`
`x
`x
`
`x
`
`+,*+/,*+76 2) 35(6&5,%,1* ,1)250$7,21
`7KHVH KLJKOLJKWV GR QRW LQFOXGH DOO WKH LQIRUPDWLRQ QHHGHG WR XVH
`725,6(/ VDIHO\ DQG HIIHFWLYHO\ 6HH IXOO SUHVFULELQJ LQIRUPDWLRQ IRU
`725,6(/
`
`725,6(/ .LW WHPVLUROLPXV
LQMHFWLRQ IRU LQWUDYHQRXV XVH
`,QLWLDO 86 $SSURYDO
`²²²²²²²²² 5(&(17 0$-25 &+$1*(6 ²²²²²²²²
`:DUQLQJV DQG 3UHFDXWLRQV 3URWHLQXULD DQG 1HSKURWLF 6\QGURPH
`,QLWLDO 86 $SSURYDO
`²²²²²²²²² 5(&(17 0$-25 &+$1*(6 ²²²²²²²²
`:DUQLQJV DQG 3UHFDXWLRQV 3URWHLQXULD DQG 1HSKURWLF 6\QGURPH
`:DUQLQJV DQG 3UHFDXWLRQV (PEU\R)HWDO 7R[LFLW\
`
`
`²²²²²²²²² ,1',&$7,216 $1' 86$*( ²²²²²²²²²
`725,6(/ LV D NLQDVH LQKLELWRU LQGLFDWHG IRU WKH WUHDWPHQW RI DGYDQFHG UHQDO
`FHOO FDUFLQRPD
`²²²²²²² '26$*( $1' $'0,1,675$7,21 ²²²²²²²
`7KH UHFRPPHQGHG GRVH RI 725,6(/ LV PJ DGPLQLVWHUHG DV DQ
`x
`LQWUDYHQRXV LQIXVLRQ RYHU D PLQXWH SHULRG RQFH D ZHHN 7UHDW XQWLO
`GLVHDVH SURJUHVVLRQ RU XQDFFHSWDEOH WR[LFLW\
`$QWLKLVWDPLQH SUHWUHDWPHQW LV UHFRPPHQGHG
`'RVH UHGXFWLRQ LV UHTXLUHG LQ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW
`
`725,6(/ WHPVLUROLPXV
LQMHFWLRQ YLDO FRQWHQWV PXVW ILUVW EH GLOXWHG
`ZLWK WKH HQFORVHG GLOXHQW EHIRUH GLOXWLQJ WKH UHVXOWDQW VROXWLRQ ZLWK
` P/ RI 6RGLXP &KORULGH ,QMHFWLRQ
`ZLWK WKH HQFORVHG GLOXHQW EHIRUH GLOXWLQJ WKH UHVXOWDQW VROXWLRQ ZLWK
` P/ RI 6RGLXP &KORULGH ,QMHFWLRQ
`
`
`²²²²²²² '26$*( )2506 $1' 675(1*7+6 ²²²²²²²
`725,6(/ LQMHFWLRQ PJP/ VXSSOLHG ZLWK ',/8(17 IRU 725,6(/
`
`²²²²²²²²²² &2175$,1',&$7,216 ²²²²²²²²²
`725,6(/ LV FRQWUDLQGLFDWHG LQ SDWLHQWV ZLWK ELOLUXELQ ! î8/1
`
`²²²²²²² :$51,1*6 $1' 35(&$87,216 ²²²²²²²²
`+\SHUVHQVLWLYLW\,QIXVLRQ 5HDFWLRQV LQFOXGLQJ VRPH OLIHWKUHDWHQLQJ DQG
`x
`UDUH IDWDO UHDFWLRQV
FDQ RFFXU HDUO\ LQ WKH ILUVW LQIXVLRQ RI 725,6(/
`3DWLHQWV VKRXOG EH PRQLWRUHG WKURXJKRXW WKH LQIXVLRQ
`3DWLHQWV VKRXOG EH PRQLWRUHG WKURXJKRXW WKH LQIXVLRQ
`7R WUHDW K\SHUVHQVLWLYLW\ UHDFWLRQV VWRS 725,6(/ DQG WUHDW ZLWK DQ
`DQWLKLVWDPLQH 725,6(/ PD\ EH UHVWDUWHG DW SK\VLFLDQ GLVFUHWLRQ DW D
`VORZHU UDWH
`+HSDWLF ,PSDLUPHQW 8VH FDXWLRQ ZKHQ WUHDWLQJ SDWLHQWV ZLWK PLOG
`KHSDWLF LPSDLUPHQW DQG UHGXFH GRVH
`+\SHUJO\FHPLD DQG K\SHUOLSLGHPLD DUH OLNHO\ DQG PD\ UHTXLUH WUHDWPHQW
`0RQLWRU JOXFRVH DQG OLSLG SURILOHV
`,QIHFWLRQV PD\ UHVXOW IURP LPPXQRVXSSUHVVLRQ
`
`x
`
`x
`
`x
`
`x
`
`x 0RQLWRU IRU V\PSWRPV RU UDGLRJUDSKLF FKDQJHV RI LQWHUVWLWLDO OXQJ
`GLVHDVH ,/'
,I ,/' LV VXVSHFWHG GLVFRQWLQXH 725,6(/ DQG FRQVLGHU
`XVH RI FRUWLFRVWHURLGV DQGRU DQWLELRWLFV
`XVH RI FRUWLFRVWHURLGV DQGRU DQWLELRWLFV
`%RZHO SHUIRUDWLRQ PD\ RFFXU (YDOXDWH IHYHU DEGRPLQDO SDLQ EORRG\
`VWRROV DQGRU DFXWH DEGRPHQ SURPSWO\
`5HQDO IDLOXUH VRPHWLPHV IDWDO KDV RFFXUUHG 0RQLWRU UHQDO IXQFWLRQ DW
`EDVHOLQH DQG ZKLOH RQ 725,6(/
`'XH WR DEQRUPDO ZRXQG KHDOLQJ XVH 725,6(/ ZLWK FDXWLRQ LQ WKH
`SHULRSHUDWLYH SHULRG
`3URWHLQXULD DQG QHSKURWLF V\QGURPH PD\ RFFXU 0RQLWRU XULQH SURWHLQ
`SULRU WR WKH VWDUW RI 725,6(/ WKHUDS\ DQG SHULRGLFDOO\ WKHUHDIWHU
`'LVFRQWLQXH 725,6(/ LQ SDWLHQWV ZLWK ZKR GHYHORS QHSKURWLF
`V\QGURPH
`/LYH YDFFLQDWLRQV DQG FORVH FRQWDFW ZLWK WKRVH ZKR UHFHLYHG OLYH
`YDFFLQHV VKRXOG EH DYRLGHG
`(PEU\R)HWDO 7R[LFLW\ &DQ FDXVH IHWDO KDUP $GYLVH SDWLHQWV RI WKH
`SRWHQWLDO KD]DUG WR WKH IHWXV DQG WR XVH HIIHFWLYH FRQWUDFHSWLRQ
`
`(OGHUO\ SDWLHQWV PD\ EH PRUH OLNHO\ WR H[SHULHQFH FHUWDLQ DGYHUVH
`UHDFWLRQV LQFOXGLQJ GLDUUKHD HGHPD DQG SQHXPRQLD
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`
`²²²²²²²²²²² $'9(56( 5($&7,216 ²²²²²²²²²
`7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH
DUH UDVK DVWKHQLD
`PXFRVLWLV QDXVHD HGHPD DQG DQRUH[LD 7KH PRVW FRPPRQ ODERUDWRU\
`DEQRUPDOLWLHV LQFLGHQFH
`PXFRVLWLV QDXVHD HGHPD DQG DQRUH[LD 7KH PRVW FRPPRQ ODERUDWRU\
`DEQRUPDOLWLHV LQFLGHQFH
DUH DQHPLD K\SHUJO\FHPLD K\SHUOLSLGHPLD
`K\SHUWULJO\FHULGHPLD HOHYDWHG DONDOLQH SKRVSKDWDVH HOHYDWHG VHUXP
`FUHDWLQLQH O\PSKRSHQLD K\SRSKRVSKDWHPLD WKURPERF\WRSHQLD HOHYDWHG
`$67 DQG OHXNRSHQLD
`K\SHUWULJO\FHULGHPLD HOHYDWHG DONDOLQH SKRVSKDWDVH HOHYDWHG VHUXP
`FUHDWLQLQH O\PSKRSHQLD K\SRSKRVSKDWHPLD WKURPERF\WRSHQLD HOHYDWHG
`$67 DQG OHXNRSHQLD
`
`7R UHSRUW 6863(&7(' $'9(56( 5($&7,216 FRQWDFW :\HWK
`3KDUPDFHXWLFDOV ,QF DW RU )'$ DW )'$ RU
`ZZZIGDJRYPHGZDWFK
`
`²²²²²²²²²² '58* ,17(5$&7,216 ²²²²²²²²²²
`6WURQJ LQGXFHUV RI &<3$ DQG LQKLELWRUV RI &<3$ PD\ DIIHFW
`FRQFHQWUDWLRQV RI WKH SULPDU\ PHWDEROLWH RI 725,6(/ ,I DOWHUQDWLYHV FDQQRW
`EH XVHG GRVH PRGLILFDWLRQV RI 725,6(/ DUH UHFRPPHQGHG
`
`²²²²²²²²86( ,1 63(&,),& 3238/$7,216
`/DFWDWLRQ 'R QRW EUHDVWIHHG
`
`6HH IRU 3$7,(17 &2816(/,1* ,1)250$7,21
`
`
`
`5HYLVHG
`
`)8// 35(6&5,%,1* ,1)250$7,21 &217(176
` ,1',&$7,216 $1' 86$*(
` '26$*( $1' $'0,1,675$7,21
` $GYDQFHG 5HQDO &HOO &DUFLQRPD
`
` 3UHPHGLFDWLRQ
`
` 'RVDJH ,QWHUUXSWLRQ$GMXVWPHQW
`
` 'RVH 0RGLILFDWLRQ *XLGHOLQHV
`
` ,QVWUXFWLRQV IRU 3UHSDUDWLRQ
`
` $GPLQLVWUDWLRQ
`
` '26$*( )2506 $1' 675(1*7+6
` &2175$,1',&$7,216
` :$51,1*6 $1' 35(&$87,216
` +\SHUVHQVLWLYLW\,QIXVLRQ 5HDFWLRQV
` +HSDWLF ,PSDLUPHQW
` +\SHUJO\FHPLD*OXFRVH ,QWROHUDQFH
` ,QIHFWLRQV
` ,QWHUVWLWLDO /XQJ 'LVHDVH
` +\SHUOLSLGHPLD
` %RZHO 3HUIRUDWLRQ
` 5HQDO )DLOXUH
` :RXQG +HDOLQJ &RPSOLFDWLRQV
