. 1538-FL6; conunercial
`
`
` cension vehicle
`
` .
`-
`
`
`
`
`
`
`Aqueous Suspension
`Treatment D
`
`
`
`Modafinil pharmacokinetics.for each treatment were evaluated after administration ofa
`single oral dose to 24 volunteers aged between 18 and 45 years and within 15% ofideal
`body weight. Following overnight fasting, modafinil (a caplet or two tablets) was
`administered as a single 200 mg dose with 180 mL water on each dosingeccasion. For
`. 30 mL ofan aqueous suspension containing 200 mg ofmoda‘inil in a glass
`was ingested in one swallow. The glass was thoroughly rinsed with 30 mL of water for 3
`times to remove the residual suspension from the glass. Following each rinse. the
`volunteer drank the rinsed suspension. There was at least a 6-day wash-out period
`between dosing of any of the 2 treatments.
`
`»
`
`“1
`
`( .
`
`Blood samples (1x10 ml.) for preparation ofplasma were collected into lithium heparin
`Vacutainer tubes“by venipuncture ofthe antecubital veins immediately before dosing and
`f ”0.5.1'2‘3‘4;
`~~
`._...
`,.
`..
`.
`‘
`'
`6. 9. 12. 24. 36. and 48 hours (hr) est-dasf In each treatment pefiocL 32
`BEST POSSIBLE COPY
`BEST POSSIBL C0
`
`
`

`

`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`33
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`
`
`

`

`1"" 190mm; r A"I8
`“’5an and Statistical
`
`
`
`98.7-104
`
`98.9-104
`
`96.2 - 106
`
`
`
`' NA; " not applicable
`" Terminal half-life.
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

` .
`
`
`
`I
`
`
`
`T‘ME (HOURS)
`
`e H CONTROL2X100
`E
`B B TEST2x1oa
`
`m SUSPENSION
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

` .
`
`
`
`SUSPENSION
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`
`
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`

`

`
`
`BEST POSSIBLE COPY
`
`

`

`Appendix E. PK Labeling Proposed By the Sponsor
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`
`

`

`
`
`
`
`
`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`

`

`APPENDIX F. STUDIES NOT REVIEWED
`
`
`
`BEST. POSSIBLE COPY
`BEST POSSIBLE COPY
`
`1
`
`

`

`
`
`
`
`BEST POSSIBLE COPY
`
`

`

`(.
`
`OCT 27 [998
`QmWWmW—MIWW
`
`' “megawatts 001291998 ’
`
`NDA 20-717
`
`PROVIGIL® (Modafinil)
`(100 mg, 200 mg)
`
`Type of submission: Amendment
`Submission Date: March 30, 1998
`
`
`
`Sponsor: Cephalon Inc., West Chester, PA
`INDICATION: Narcolepsy -
`T
`REVIEWER: Rae Yuan, Ph.D._=
`
`‘
`
`:
`
`,
`
`_
`
`,
`
`_
`
`‘
`
`-:
`
`,__
`
`»
`
`'
`
`A,
`
`This submission is a response to the approvable letter from our agency dated December
`29, 1997. Two issues have been responded to in the submission: 1) interconversion ’
`between the enantiomers of modafil, and 2) drug interaction of modafinil with other
`major metabolic enzymes, specifically, CYP2C19 and CYP3A. On Sept 23, 1998, a
`meeting between the sponsor and the agency was held to discuss further evaluations on
`drug—drug interactions. Three drug interaction studies were proposed and discussed
`during the meeting:
`.
`
`7
`
`‘
`
`.
`
`f ‘
`
`'
`
`'
`
`-'
`( ‘
`
`1)
`
`In vitro study ofmodafinil and modafinil sulfone effects on CYP2C19 substrate
`(clomipramine) metabolism in microsomes obtained from CYP2D6 poor-
`metabolizers, extensive-metabolizers and super-metabolizers;
`2) Clinical study of modafinil effect on CYP3A4 substrate, ethinylestradiol;
`3) Clinical study of modafinil effect on CYP2C9 substrate, S-Warfarin. ‘
`
`
`
`The rationales for studies ( 1) and (2) were based on previous in vitro evidence and case
`reports (see OCPB review dated Nov 17, 1997 for details). The inhibitory effect of
`modafinil on CYP2C9, as stated by the sponsor during the September meeting, was
`discovered recently in an in vitro study (data not submitted yet).
`
`The outline of these three studies has been reviewed. The concerns of the reviewer on the
`studies were communicated to the sponsor during the meeting, especially regarding the
`specificity of using ethinylestradiol as an in vivo CYP3A4 substrate. Additional
`CYP3A4 substrate, midazolam, was suggested by the reviewer during the meeting. The
`sponsor agreed to submit a detailed study protocol for review.
`
`— »
`
`,
`
`Comment:
`
`The enantiomer issue was discussed within the OCPB review team. We conSider the
`sponsor’s response is acceptable.
`a"?
`g
`' 5.331;
`.
`‘
`
`
`
`k
`*B'EST ~i5CSSSIBLE 66pr _
`BEST POSSIBLE COPY
`
`
`
`

`

`(
`
`Recommendations:
`The sponsor has designed three drug interaction studies to address the concerns raised in
`agency’s Dec 29‘'1 letter. The three proposed studies are acceptable, provided that the
`study protocol (to be submitted in the fixture) incorporates the reviewer’s comments. The
`response to the enantiomer issue and dissolution change is acceptable.
`
`Rae Yuan, Ph.D.
`
`/S/
`
`9”
`
`_Team Leader: Chandra Sahajwalla, PhD.
`
`/S/
`
`Date of Signature:
`
`[6 [7,1 IT?
`
`Office of Clinical Pharmacology and Biophannaceutics/Division I
`
`cc list: rim-120; Cso; HFD-860 (Yuan, Sahajwalla, Mehta); CDR (Barbara Murphy)
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`Basaaaaaae"c6w
`BEST POSSIBLE COPY
`
`
`