` ,QWUDFHUHEUDO +HPRUUKDJH
` 3URWHLQXULD DQG 1HSKURWLF 6\QGURPH
` &RDGPLQLVWUDWLRQ ZLWK ,QGXFHUV RU ,QKLELWRUV RI &<3$ 0HWDEROLVP
` &RQFRPLWDQW XVH RI 725,6(/ ZLWK VXQLWLQLE
` 9DFFLQDWLRQV
` (PEU\R)HWDO 7R[LFLW\
` (OGHUO\ 3DWLHQWV
`
` $'9(56( 5($&7,216
` &OLQLFDO 7ULDOV ([SHULHQFH
`
` 3RVWPDUNHWLQJ DQG 2WKHU &OLQLFDO ([SHULHQFH
`
` '58* ,17(5$&7,216
` $JHQWV ,QGXFLQJ &<3$ 0HWDEROLVP
` $JHQWV ,QKLELWLQJ &<3$ 0HWDEROLVP
` $QJLRHGHPD ZLWK $&( LQKLELWRUV DQG &DOFLXP &KDQQHO %ORFNHUV
` 86( ,1 63(&,),& 3238/$7,216
` 3UHJQDQF\
`
` /DFWDWLRQ
`
` )HPDOHV DQG 0DOHV RI 5HSURGXFWLYH 3RWHQWLDO
`
` 3HGLDWULF 8VH
`
` *HULDWULF 8VH
`
` 5HQDO ,PSDLUPHQW
`
` +HSDWLF ,PSDLUPHQW
`
` 29(5'26$*(
` '(6&5,37,21
` &/,1,&$/ 3+$50$&2/2*<
` 0HFKDQLVP RI $FWLRQ
`
` 3KDUPDFRG\QDPLFV
`
` 3KDUPDFRNLQHWLFV
`
` 121&/,1,&$/ 72;,&2/2*<
` &DUFLQRJHQHVLV 0XWDJHQHVLV ,PSDLUPHQW RI )HUWLOLW\
` &/,1,&$/ 678',(6
` 5()(5(1&(6
` +2: 6833/,('6725$*( $1' +$1'/,1*
` 3$7,(17 &2816(/,1* ,1)250$7,21
` 6HFWLRQV RU VXEVHFWLRQV RPLWWHG IURP WKH IXOO SUHVFULELQJ LQIRUPDWLRQ DUH QRW
`OLVWHG
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`)8// 35(6&5,%,1* ,1)250$7,21
`,1',&$7,216 $1' 86$*(
`
`
`725,6(/ LV LQGLFDWHG IRU WKH WUHDWPHQW RI DGYDQFHG UHQDO FHOO FDUFLQRPD
`
` '26$*( $1' $'0,1,675$7,21
`
` $GYDQFHG 5HQDO &HOO &DUFLQRPD
`
`7KH UHFRPPHQGHG GRVH RI 725,6(/ IRU DGYDQFHG UHQDO FHOO FDUFLQRPD LV PJ DGPLQLVWHUHG DV DQ
`LQWUDYHQRXV LQIXVLRQ RYHU D ± PLQXWH SHULRG RQFH D ZHHN
`
`7UHDWPHQW VKRXOG FRQWLQXH XQWLO GLVHDVH SURJUHVVLRQ RU XQDFFHSWDEOH WR[LFLW\ RFFXUV
`
` 3UHPHGLFDWLRQ
`
`3DWLHQWV VKRXOG UHFHLYH SURSK\ODFWLF LQWUDYHQRXV GLSKHQK\GUDPLQH WR PJ RU VLPLODU DQWLKLVWDPLQH
`DSSUR[LPDWHO\ PLQXWHV EHIRUH WKH VWDUW RI HDFK GRVH RI 725,6(/ [see Warnings and Precautions
`(5.1)]
`
` 'RVDJH ,QWHUUXSWLRQ$GMXVWPHQW
`
`725,6(/ VKRXOG EH KHOG IRU DEVROXWH QHXWURSKLO FRXQW $1&
PP SODWHOHW FRXQW PP
`RU 1&, &7&$( JUDGH RU JUHDWHU DGYHUVH UHDFWLRQV 2QFH WR[LFLWLHV KDYH UHVROYHG WR JUDGH RU OHVV
`725,6(/ PD\ EH UHVWDUWHG ZLWK WKH GRVH UHGXFHG E\ PJZHHN WR D GRVH QR ORZHU WKDQ PJZHHN
`
` 'RVH 0RGLILFDWLRQ *XLGHOLQHV
`
`+HSDWLF ,PSDLUPHQW 8VH FDXWLRQ ZKHQ WUHDWLQJ SDWLHQWV ZLWK KHSDWLF LPSDLUPHQW ,I 725,6(/ PXVW EH
`JLYHQ LQ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW ELOLUXELQ ! ± î8/1 RU $67 !8/1 EXW ELOLUXELQ
`8/1
`RU 1&, &7&$( JUDGH RU JUHDWHU DGYHUVH UHDFWLRQV 2QFH WR[LFLWLHV KDYH UHVROYHG WR JUDGH RU OHVV
`725,6(/ PD\ EH UHVWDUWHG ZLWK WKH GRVH UHGXFHG E\ PJZHHN WR D GRVH QR ORZHU WKDQ PJZHHN
`
` 'RVH 0RGLILFDWLRQ *XLGHOLQHV
`
`+HSDWLF ,PSDLUPHQW 8VH FDXWLRQ ZKHQ WUHDWLQJ SDWLHQWV ZLWK KHSDWLF LPSDLUPHQW ,I 725,6(/ PXVW EH
`JLYHQ LQ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW ELOLUXELQ ! ± î8/1 RU $67 !8/1 EXW ELOLUXELQ
`8/1
UHGXFH WKH GRVH RI 725,6(/ WR PJZHHN 725,6(/ LV FRQWUDLQGLFDWHG LQ SDWLHQWV ZLWK
`
`ELOLUXELQ !î8/1 [see Contraindications (4), Warnings and Precautions (5.2) and Use in Specific
`Populations (8.7)]
`
`&RQFRPLWDQW 6WURQJ &<3$ ,QKLELWRUV 7KH FRQFRPLWDQW XVH RI VWURQJ &<3$ LQKLELWRUV VKRXOG EH
`DYRLGHG HJ NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ DWD]DQDYLU LQGLQDYLU QHID]RGRQH QHOILQDYLU
`ULWRQDYLU VDTXLQDYLU WHOLWKURP\FLQ DQG YRULFRQD]ROH
`
`ELOLUXELQ !î8/1 [see Contraindications (4), Warnings and Precautions (5.2) and Use in Specific
`Populations (8.7)]
`
`&RQFRPLWDQW 6WURQJ &<3$ ,QKLELWRUV 7KH FRQFRPLWDQW XVH RI VWURQJ &<3$ LQKLELWRUV VKRXOG EH
`DYRLGHG HJ NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ DWD]DQDYLU LQGLQDYLU QHID]RGRQH QHOILQDYLU
`ULWRQDYLU VDTXLQDYLU WHOLWKURP\FLQ DQG YRULFRQD]ROH
*UDSHIUXLW MXLFH PD\ DOVR LQFUHDVH SODVPD
`FRQFHQWUDWLRQV RI VLUROLPXV D PDMRU PHWDEROLWH RI WHPVLUROLPXV
`FRQFHQWUDWLRQV RI VLUROLPXV D PDMRU PHWDEROLWH RI WHPVLUROLPXV
DQG VKRXOG EH DYRLGHG ,I SDWLHQWV PXVW EH
`FRDGPLQLVWHUHG D VWURQJ &<3$ LQKLELWRU EDVHG RQ SKDUPDFRNLQHWLF VWXGLHV D 725,6(/ GRVH UHGXFWLRQ
`WR PJZHHN VKRXOG EH FRQVLGHUHG 7KLV GRVH RI 725,6(/ LV SUHGLFWHG WR DGMXVW WKH $8& WR WKH UDQJH
`REVHUYHG ZLWKRXW LQKLELWRUV +RZHYHU WKHUH DUH QR FOLQLFDO GDWD ZLWK WKLV GRVH DGMXVWPHQW LQ SDWLHQWV
`UHFHLYLQJ VWURQJ &<3$ LQKLELWRUV ,I WKH VWURQJ LQKLELWRU LV GLVFRQWLQXHG D ZDVKRXW SHULRG RI
`DSSUR[LPDWHO\ ZHHN VKRXOG EH DOORZHG EHIRUH WKH 725,6(/ GRVH LV DGMXVWHG EDFN WR WKH GRVH XVHG SULRU
`WR LQLWLDWLRQ RI WKH VWURQJ &<3$ LQKLELWRU [see Warnings and Precautions (5.12) and Drug Interactions
`(7.2)]
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`FRDGPLQLVWHUHG D VWURQJ &<3$ LQKLELWRU EDVHG RQ SKDUPDFRNLQHWLF VWXGLHV D 725,6(/ GRVH UHGXFWLRQ
`WR PJZHHN VKRXOG EH FRQVLGHUHG 7KLV GRVH RI 725,6(/ LV SUHGLFWHG WR DGMXVW WKH $8& WR WKH UDQJH
`REVHUYHG ZLWKRXW LQKLELWRUV +RZHYHU WKHUH DUH QR FOLQLFDO GDWD ZLWK WKLV GRVH DGMXVWPHQW LQ SDWLHQWV
`UHFHLYLQJ VWURQJ &<3$ LQKLELWRUV ,I WKH VWURQJ LQKLELWRU LV GLVFRQWLQXHG D ZDVKRXW SHULRG RI
`DSSUR[LPDWHO\ ZHHN VKRXOG EH DOORZHG EHIRUH WKH 725,6(/ GRVH LV DGMXVWHG EDFN WR WKH GRVH XVHG SULRU
`WR LQLWLDWLRQ RI WKH VWURQJ &<3$ LQKLELWRU [see Warnings and Precautions (5.12) and Drug Interactions
`(7.2)]
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`&RQFRPLWDQW 6WURQJ &<3$ ,QGXFHUV 7KH XVH RI FRQFRPLWDQW VWURQJ &<3$ LQGXFHUV VKRXOG EH
`DYRLGHG HJ GH[DPHWKDVRQH SKHQ\WRLQ FDUEDPD]HSLQH ULIDPSLQ ULIDEXWLQ ULIDPSDFLQ SKHQREDUELWDO
,I
`SDWLHQWV PXVW EH FRDGPLQLVWHUHG D VWURQJ &<3$ LQGXFHU EDVHG RQ SKDUPDFRNLQHWLF VWXGLHV D 725,6(/
`GRVH LQFUHDVH IURP PJZHHN XS WR PJZHHN VKRXOG EH FRQVLGHUHG 7KLV GRVH RI 725,6(/ LV
`SUHGLFWHG WR DGMXVW WKH $8& WR WKH UDQJH REVHUYHG ZLWKRXW LQGXFHUV +RZHYHU WKHUH DUH QR FOLQLFDO GDWD
`ZLWK WKLV GRVH DGMXVWPHQW LQ SDWLHQWV UHFHLYLQJ VWURQJ &<3$ LQGXFHUV ,I WKH VWURQJ LQGXFHU LV
`GLVFRQWLQXHG WKH WHPVLUROLPXV GRVH VKRXOG EH UHWXUQHG WR WKH GRVH XVHG SULRU WR LQLWLDWLRQ RI WKH VWURQJ
`&<3$ LQGXFHU [see Warnings and Precautions (5.12) and Drug Interactions (7.1)]
`
` ,QVWUXFWLRQV IRU 3UHSDUDWLRQ
`725,6(/ LV D F\WRWR[LF GUXJ )ROORZ DSSOLFDEOH VSHFLDO KDQGOLQJ DQG GLVSRVDO SURFHGXUHV1
`
`725,6(/ PXVW EH VWRUHG XQGHU UHIULJHUDWLRQ DW ±& ±)
`SDWLHQWV PXVW EH FRDGPLQLVWHUHG D VWURQJ &<3$ LQGXFHU EDVHG RQ SKDUPDFRNLQHWLF VWXGLHV D 725,6(/
`GRVH LQFUHDVH IURP PJZHHN XS WR PJZHHN VKRXOG EH FRQVLGHUHG 7KLV GRVH RI 725,6(/ LV
`SUHGLFWHG WR DGMXVW WKH $8& WR WKH UDQJH REVHUYHG ZLWKRXW LQGXFHUV +RZHYHU WKHUH DUH QR FOLQLFDO GDWD
`ZLWK WKLV GRVH DGMXVWPHQW LQ SDWLHQWV UHFHLYLQJ VWURQJ &<3$ LQGXFHUV ,I WKH VWURQJ LQGXFHU LV
`GLVFRQWLQXHG WKH WHPVLUROLPXV GRVH VKRXOG EH UHWXUQHG WR WKH GRVH XVHG SULRU WR LQLWLDWLRQ RI WKH VWURQJ
`&<3$ LQGXFHU [see Warnings and Precautions (5.12) and Drug Interactions (7.1)]
`
` ,QVWUXFWLRQV IRU 3UHSDUDWLRQ
`725,6(/ LV D F\WRWR[LF GUXJ )ROORZ DSSOLFDEOH VSHFLDO KDQGOLQJ DQG GLVSRVDO SURFHGXUHV1
`
`725,6(/ PXVW EH VWRUHG XQGHU UHIULJHUDWLRQ DW ±& ±)
DQG SURWHFWHG IURP OLJKW 'XULQJ
`KDQGOLQJ DQG SUHSDUDWLRQ RI DGPL[WXUHV 725,6(/ VKRXOG EH SURWHFWHG IURP H[FHVVLYH URRP OLJKW DQG
`VXQOLJKW 3DUHQWHUDO GUXJ SURGXFWV VKRXOG EH LQVSHFWHG YLVXDOO\ IRU SDUWLFXODWH PDWWHU DQG GLVFRORUDWLRQ
`SULRU WR DGPLQLVWUDWLRQ ZKHQHYHU VROXWLRQ DQG FRQWDLQHU SHUPLW
`
`,Q RUGHU WR PLQLPL]H WKH SDWLHQW H[SRVXUH WR WKH SODVWLFL]HU '(+3 GLHWK\OKH[\O SKWKDODWH
`KDQGOLQJ DQG SUHSDUDWLRQ RI DGPL[WXUHV 725,6(/ VKRXOG EH SURWHFWHG IURP H[FHVVLYH URRP OLJKW DQG
`VXQOLJKW 3DUHQWHUDO GUXJ SURGXFWV VKRXOG EH LQVSHFWHG YLVXDOO\ IRU SDUWLFXODWH PDWWHU DQG GLVFRORUDWLRQ
`SULRU WR DGPLQLVWUDWLRQ ZKHQHYHU VROXWLRQ DQG FRQWDLQHU SHUPLW
`
`,Q RUGHU WR PLQLPL]H WKH SDWLHQW H[SRVXUH WR WKH SODVWLFL]HU '(+3 GLHWK\OKH[\O SKWKDODWH
ZKLFK PD\
`EH OHDFKHG IURP 39& LQIXVLRQ EDJV RU VHWV WKH ILQDO 725,6(/ GLOXWLRQ IRU LQIXVLRQ VKRXOG EH VWRUHG LQ
`ERWWOHV JODVV SRO\SURS\OHQH
`EH OHDFKHG IURP 39& LQIXVLRQ EDJV RU VHWV WKH ILQDO 725,6(/ GLOXWLRQ IRU LQIXVLRQ VKRXOG EH VWRUHG LQ
`ERWWOHV JODVV SRO\SURS\OHQH
RU SODVWLF EDJV SRO\SURS\OHQH SRO\ROHILQ
DQG DGPLQLVWHUHG WKURXJK
`SRO\HWK\OHQHOLQHG DGPLQLVWUDWLRQ VHWV
`
`725,6(/ PJP/ LQMHFWLRQ PXVW EH GLOXWHG ZLWK WKH VXSSOLHG GLOXHQW EHIRUH IXUWKHU GLOXWLRQ LQ
`6RGLXP &KORULGH ,QMHFWLRQ 863
`
`3OHDVH QRWH WKDW ERWK WKH 725,6(/ LQMHFWLRQ DQG GLOXHQW YLDOV FRQWDLQ DQ RYHUILOO WR HQVXUH WKH
`UHFRPPHQGHG YROXPH FDQ EH ZLWKGUDZQ
`
`)ROORZ WKLV WZRVWHS GLOXWLRQ SURFHVV LQ DQ DVHSWLF PDQQHU
`
`6WHS
`
`',/87,21 2) 725,6(/ ,1-(&7,21 0*0/ :,7+ 6833/,(' ',/8(17
`
`x (DFK 9LDO RI 725,6(/ WHPVLUROLPXV
`SRO\HWK\OHQHOLQHG DGPLQLVWUDWLRQ VHWV
`
`725,6(/ PJP/ LQMHFWLRQ PXVW EH GLOXWHG ZLWK WKH VXSSOLHG GLOXHQW EHIRUH IXUWKHU GLOXWLRQ LQ
`6RGLXP &KORULGH ,QMHFWLRQ 863
`
`3OHDVH QRWH WKDW ERWK WKH 725,6(/ LQMHFWLRQ DQG GLOXHQW YLDOV FRQWDLQ DQ RYHUILOO WR HQVXUH WKH
`UHFRPPHQGHG YROXPH FDQ EH ZLWKGUDZQ
`
`)ROORZ WKLV WZRVWHS GLOXWLRQ SURFHVV LQ DQ DVHSWLF PDQQHU
`
`6WHS
`
`',/87,21 2) 725,6(/ ,1-(&7,21 0*0/ :,7+ 6833/,(' ',/8(17
`
`x (DFK 9LDO RI 725,6(/ WHPVLUROLPXV
PXVW ILUVW EH PL[HG ZLWK P/ RI WKH HQFORVHG GLOXHQW 7KH
`UHVXOWDQW VROXWLRQ FRQWDLQV PJ P/ PJP/
`UHVXOWDQW VROXWLRQ FRQWDLQV PJ P/ PJP/
`
`x 0L[ ZHOO E\ LQYHUVLRQ RI WKH YLDO $OORZ VXIILFLHQW WLPH IRU WKH DLU EXEEOHV WR VXEVLGH 7KH VROXWLRQ
`VKRXOG EH FOHDU WR VOLJKWO\ WXUELG FRORUOHVV WR OLJKW\HOORZ VROXWLRQ HVVHQWLDOO\ IUHH IURP YLVXDO
`SDUWLFXODWHV
`
`7KH FRQFHQWUDWHGLOXHQW PL[WXUH LV VWDEOH EHORZ & IRU XS WR KRXUV
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`
`6WHS
`
`',/87,21 2) &21&(175$7(',/8(17 0,;785( :,7+ 62',80 &+/25,'(
`,1-(&7,21 863
`
`
`x :LWKGUDZ SUHFLVHO\ WKH UHTXLUHG DPRXQW RI FRQFHQWUDWHGLOXHQW PL[WXUH FRQWDLQLQJ WHPVLUROLPXV
` PJP/ DV SUHSDUHG LQ 6WHS IURP WKH YLDO LH P/ IRU D WHPVLUROLPXV GRVH RI PJ
DQG
`IXUWKHU GLOXWH LQWR DQ LQIXVLRQ EDJ FRQWDLQLQJ P/ RI 6RGLXP &KORULGH ,QMHFWLRQ 863
`
`x 0L[ E\ LQYHUVLRQ RI WKH EDJ RU ERWWOH DYRLGLQJ H[FHVVLYH VKDNLQJ DV WKLV PD\ FDXVH IRDPLQJ
`
`7KH UHVXOWLQJ VROXWLRQ VKRXOG EH LQVSHFWHG YLVXDOO\ IRU SDUWLFXODWH PDWWHU DQG GLVFRORUDWLRQ SULRU WR
`DGPLQLVWUDWLRQ 7KH DGPL[WXUH RI 725,6(/ LQ 6RGLXP &KORULGH ,QMHFWLRQ 863 VKRXOG EH SURWHFWHG
`IURP H[FHVVLYH URRP OLJKW DQG VXQOLJKW
`
` $GPLQLVWUDWLRQ
`
`x $GPLQLVWUDWLRQ RI WKH ILQDO GLOXWHG VROXWLRQ VKRXOG EH FRPSOHWHG ZLWKLQ VL[ KRXUV IURP WKH WLPH WKDW
`725,6(/ LV ILUVW DGGHG WR 6ROXWLRQ &KORULGH ,QMHFWLRQ 863
`
`x 725,6(/ LV DGPLQLVWHUHG DV DQ LQWUDYHQRXV LQIXVLRQ RYHU D WR PLQXWH SHULRG RQFH ZHHNO\
`7KH XVH RI DQ LQIXVLRQ SXPS LV WKH SUHIHUUHG PHWKRG RI DGPLQLVWUDWLRQ WR HQVXUH DFFXUDWH GHOLYHU\
`RI WKH SURGXFW
`
`x $SSURSULDWH DGPLQLVWUDWLRQ PDWHULDOV VKRXOG EH FRPSRVHG RI JODVV SRO\ROHILQ RU SRO\HWK\OHQH WR
`DYRLG H[FHVVLYH ORVV RI SURGXFW DQG GLHWK\OKH[\OSWKDODWH '(+3
`IXUWKHU GLOXWH LQWR DQ LQIXVLRQ EDJ FRQWDLQLQJ P/ RI 6RGLXP &KORULGH ,QMHFWLRQ 863
`
`x 0L[ E\ LQYHUVLRQ RI WKH EDJ RU ERWWOH DYRLGLQJ H[FHVVLYH VKDNLQJ DV WKLV PD\ FDXVH IRDPLQJ
`
`7KH UHVXOWLQJ VROXWLRQ VKRXOG EH LQVSHFWHG YLVXDOO\ IRU SDUWLFXODWH PDWWHU DQG GLVFRORUDWLRQ SULRU WR
`DGPLQLVWUDWLRQ 7KH DGPL[WXUH RI 725,6(/ LQ 6RGLXP &KORULGH ,QMHFWLRQ 863 VKRXOG EH SURWHFWHG
`IURP H[FHVVLYH URRP OLJKW DQG VXQOLJKW
`
` $GPLQLVWUDWLRQ
`
`x $GPLQLVWUDWLRQ RI WKH ILQDO GLOXWHG VROXWLRQ VKRXOG EH FRPSOHWHG ZLWKLQ VL[ KRXUV IURP WKH WLPH WKDW
`725,6(/ LV ILUVW DGGHG WR 6ROXWLRQ &KORULGH ,QMHFWLRQ 863
`
`x 725,6(/ LV DGPLQLVWHUHG DV DQ LQWUDYHQRXV LQIXVLRQ RYHU D WR PLQXWH SHULRG RQFH ZHHNO\
`7KH XVH RI DQ LQIXVLRQ SXPS LV WKH SUHIHUUHG PHWKRG RI DGPLQLVWUDWLRQ WR HQVXUH DFFXUDWH GHOLYHU\
`RI WKH SURGXFW
`
`x $SSURSULDWH DGPLQLVWUDWLRQ PDWHULDOV VKRXOG EH FRPSRVHG RI JODVV SRO\ROHILQ RU SRO\HWK\OHQH WR
`DYRLG H[FHVVLYH ORVV RI SURGXFW DQG GLHWK\OKH[\OSWKDODWH '(+3
H[WUDFWLRQ 7KH DGPLQLVWUDWLRQ
`PDWHULDOV VKRXOG FRQVLVW RI QRQ'(+3 QRQSRO\YLQ\OFKORULGH 39&
`PDWHULDOV VKRXOG FRQVLVW RI QRQ'(+3 QRQSRO\YLQ\OFKORULGH 39&
WXELQJ ZLWK DSSURSULDWH ILOWHU
`,Q WKH FDVH ZKHQ D 39& DGPLQLVWUDWLRQ VHW KDV WR EH XVHG LW VKRXOG QRW FRQWDLQ '(+3 $Q LQOLQH
`SRO\HWKHUVXOIRQH ILOWHU ZLWK D SRUH VL]H RI QRW JUHDWHU WKDQ PLFURQV LV UHFRPPHQGHG IRU
`DGPLQLVWUDWLRQ WR DYRLG WKH SRVVLELOLW\ RI SDUWLFOHV ELJJHU WKDQ PLFURQV EHLQJ LQIXVHG ,I WKH
`DGPLQLVWUDWLRQ VHW DYDLODEOH GRHV QRW KDYH DQ LQOLQH ILOWHU LQFRUSRUDWHG D SRO\HWKHUVXOIRQH ILOWHU
`VKRXOG EH DGGHG DW WKH VHW LH DQ HQGILOWHU
`,Q WKH FDVH ZKHQ D 39& DGPLQLVWUDWLRQ VHW KDV WR EH XVHG LW VKRXOG QRW FRQWDLQ '(+3 $Q LQOLQH
`SRO\HWKHUVXOIRQH ILOWHU ZLWK D SRUH VL]H RI QRW JUHDWHU WKDQ PLFURQV LV UHFRPPHQGHG IRU
`DGPLQLVWUDWLRQ WR DYRLG WKH SRVVLELOLW\ RI SDUWLFOHV ELJJHU WKDQ PLFURQV EHLQJ LQIXVHG ,I WKH
`DGPLQLVWUDWLRQ VHW DYDLODEOH GRHV QRW KDYH DQ LQOLQH ILOWHU LQFRUSRUDWHG D SRO\HWKHUVXOIRQH ILOWHU
`VKRXOG EH DGGHG DW WKH VHW LH DQ HQGILOWHU
EHIRUH WKH DGPL[WXUH UHDFKHV WKH YHLQ RI WKH SDWLHQW
`'LIIHUHQW HQGILOWHUV FDQ EH XVHG UDQJLQJ LQ ILOWHU SRUH VL]H IURP PLFURQV XS WR PLFURQV 7KH
`XVH RI ERWK DQ LQOLQH DQG HQGILOWHU LV QRW UHFRPPHQGHG
`
`x 725,6(/ ZKHQ GLOXWHG FRQWDLQV SRO\VRUEDWH ZKLFK LV NQRZQ WR LQFUHDVH WKH UDWH RI '(+3
`H[WUDFWLRQ IURP 39& 7KLV VKRXOG EH FRQVLGHUHG GXULQJ WKH SUHSDUDWLRQ DQG DGPLQLVWUDWLRQ RI
`725,6(/ LQFOXGLQJ VWRUDJH WLPH HODSVHG ZKHQ LQ GLUHFW FRQWDFW ZLWK 39& IROORZLQJ FRQVWLWXWLRQ
`
`&RPSDWLELOLWLHV DQG ,QFRPSDWLELOLWLHV
`
`8QGLOXWHG 725,6(/ LQMHFWLRQ VKRXOG QRW EH DGGHG GLUHFWO\ WR DTXHRXV LQIXVLRQ VROXWLRQV 'LUHFW DGGLWLRQ
`RI 725,6(/ LQMHFWLRQ WR DTXHRXV VROXWLRQV ZLOO UHVXOW LQ SUHFLSLWDWLRQ RI GUXJ $OZD\V FRPELQH 725,6(/
`LQMHFWLRQ ZLWK ',/8(17 IRU 725,6(/ EHIRUH DGGLQJ WR LQIXVLRQ VROXWLRQV ,W LV UHFRPPHQGHG WKDW
`725,6(/ EH DGPLQLVWHUHG LQ 6RGLXP &KORULGH ,QMHFWLRQ DIWHU FRPELQLQJ ZLWK GLOXHQW 7KH VWDELOLW\
`RI 725,6(/ LQ RWKHU LQIXVLRQ VROXWLRQV KDV QRW EHHQ HYDOXDWHG $GGLWLRQ RI RWKHU GUXJV RU QXWULWLRQDO
`DJHQWV WR DGPL[WXUHV RI 725,6(/ LQ 6RGLXP &KORULGH ,QMHFWLRQ KDV QRW EHHQ HYDOXDWHG DQG VKRXOG
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`'LIIHUHQW HQGILOWHUV FDQ EH XVHG UDQJLQJ LQ ILOWHU SRUH VL]H IURP PLFURQV XS WR PLFURQV 7KH
`XVH RI ERWK DQ LQOLQH DQG HQGILOWHU LV QRW UHFRPPHQGHG
`
`x 725,6(/ ZKHQ GLOXWHG FRQWDLQV SRO\VRUEDWH ZKLFK LV NQRZQ WR LQFUHDVH WKH UDWH RI '(+3
`H[WUDFWLRQ IURP 39& 7KLV VKRXOG EH FRQVLGHUHG GXULQJ WKH SUHSDUDWLRQ DQG DGPLQLVWUDWLRQ RI
`725,6(/ LQFOXGLQJ VWRUDJH WLPH HODSVHG ZKHQ LQ GLUHFW FRQWDFW ZLWK 39& IROORZLQJ FRQVWLWXWLRQ
`
`&RPSDWLELOLWLHV DQG ,QFRPSDWLELOLWLHV
`
`8QGLOXWHG 725,6(/ LQMHFWLRQ VKRXOG QRW EH DGGHG GLUHFWO\ WR DTXHRXV LQIXVLRQ VROXWLRQV 'LUHFW DGGLWLRQ
`RI 725,6(/ LQMHFWLRQ WR DTXHRXV VROXWLRQV ZLOO UHVXOW LQ SUHFLSLWDWLRQ RI GUXJ $OZD\V FRPELQH 725,6(/
`LQMHFWLRQ ZLWK ',/8(17 IRU 725,6(/ EHIRUH DGGLQJ WR LQIXVLRQ VROXWLRQV ,W LV UHFRPPHQGHG WKDW
`725,6(/ EH DGPLQLVWHUHG LQ 6RGLXP &KORULGH ,QMHFWLRQ DIWHU FRPELQLQJ ZLWK GLOXHQW 7KH VWDELOLW\
`RI 725,6(/ LQ RWKHU LQIXVLRQ VROXWLRQV KDV QRW EHHQ HYDOXDWHG $GGLWLRQ RI RWKHU GUXJV RU QXWULWLRQDO
`DJHQWV WR DGPL[WXUHV RI 725,6(/ LQ 6RGLXP &KORULGH ,QMHFWLRQ KDV QRW EHHQ HYDOXDWHG DQG VKRXOG
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`
`EH DYRLGHG 7HPVLUROLPXV LV GHJUDGHG E\ ERWK DFLGV DQG EDVHV DQG WKXV FRPELQDWLRQV RI WHPVLUROLPXV ZLWK
`DJHQWV FDSDEOH RI PRGLI\LQJ VROXWLRQ S+ VKRXOG EH DYRLGHG
`
` '26$*( )2506 $1' 675(1*7+6
`
`725,6(/ WHPVLUROLPXV
LV VXSSOLHG DV D NLW FRQVLVWLQJ RI WKH IROORZLQJ
`
`725,6(/ WHPVLUROLPXV
`
`725,6(/ WHPVLUROLPXV
LQMHFWLRQ PJP/
7KH 725,6(/ YLDO FRQWDLQV WHPVLUROLPXV DW D
`FRQFHQWUDWLRQ RI PJP/ 7KH YLDO FRQWDLQV DQ RYHUILOO RI P/ WR HQVXUH WKH DELOLW\ WR ZLWKGUDZ WKH
`UHFRPPHQGHG GRVH
`
`',/8(17 IRU 725,6(/ 7KH ',/8(17 YLDO LQFOXGHV D GHOLYHUDEOH YROXPH RI P/ 7KLV YLDO FRQWDLQV
`DQ RYHUILOO LQ RUGHU WR HQVXUH WKDW WKH DSSURSULDWH YROXPH FDQ EH ZLWKGUDZQ
`
` &2175$,1',&$7,216
`
`
`725,6(/ LV FRQWUDLQGLFDWHG LQ SDWLHQWV ZLWK ELOLUXELQ !î8/1 [see Warnings and Precautions (5.2)]
`
` :$51,1*6 $1' 35(&$87,216
`
` +\SHUVHQVLWLYLW\,QIXVLRQ 5HDFWLRQV
`
`+\SHUVHQVLWLYLW\LQIXVLRQ UHDFWLRQV LQFOXGLQJ EXW QRW OLPLWHG WR IOXVKLQJ FKHVW SDLQ G\VSQHD K\SRWHQVLRQ
`DSQHD ORVV RI FRQVFLRXVQHVV K\SHUVHQVLWLYLW\ DQG DQDSK\OD[LV KDYH EHHQ DVVRFLDWHG ZLWK WKH
`DGPLQLVWUDWLRQ RI WHPVLUROLPXV 7KHVH UHDFWLRQV FDQ RFFXU YHU\ HDUO\ LQ WKH ILUVW LQIXVLRQ EXW PD\ DOVR
`RFFXU ZLWK VXEVHTXHQW LQIXVLRQV 3DWLHQWV VKRXOG EH PRQLWRUHG WKURXJKRXW WKH LQIXVLRQ DQG DSSURSULDWH
`VXSSRUWLYH FDUH VKRXOG EH DYDLODEOH 7HPVLUROLPXV LQIXVLRQ VKRXOG EH LQWHUUXSWHG LQ DOO SDWLHQWV ZLWK VHYHUH
`LQIXVLRQ UHDFWLRQV DQG DSSURSULDWH PHGLFDO WKHUDS\ DGPLQLVWHUHG
`
`725,6(/ VKRXOG EH XVHG ZLWK FDXWLRQ LQ SHUVRQV ZLWK NQRZQ K\SHUVHQVLWLYLW\ WR WHPVLUROLPXV RU LWV
`PHWDEROLWHV LQFOXGLQJ VLUROLPXV
`FRQFHQWUDWLRQ RI PJP/ 7KH YLDO FRQWDLQV DQ RYHUILOO RI P/ WR HQVXUH WKH DELOLW\ WR ZLWKGUDZ WKH
`UHFRPPHQGHG GRVH
`
`',/8(17 IRU 725,6(/ 7KH ',/8(17 YLDO LQFOXGHV D GHOLYHUDEOH YROXPH RI P/ 7KLV YLDO FRQWDLQV
`DQ RYHUILOO LQ RUGHU WR HQVXUH WKDW WKH DSSURSULDWH YROXPH FDQ EH ZLWKGUDZQ
`
` &2175$,1',&$7,216
`
`
`725,6(/ LV FRQWUDLQGLFDWHG LQ SDWLHQWV ZLWK ELOLUXELQ !î8/1 [see Warnings and Precautions (5.2)]
`
` :$51,1*6 $1' 35(&$87,216
`
` +\SHUVHQVLWLYLW\,QIXVLRQ 5HDFWLRQV
`
`+\SHUVHQVLWLYLW\LQIXVLRQ UHDFWLRQV LQFOXGLQJ EXW QRW OLPLWHG WR IOXVKLQJ FKHVW SDLQ G\VSQHD K\SRWHQVLRQ
`DSQHD ORVV RI FRQVFLRXVQHVV K\SHUVHQVLWLYLW\ DQG DQDSK\OD[LV KDYH EHHQ DVVRFLDWHG ZLWK WKH
`DGPLQLVWUDWLRQ RI WHPVLUROLPXV 7KHVH UHDFWLRQV FDQ RFFXU YHU\ HDUO\ LQ WKH ILUVW LQIXVLRQ EXW PD\ DOVR
`RFFXU ZLWK VXEVHTXHQW LQIXVLRQV 3DWLHQWV VKRXOG EH PRQLWRUHG WKURXJKRXW WKH LQIXVLRQ DQG DSSURSULDWH
`VXSSRUWLYH FDUH VKRXOG EH DYDLODEOH 7HPVLUROLPXV LQIXVLRQ VKRXOG EH LQWHUUXSWHG LQ DOO SDWLHQWV ZLWK VHYHUH
`LQIXVLRQ UHDFWLRQV DQG DSSURSULDWH PHGLFDO WKHUDS\ DGPLQLVWHUHG
`
`725,6(/ VKRXOG EH XVHG ZLWK FDXWLRQ LQ SHUVRQV ZLWK NQRZQ K\SHUVHQVLWLYLW\ WR WHPVLUROLPXV RU LWV
`PHWDEROLWHV LQFOXGLQJ VLUROLPXV
SRO\VRUEDWH RU WR DQ\ RWKHU FRPSRQHQW LQFOXGLQJ WKH H[FLSLHQWV
RI
`725,6(/
`
`$Q + DQWLKLVWDPLQH VKRXOG EH DGPLQLVWHUHG WR SDWLHQWV EHIRUH WKH VWDUW RI WKH LQWUDYHQRXV WHPVLUROLPXV
`LQIXVLRQ 725,6(/ VKRXOG EH XVHG ZLWK FDXWLRQ LQ SDWLHQWV ZLWK NQRZQ K\SHUVHQVLWLYLW\ WR DQ
`DQWLKLVWDPLQH RU SDWLHQWV ZKR FDQQRW UHFHLYH DQ DQWLKLVWDPLQH IRU RWKHU PHGLFDO UHDVRQV
`
`,I D SDWLHQW GHYHORSV D K\SHUVHQVLWLYLW\ UHDFWLRQ GXULQJ WKH 725,6(/ LQIXVLRQ WKH LQIXVLRQ VKRXOG EH
`VWRSSHG DQG WKH SDWLHQW VKRXOG EH REVHUYHG IRU DW OHDVW WR PLQXWHV GHSHQGLQJ RQ WKH VHYHULW\ RI WKH
`UHDFWLRQ
`725,6(/
`
`$Q + DQWLKLVWDPLQH VKRXOG EH DGPLQLVWHUHG WR SDWLHQWV EHIRUH WKH VWDUW RI WKH LQWUDYHQRXV WHPVLUROLPXV
`LQIXVLRQ 725,6(/ VKRXOG EH XVHG ZLWK FDXWLRQ LQ SDWLHQWV ZLWK NQRZQ K\SHUVHQVLWLYLW\ WR DQ
`DQWLKLVWDPLQH RU SDWLHQWV ZKR FDQQRW UHFHLYH DQ DQWLKLVWDPLQH IRU RWKHU PHGLFDO UHDVRQV
`
`,I D SDWLHQW GHYHORSV D K\SHUVHQVLWLYLW\ UHDFWLRQ GXULQJ WKH 725,6(/ LQIXVLRQ WKH LQIXVLRQ VKRXOG EH
`VWRSSHG DQG WKH SDWLHQW VKRXOG EH REVHUYHG IRU DW OHDVW WR PLQXWHV GHSHQGLQJ RQ WKH VHYHULW\ RI WKH
`UHDFWLRQ
$W WKH GLVFUHWLRQ RI WKH SK\VLFLDQ WUHDWPHQW PD\ EH UHVXPHG ZLWK WKH DGPLQLVWUDWLRQ RI DQ +
`UHFHSWRU DQWDJRQLVW VXFK DV GLSKHQK\GUDPLQH
`UHFHSWRU DQWDJRQLVW VXFK DV GLSKHQK\GUDPLQH
LI QRW SUHYLRXVO\ DGPLQLVWHUHG [see Dosage and
`Administration (2.2)] DQGRU DQ +UHFHSWRU DQWDJRQLVW VXFK DV LQWUDYHQRXV IDPRWLGLQH PJ RU
`LQWUDYHQRXV UDQLWLGLQH PJ
`Administration (2.2)] DQGRU DQ +UHFHSWRU DQWDJRQLVW VXFK DV LQWUDYHQRXV IDPRWLGLQH PJ RU
`LQWUDYHQRXV UDQLWLGLQH PJ
DSSUR[LPDWHO\ PLQXWHV EHIRUH UHVWDUWLQJ WKH 725,6(/ LQIXVLRQ 7KH
`LQIXVLRQ PD\ WKHQ EH UHVXPHG DW D VORZHU UDWH XS WR PLQXWHV
`LQIXVLRQ PD\ WKHQ EH UHVXPHG DW D VORZHU UDWH XS WR PLQXWHV
`
`$ EHQHILWULVN DVVHVVPHQW VKRXOG EH GRQH SULRU WR WKH FRQWLQXDWLRQ RI WHPVLUROLPXV WKHUDS\ LQ SDWLHQWV ZLWK
`VHYHUH RU OLIHWKUHDWHQLQJ UHDFWLRQV
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`
` +HSDWLF ,PSDLUPHQW
`
`7KH VDIHW\ DQG SKDUPDFRNLQHWLFV RI 725,6(/ ZHUH HYDOXDWHG LQ D GRVH HVFDODWLRQ SKDVH VWXG\ LQ
`SDWLHQWV ZLWK QRUPDO RU YDU\LQJ GHJUHHV RI KHSDWLF LPSDLUPHQW 3DWLHQWV ZLWK EDVHOLQH ELOLUXELQ !î8/1
`H[SHULHQFHG JUHDWHU WR[LFLW\ WKDQ SDWLHQWV ZLWK EDVHOLQH ELOLUXELQ î8/1 ZKHQ WUHDWHG ZLWK 725,6(/
`7KH RYHUDOO IUHTXHQF\ RI JUDGH DGYHUVH UHDFWLRQV DQG GHDWKV LQFOXGLQJ GHDWKV GXH WR SURJUHVVLYH
`GLVHDVH ZHUH JUHDWHU LQ SDWLHQWV ZLWK EDVHOLQH ELOLUXELQ !î8/1 GXH WR LQFUHDVHG ULVN RI GHDWK [see
`Contraindications (4)]
`
`8VH FDXWLRQ ZKHQ WUHDWLQJ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW &RQFHQWUDWLRQV RI WHPVLUROLPXV DQG LWV
`PHWDEROLWH VLUROLPXV ZHUH LQFUHDVHG LQ SDWLHQWV ZLWK HOHYDWHG $67 RU ELOLUXELQ OHYHOV ,I 725,6(/ PXVW EH
`JLYHQ LQ SDWLHQWV ZLWK PLOG KHSDWLF LPSDLUPHQW ELOLUXELQ ! ± î8/1 RU $67 !8/1 EXW ELOLUXELQ
`8/1
UHGXFH WKH GRVH RI 725,6(/ WR PJZHHN [see Dosage and Administration (2.4)]
`
` +\SHUJO\FHPLD*OXFRVH ,QWROHUDQFH
`
`7KH XVH RI 725,6(/ LV OLNHO\ WR UHVXOW LQ LQFUHDVHV LQ VHUXP JOXFRVH ,Q WKH SKDVH WULDO RI SDWLHQWV
`UHFHLYLQJ 725,6(/ KDG DW OHDVW RQH HOHYDWHG VHUXP JOXFRVH ZKLOH RQ WUHDWPHQW DQG RI SDWLHQWV
`UHSRUWHG K\SHUJO\FHPLD DV DQ DGYHUVH HYHQW 7KLV PD\ UHVXOW LQ WKH QHHG IRU DQ LQFUHDVH LQ WKH GRVH RI RU
`LQLWLDWLRQ RI LQVXOLQ DQGRU RUDO K\SRJO\FHPLF DJHQW WKHUDS\ 6HUXP JOXFRVH VKRXOG EH WHVWHG EHIRUH DQG
`GXULQJ WUHDWPHQW ZLWK 725,6(/ 3DWLHQWV VKRXOG EH DGYLVHG WR UHSRUW H[FHVVLYH WKLUVW RU DQ\ LQFUHDVH LQ WKH
`YROXPH RU IUHTXHQF\ RI XULQDWLRQ
`
` ,QIHFWLRQV
`
`7KH XVH RI 725,6(/ PD\ UHVXOW LQ LPPXQRVXSSUHVVLRQ 3DWLHQWV VKRXOG EH FDUHIXOO\ REVHUYHG IRU WKH
`RFFXUUHQFH RI LQIHFWLRQV LQFOXGLQJ RSSRUWXQLVWLF LQIHFWLRQV [see Adverse Reactions (6.1)]
`
`3QHXPRF\VWLV MLURYHFL SQHXPRQLD 3-3
`
` +\SHUJO\FHPLD*OXFRVH ,QWROHUDQFH
`
`7KH XVH RI 725,6(/ LV OLNHO\ WR UHVXOW LQ LQFUHDVHV LQ VHUXP JOXFRVH ,Q WKH SKDVH WULDO RI SDWLHQWV
`UHFHLYLQJ 725,6(/ KDG DW OHDVW RQH HOHYDWHG VHUXP JOXFRVH ZKLOH RQ WUHDWPHQW DQG RI SDWLHQWV
`UHSRUWHG K\SHUJO\FHPLD DV DQ DGYHUVH HYHQW 7KLV PD\ UHVXOW LQ WKH QHHG IRU DQ LQFUHDVH LQ WKH GRVH RI RU
`LQLWLDWLRQ RI LQVXOLQ DQGRU RUDO K\SRJO\FHPLF DJHQW WKHUDS\ 6HUXP JOXFRVH VKRXOG EH WHVWHG EHIRUH DQG
`GXULQJ WUHDWPHQW ZLWK 725,6(/ 3DWLHQWV VKRXOG EH DGYLVHG WR UHSRUW H[FHVVLYH WKLUVW RU DQ\ LQFUHDVH LQ WKH
`YROXPH RU IUHTXHQF\ RI XULQDWLRQ
`
` ,QIHFWLRQV
`
`7KH XVH RI 725,6(/ PD\ UHVXOW LQ LPPXQRVXSSUHVVLRQ 3DWLHQWV VKRXOG EH FDUHIXOO\ REVHUYHG IRU WKH
`RFFXUUHQFH RI LQIHFWLRQV LQFOXGLQJ RSSRUWXQLVWLF LQIHFWLRQV [see Adverse Reactions (6.1)]
`
`3QHXPRF\VWLV MLURYHFL SQHXPRQLD 3-3
LQFOXGLQJ IDWDOLWLHV KDV EHHQ UHSRUWHG LQ SDWLHQWV ZKR UHFHLYHG
`WHPVLUROLPXV 7KLV PD\ EH DVVRFLDWHG ZLWK FRQFRPLWDQW XVH RI FRUWLFRVWHURLGV RU RWKHU LPPXQRVXSSUHVVLYH
`DJHQWV 3URSK\OD[LV RI 3-3 VKRXOG EH FRQVLGHUHG ZKHQ FRQFRPLWDQW XVH RI FRUWLFRVWHURLGV RU RWKHU
`LPPXQRVXSSUHVVLYH DJHQWV DUH UHTXLUHG
`
` ,QWHUVWLWLDO /XQJ 'LVHDVH
`
`&DVHV RI LQWHUVWLWLDO OXQJ GLVHDVH VRPH UHVXOWLQJ LQ GHDWK RFFXUUHG LQ SDWLHQWV ZKR UHFHLYHG 725,6(/
`6RPH SDWLHQWV ZHUH DV\PSWRPDWLF RU KDG PLQLPDO V\PSWRPV ZLWK LQILOWUDWHV GHWHFWHG RQ FRPSXWHG
`WRPRJUDSK\ VFDQ RU FKHVW UDGLRJUDSK 2WKHUV SUHVHQWHG ZLWK V\PSWRPV VXFK DV G\VSQHD FRXJK K\SR[LD
`DQG IHYHU 6RPH SDWLHQWV UHTXLUHG GLVFRQWLQXDWLRQ RI 725,6(/ DQGRU WUHDWPHQW ZLWK FRUWLFRVWHURLGV
`DQGRU DQWLELRWLFV ZKLOH VRPH SDWLHQWV FRQWLQXHG WUHDWPHQW ZLWKRXW DGGLWLRQDO LQWHUYHQWLRQ 3DWLHQWV VKRXOG
`EH DGYLVHG WR UHSRUW SURPSWO\ DQ\ QHZ RU ZRUVHQLQJ UHVSLUDWRU\ V\PSWRPV
`
`,W LV UHFRPPHQGHG WKDW SDWLHQWV XQGHUJR EDVHOLQH UDGLRJUDSKLF DVVHVVPHQW E\ OXQJ FRPSXWHG WRPRJUDSK\
`VFDQ RU FKHVW UDGLRJUDSK SULRU WR WKH LQLWLDWLRQ RI 725,6(/ WKHUDS\ )ROORZ VXFK DVVHVVPHQWV SHULRGLFDOO\
`HYHQ LQ WKH DEVHQFH RI FOLQLFDO UHVSLUDWRU\ V\PSWRPV
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`WHPVLUROLPXV 7KLV PD\ EH DVVRFLDWHG ZLWK FRQFRPLWDQW XVH RI FRUWLFRVWHURLGV RU RWKHU LPPXQRVXSSUHVVLYH
`DJHQWV 3URSK\OD[LV RI 3-3 VKRXOG EH FRQVLGHUHG ZKHQ FRQFRPLWDQW XVH RI FRUWLFRVWHURLGV RU RWKHU
`LPPXQRVXSSUHVVLYH DJHQWV DUH UHTXLUHG
`
` ,QWHUVWLWLDO /XQJ 'LVHDVH
`
`&DVHV RI LQWHUVWLWLDO OXQJ GLVHDVH VRPH UHVXOWLQJ LQ GHDWK RFFXUUHG LQ SDWLHQWV ZKR UHFHLYHG 725,6(/
`6RPH SDWLHQWV ZHUH DV\PSWRPDWLF RU KDG PLQLPDO V\PSWRPV ZLWK LQILOWUDWHV GHWHFWHG RQ FRPSXWHG
`WRPRJUDSK\ VFDQ RU FKHVW UDGLRJUDSK 2WKHUV SUHVHQWHG ZLWK V\PSWRPV VXFK DV G\VSQHD FRXJK K\SR[LD
`DQG IHYHU 6RPH SDWLHQWV UHTXLUHG GLVFRQWLQXDWLRQ RI 725,6(/ DQGRU WUHDWPHQW ZLWK FRUWLFRVWHURLGV
`DQGRU DQWLELRWLFV ZKLOH VRPH SDWLHQWV FRQWLQXHG WUHDWPHQW ZLWKRXW DGGLWLRQDO LQWHUYHQWLRQ 3DWLHQWV VKRXOG
`EH DGYLVHG WR UHSRUW SURPSWO\ DQ\ QHZ RU ZRUVHQLQJ UHVSLUDWRU\ V\PSWRPV
`
`,W LV UHFRPPHQGHG WKDW SDWLHQWV XQGHUJR EDVHOLQH UDGLRJUDSKLF DVVHVVPHQW E\ OXQJ FRPSXWHG WRPRJUDSK\
`VFDQ RU FKHVW UDGLRJUDSK SULRU WR WKH LQLWLDWLRQ RI 725,6(/ WKHUDS\ )ROORZ VXFK DVVHVVPHQWV SHULRGLFDOO\
`HYHQ LQ WKH DEVHQFH RI FOLQLFDO UHVSLUDWRU\ V\PSWRPV
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`,W LV UHFRPPHQGHG WKDW SDWLHQWV EH IROORZHG FORVHO\ IRU RFFXUUHQFH RI FOLQLFDO UHVSLUDWRU\ V\PSWRPV ,I
`FOLQLFDOO\ VLJQLILFDQW UHVSLUDWRU\ V\PSWRPV GHYHORS FRQVLGHU ZLWKKROGLQJ 725,6(/ DGPLQLVWUDWLRQ XQWLO
`DIWHU UHFRYHU\ RI V\PSWRPV DQG LPSURYHPHQW RI UDGLRJUDSKLF ILQGLQJV UHODWHG WR SQHXPRQLWLV (PSLULF
`WUHDWPHQW ZLWK FRUWLFRVWHURLGV DQGRU DQWLELRWLFV PD\ EH FRQVLGHUHG 2SSRUWXQLVWLF LQIHFWLRQV VXFK DV 3-3
`VKRXOG EH FRQVLGHUHG LQ WKH GLIIHUHQWLDO GLDJQRVLV )RU SDWLHQWV ZKR UHTXLUH XVH RI FRUWLFRVWHURLGV
`SURSK\OD[LV RI 3-3 PD\ EH FRQVLGHUHG
`
` +\SHUOLSLGHPLD
`
`7KH XVH RI 725,6(/ LV OLNHO\ WR UHVXOW LQ LQFUHDVHV LQ VHUXP WULJO\FHULGHV DQG FKROHVWHURO ,Q WKH SKDVH
`WULDO RI SDWLHQWV UHFHLYLQJ 725,6(/ KDG DW OHDVW RQH HOHYDWHG VHUXP FKROHVWHURO YDOXH DQG KDG DW
`OHDVW RQH HOHYDWHG VHUXP WULJO\FHULGH YDOXH 7KLV PD\ UHTXLUH LQLWLDWLRQ RU LQFUHDVH LQ WKH GRVH RI OLSLG
`ORZHULQJ DJHQWV 6HUXP FKROHVWHURO DQG WULJO\FHULGHV VKRXOG EH WHVWHG EHIRUH DQG GXULQJ WUHDWPHQW ZLWK
`725,6(/
`
` %RZHO 3HUIRUDWLRQ
`
`&DVHV RI IDWDO ERZHO SHUIRUDWLRQ RFFXUUHG LQ SDWLHQWV ZKR UHFHLYHG 725,6(/ 7KHVH SDWLHQWV SUHVHQWHG
`ZLWK IHYHU DEGRPLQDO SDLQ PHWDEROLF DFLGRVLV EORRG\ VWRROV GLDUUKHD DQGRU DFXWH DEGRPHQ 3DWLHQWV
`VKRXOG EH DGYLVHG WR UHSRUW SURPSWO\ DQ\ QHZ RU ZRUVHQLQJ DEGRPLQDO SDLQ RU EORRG LQ WKHLU VWRROV
`
` 5HQDO )DLOXUH
`
`&DVHV RI UDSLGO\ SURJUHVVLYH DQG VRPHWLPHV IDWDO DFXWH UHQDO IDLOXUH QRW FOHDUO\ UHODWHG WR GLVHDVH
`SURJUHVVLRQ RFFXUUHG LQ SDWLHQWV ZKR UHFHLYHG 725,6(/ 6RPH RI WKHVH FDVHV ZHUH QRW UHVSRQVLYH WR
`GLDO\VLV
`
` :RXQG +HDOLQJ &RPSOLFDWLRQV
`
`8VH RI 725,6(/ KDV EHHQ DVVRFLDWHG ZLWK DEQRUPDO ZRXQG KHDOLQJ 7KHUHIRUH FDXWLRQ VKRXOG EH
`H[HUFLVHG ZLWK WKH XVH RI 725,6(/ LQ WKH SHULRSHUDWLYH SHULRG
`
` ,QWUDFHUHEUDO +HPRUUKDJH
`
`3DWLHQWV ZLWK FHQWUDO QHUYRXV V\VWHP WXPRUV SULPDU\ &16 WXPRU RU PHWDVWDVHV
DQGRU UHFHLYLQJ
`DQWLFRDJXODWLRQ WKHUDS\ PD\ EH DW DQ LQFUHDVHG ULVN RI GHYHORSLQJ LQWUDFHUHEUDO EOHHGLQJ LQFOXGLQJ IDWDO
`RXWFRPHV
`DQWLFRDJXODWLRQ WKHUDS\ PD\ EH DW DQ LQFUHDVHG ULVN RI GHYHORSLQJ LQWUDFHUHEUDO EOHHGLQJ LQFOXGLQJ IDWDO
`RXWFRPHV
ZKLOH UHFHLYLQJ 725,6(/
`
` 3URWHLQXULD DQG 1HSKURWLF V\QGURPH
`
`3URWHLQXULD LQFOXGLQJ FDVHV RI QHSKURWLF V\QGURPH
`
` 3URWHLQXULD DQG 1HSKURWLF V\QGURPH
`
`3URWHLQXULD LQFOXGLQJ FDVHV RI QHSKURWLF V\QGURPH
KDV RFFXUUHG LQ SDWLHQWV WUHDWHG ZLWK 725,6(/
`0RQLWRU XULQH SURWHLQ SULRU WR WKH VWDUW RI 725,6(/ WKHUDS\ DQG SHULRGLFDOO\ WKHUHDIWHU 'LVFRQWLQXH
`725,6(/ LQ SDWLHQWV ZKR GHYHORS QHSKURWLF V\QGURPH
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`0RQLWRU XULQH SURWHLQ SULRU WR WKH VWDUW RI 725,6(/ WKHUDS\ DQG SHULRGLFDOO\ WKHUHDIWHU 'LVFRQWLQXH
`725,6(/ LQ SDWLHQWV ZKR GHYHORS QHSKURWLF V\QGURPH
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`
` &RDGPLQLVWUDWLRQ ZLWK ,QGXFHUV RU ,QKLELWRUV RI &<3$ 0HWDEROLVP
`
`$JHQWV ,QGXFLQJ &<3$ 0HWDEROLVP
`
`6WURQJ LQGXFHUV RI &<3$ VXFK DV GH[DPHWKDVRQH FDUEDPD]HSLQH SKHQ\WRLQ SKHQREDUELWDO ULIDPSLQ
`ULIDEXWLQ DQG ULIDPSDFLQ PD\ GHFUHDVH H[SRVXUH RI WKH DFWLYH PHWDEROLWH VLUROLPXV ,I DOWHUQDWLYH WUHDWPHQW
`FDQQRW EH DGPLQLVWHUHG D GRVH DGMXVWPHQW VKRXOG EH FRQVLGHUHG 6W -RKQ¶V :RUW PD\ GHFUHDVH 725,6(/
`SODVPD FRQFHQWUDWLRQV XQSUHGLFWDEO\ 3DWLHQWV UHFHLYLQJ 725,6(/ VKRXOG QRW WDNH 6W -RKQ¶V :RUW
`FRQFRPLWDQWO\ [see Dosage and Administration (2.4) and Drug Interactions (7.1)]
`
`$JHQWV ,QKLELWLQJ &<3$ 0HWDEROLVP
`
`6WURQJ &<3$ LQKLELWRUV VXFK DV DWD]DQDYLU FODULWKURP\FLQ LQGLQDYLU LWUDFRQD]ROH NHWRFRQD]ROH
`QHID]RGRQH QHOILQDYLU ULWRQDYLU VDTXLQDYLU DQG WHOLWKURP\FLQ PD\ LQFUHDVH EORRG FRQFHQWUDWLRQV RI WKH
`DFWLYH PHWDEROLWH VLUROLPXV ,I DOWHUQDWLYH WUHDWPHQWV FDQQRW EH DGPLQLVWHUHG D GRVH DGMXVWPHQW VKRXOG EH
`
`FRQVLGHUHG [see Dosage and Administration (2.4) and Drug Interactions (7.2)]
`
` &RQFRPLWDQW XVH RI 725,6(/ ZLWK VXQLWLQLE
`
`7KH FRPELQDWLRQ RI 725,6(/ DQG VXQLWLQLE UHVXOWHG LQ GRVHOLPLWLQJ WR[LFLW\ 'RVHOLPLWLQJ WR[LFLWLHV
` *UDGH HU\WKHPDWRXV PDFXORSDSXODU UDVK DQG JRXWFHOOXOLWLV UHTXLULQJ KRVSLWDOL]DWLRQ
ZHUH REVHUYHG
`LQ WZR RXW RI WKUHH SDWLHQWV WUHDWHG LQ WKH ILUVW FRKRUW RI D SKDVH VWXG\ DW GRVHV RI 725,6(/ PJ ,9 SHU
`ZHHN DQG VXQLWLQLE PJ RUDO SHU GD\ 'D\V IROORZHG E\ D ZHHN UHVW
`LQ WZR RXW RI WKUHH SDWLHQWV WUHDWHG LQ WKH ILUVW FRKRUW RI D SKDVH VWXG\ DW GRVHV RI 725,6(/ PJ ,9 SHU
`ZHHN DQG VXQLWLQLE PJ RUDO SHU GD\ 'D\V IROORZHG E\ D ZHHN UHVW
`
` 9DFFLQDWLRQV
`
`7KH XVH RI OLYH YDFFLQHV DQG FORVH FRQWDFW ZLWK WKRVH ZKR KDYH UHFHLYHG OLYH YDFFLQHV VKRXOG EH DYRLGHG
`GXULQJ WUHDWPHQW ZLWK 725,6(/ ([DPSOHV RI OLYH YDFFLQHV DUH LQWUDQDVDO LQIOXHQ]D PHDVOHV PXPSV
`UXEHOOD RUDO SROLR %&* \HOORZ IHYHU YDULFHOOD DQG 7<D W\SKRLG YDFFLQHV
`
` (PEU\R)HWDO 7R[LFLW\
`
`%DVHG RQ ILQGLQJV LQ DQLPDO VWXGLHV DQG LWV PHFKDQLVP RI DFWLRQ 725,6(/ FDQ FDXVH IHWDO KDUP ZKHQ
`DGPLQLVWHUHG WR D SUHJQDQW ZRPDQ ,Q DQLPDO UHSURGXFWLRQ VWXGLHV GDLO\ RUDO DGPLQLVWUDWLRQ RI
`WHPVLUROLPXV WR SUHJQDQW DQLPDOV GXULQJ RUJDQRJHQHVLV FDXVHG DGYHUVH HPEU\RIHWDO HIIHFWV LQ UDWV DQG
`UDEELWV DW DSSUR[LPDWHO\ DQG WLPHV WKH $8& LQ SDWLHQWV DW WKH UHFRPPHQGHG KXPDQ GRVH
`UHVSHFWLYHO\ $GYLVH SUHJQDQW ZRPHQ DQG IHPDOHV RI UHSURGXFWLYH SRWHQWLDO RI WKH SRWHQWLDO ULVN WR D IHWXV
`$GYLVH IHPDOHV RI UHSURGXFWLYH SRWHQWLDO WR XVH HIIHFWLYH FRQWUDFHSWLRQ GXULQJ WUHDWPHQW ZLWK 725,6(/
`DQG IRU PRQWKV DIWHU WKH ODVW GRVH $GYLVH PDOHV ZLWK IHPDOH SDUWQHUV RI UHSURGXFWLYH SRWHQWLDO WR XVH
`HIIHFWLYH FRQWUDFHSWLRQ GXULQJ WUHDWPHQW ZLWK 725,6(/ DQG IRU PRQWKV DIWHU WKH ODVW GRVH [see Clinical
`
`Pharmacology (12.1) and Use in Specific Populations (8.1, 8.3)].
`
` (OGHUO\ 3DWLHQWV
`
`%DVHG RQ WKH UHVXOWV RI D SKDVH VWXG\ HOGHUO\ SDWLHQWV PD\ EH PRUH OLNHO\ WR H[SHULHQFH FHUWDLQ DGYHUVH
`
`UHDFWLRQV LQFOXGLQJ GLDUUKHD HGHPD DQG SQHXPRQLD [see Use in Specific Populations (8.5)].
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
` $'9(56( 5($&7,216
`
`7KH IROORZLQJ VHULRXV DGYHUVH UHDFWLRQV KDYH EHHQ DVVRFLDWHG ZLWK 725,6(/ LQ FOLQLFDO WULDOV DQG DUH
`
`GLVFXVVHG LQ JUHDWHU GHWDLO LQ RWKHU VHFWLRQV RI WKH ODEHO [see Warnings and Precautions (5)]
`
`
`x +\SHUVHQVLWLYLW\,QIXVLRQ 5HDFWLRQV [see Warnings and Precautions (5.1)]
`
` x +HSDWLF ,PSDLUPHQW [see Warnings and Precautions (5.2)]
`x +\SHUJO\FHPLD*OXFRVH ,QWROHUDQFH [see Warnings and Precautions (5.3)]
`,QIHFWLRQV [see Warnings and Precautions (5.4)]
`x
`,QWHUVWLWLDO /XQJ 'LVHDVH [see Warnings and Precautions (5.5)]
`x
`x +\SHUOLSLGHPLD [see Warnings and Precautions (5.6)]
`x %RZHO 3HUIRUDWLRQ [see Warnings and Precautions (5.7)]
`
`x 5HQDO )DLOXUH [see Warnings and Precautions (5.8)]
`
`x :RXQG +HDOLQJ &RPSOLFDWLRQV [see Warnings and Precautions (5.9)]
`
`
`,QWUDFHUHEUDO +HPRUUKDJH [see Warnings and Precautions (5.10)]
`
`x
`
`
`7KH PRVW FRPPRQ
DGYHUVH UHDFWLRQV REVHUYHG ZLWK 725,6(/ DUH UDVK DVWKHQLD PXFRVLWLV
`QDXVHD HGHPD DQG DQRUH[LD 7KH PRVW FRPPRQ
`QDXVHD HGHPD DQG DQRUH[LD 7KH PRVW FRPPRQ
ODERUDWRU\ DEQRUPDOLWLHV REVHUYHG ZLWK 725,6(/
`DUH DQHPLD K\SHUJO\FHPLD K\SHUOLSLGHPLD K\SHUWULJO\FHULGHPLD O\PSKRSHQLD HOHYDWHG DONDOLQH
`SKRVSKDWDVH HOHYDWHG VHUXP FUHDWLQLQH K\SRSKRVSKDWHPLD WKURPERF\WRSHQLD HOHYDWHG $67 DQG
`OHXNRSHQLD
`
` &OLQLFDO 7ULDOV ([SHULHQFH
`
`%HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV WKH DGYHUVH UHDFWLRQ UDWHV REVHUYHG
`FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ RWKHU WULDOV DQG PD\ QRW UHIOHFW WKH UDWHV REVHUYHG LQ FOLQLFDO
`SUDFWLFH
`
`,Q WKH SKDVH UDQGRPL]HG RSHQODEHO VWXG\ RI LQWHUIHURQ DOID ,)1Į
`DUH DQHPLD K\SHUJO\FHPLD K\SHUOLSLGHPLD K\SHUWULJO\FHULGHPLD O\PSKRSHQLD HOHYDWHG DONDOLQH
`SKRVSKDWDVH HOHYDWHG VHUXP FUHDWLQLQH K\SRSKRVSKDWHPLD WKURPERF\WRSHQLD HOHYDWHG $67 DQG
`OHXNRSHQLD
`
` &OLQLFDO 7ULDOV ([SHULHQFH
`
`%HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV WKH DGYHUVH UHDFWLRQ UDWHV REVHUYHG
`FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ RWKHU WULDOV DQG PD\ QRW UHIOHFW WKH UDWHV REVHUYHG LQ FOLQLFDO
`SUDFWLFH
`
`,Q WKH SKDVH UDQGRPL]HG RSHQODEHO VWXG\ RI LQWHUIHURQ DOID ,)1Į
DORQH 725,6(/ DORQH DQG
`725,6(/ DQG ,)1Į D WRWDO RI SDWLHQWV ZHUH WUHDWHG 7ZR KXQGUHG SDWLHQWV UHFHLYHG ,)1Į ZHHNO\
` UHFHLYHG 725,6(/ PJ ZHHNO\ DQG SDWLHQWV UHFHLYHG D FRPELQDWLRQ RI 725,6(/ DQG ,)1Į
`ZHHNO\ [see Clinical Studies (14)]
`
`7UHDWPHQW ZLWK WKH FRPELQDWLRQ RI 725,6(/ PJ DQG ,)1Į ZDV DVVRFLDWHG ZLWK DQ LQFUHDVHG LQFLGHQFH
`RI PXOWLSOH DGYHUVH UHDFWLRQV DQG GLG QRW UHVXOW LQ D VLJQLILFDQW LQFUHDVH LQ RYHUDOO VXUYLYDO ZKHQ FRPSDUHG
`ZLWK ,)1Į DORQH
`
`7DEOH VKRZV WKH SHUFHQWDJH RI SDWLHQWV H[SHULHQFLQJ WUHDWPHQW HPHUJHQW DGYHUVH UHDFWLRQV 5HDFWLRQV
`UHSRUWHG LQ DW OHDVW RI SDWLHQWV ZKR UHFHLYHG 725,6(/ PJ DORQH RU ,)1Į DORQH DUH OLVWHG 7DEOH
`VKRZV WKH SHUFHQWDJH RI SDWLHQWV H[SHULHQFLQJ VHOHFWHG ODERUDWRU\ DEQRUPDOLWLHV 'DWD IRU WKH VDPH DGYHUVH
`UHDFWLRQV DQG ODERUDWRU\ DEQRUPDOLWLHV LQ WKH ,)1Į DORQH DUP DUH VKRZQ IRU FRPSDULVRQ
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`725,6(/ DQG ,)1Į D WRWDO RI SDWLHQWV ZHUH WUHDWHG 7ZR KXQGUHG SDWLHQWV UHFHLYHG ,)1Į ZHHNO\
` UHFHLYHG 725,6(/ PJ ZHHNO\ DQG SDWLHQWV UHFHLYHG D FRPELQDWLRQ RI 725,6(/ DQG ,)1Į
`ZHHNO\ [see Clinical Studies (14)]
`
`7UHDWPHQW ZLWK WKH FRPELQDWLRQ RI 725,6(/ PJ DQG ,)1Į ZDV DVVRFLDWHG ZLWK DQ LQFUHDVHG LQFLGHQFH
`RI PXOWLSOH DGYHUVH UHDFWLRQV DQG GLG QRW UHVXOW LQ D VLJQLILFDQW LQFUHDVH LQ RYHUDOO VXUYLYDO ZKHQ FRPSDUHG
`ZLWK ,)1Į DORQH
`
`7DEOH VKRZV WKH SHUFHQWDJH RI SDWLHQWV H[SHULHQFLQJ WUHDWPHQW HPHUJHQW DGYHUVH UHDFWLRQV 5HDFWLRQV
`UHSRUWHG LQ DW OHDVW RI SDWLHQWV ZKR UHFHLYHG 725,6(/ PJ DORQH RU ,)1Į DORQH DUH OLVWHG 7DEOH
`VKRZV WKH SHUFHQWDJH RI SDWLHQWV H[SHULHQFLQJ VHOHFWHG ODERUDWRU\ DEQRUPDOLWLHV 'DWD IRU WKH VDPH DGYHUVH
`UHDFWLRQV DQG ODERUDWRU\ DEQRUPDOLWLHV LQ WKH ,)1Į DORQH DUP DUH VKRZQ IRU FRPSDULVRQ
`
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`
`7DEOH ± $GYHUVH 5HDFWLRQV 5HSRUWHG LQ DW /HDVW RI 3DWLHQWV :KR 5HFHLYHG PJ ,9 725,6(/ RU ,)1
`Į LQ WKH 5DQGRPL]HG 7ULDO
`
`$OO
`*UDGHV
`Q
`
`725,6(/
` PJ
`Q
`*UDGHV
`
`Q
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`,)1Į
`
`Q
`*UDGHV
`
`Q
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`$OO
`*UDGHV
`Q
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`$GYHUVH 5HDFWLRQ
`*HQHUDO GLVRUGHUV
` $VWKHQLD
` (GHPDD
` 3DLQ
` 3\UH[LD
` :HLJKW /RVV
` +HDGDFKH
` &KHVW 3DLQ
` &KLOOV
`*DVWURLQWHVWLQDO GLVRUGHUV
` 0XFRVLWLVE
` $QRUH[LD
` 1DXVHD
` 'LDUUKHD
` $EGRPLQDO 3DLQ
` &RQVWLSDWLRQ
` 9RPLWLQJ
`,QIHFWLRQV
` ,QIHFWLRQVF
` 8ULQDU\ WUDFW LQIHFWLRQG
` 3KDU\QJLWLV
` 5KLQLWLV
`0XVFXORVNHOHWDO DQG FRQQHFWLYH WLVVXH GLVRUGHUV
` %DFN 3DLQ
` $UWKUDOJLD
` 0\DOJLD
`5HVSLUDWRU\ WKRUDFLF DQG PHGLDVWLQDO GLVRUGHUV
` '\VSQHD
` &RXJK
` (SLVWD[LV
`6NLQ DQG VXEFXWDQHRXV WLVVXH GLVRUGHUV
` 5DVKH
` 3UXULWXV
` 1DLO 'LVRUGHU
` 'U\ 6NLQ
` $FQH
`
`
`
`Reference ID: 4238713
`
`
`
`
`
`7DEOH ± $GYHUVH 5HDFWLRQV 5HSRUWHG LQ DW /HDVW RI 3DWLHQWV :KR 5HFHLYHG PJ ,9 725,6(/ RU ,)1
`Į LQ WKH 5DQGRPL]HG 7ULDO
`
`725,6(/
` PJ
`Q
`
`,)1Į
`
`Q
`
`
`
`
`
`
`
`
`
`
`
`
`
`$GYHUVH 5HDFWLRQ
`1HUYRXV V\VWHP GLVRUGHUV
` '\VJHXVLDI
`
`
` ,QVRPQLD
`
` 'HSUHVVLRQ
` &RPPRQ 7R[LFLW\ &ULWHULD IRU $GYHUVH (YHQWV &7&$(
9HUVLRQ
`D ,QFOXGHV HGHPD IDFLDO HGHPD DQG SHULSKHUDO HGHPD
`E ,QFOXGHV DSKWKRXV VWRPDWLWLV JORVVLWLV PRXWK XOFHUDWLRQ PXFRVLWLV DQG VWRPDWLWLV
`F ,QFOXGHV LQIHFWLRQV QRW RWKHUZLVH VSHFLILHG 126
`D ,QFOXGHV HGHPD IDFLDO HGHPD DQG SHULSKHUDO HGHPD
`E ,QFOXGHV DSKWKRXV VWRPDWLWLV JORVVLWLV PRXWK XOFHUDWLRQ PXFRVLWLV DQG VWRPDWLWLV
`F ,QFOXGHV LQIHFWLRQV QRW RWKHUZLVH VSHFLILHG 126
DQG WKH IROORZLQJ LQIHFWLRQV WKDW RFFXUUHG LQIUHTXHQWO\ DV GLVWLQFW
`HQWLWLHV DEVFHVV EURQFKLWLV FHOOXOLWLV KHUSHV VLPSOH[ DQG KHUSHV ]RVWHU
`G ,QFOXGHV F\VWLWLV G\VXULD KHPDWXULD XULQDU\ IUHTXHQF\ DQG XULQDU\ WUDFW LQIHFWLRQ
`H ,QFOXGHV HF]HPD H[IROLDWLYH GHUPDWLWLV PDFXORSDSXODU UDVK SUXULWLF UDVK SXVWXODU UDVK UDVK 126
`HQWLWLHV DEVFHVV EURQFKLWLV FHOOXOLWLV KHUSHV VLPSOH[ DQG KHUSHV ]RVWHU
`G ,QFOXGHV F\VWLWLV G\VXULD KHPDWXULD XULQDU\ IUHTXHQF\ DQG XULQDU\ WUDFW LQIHFWLRQ
`H ,QFOXGHV HF]HPD H[IROLDWLYH GHUPDWLWLV PDFXORSDSXODU UDVK SUXULWLF UDVK SXVWXODU UDVK UDVK 126
DQG
`YHVLFXOREXOORXV UDVK
`I ,QFOXGHV WDVWH ORVV DQG WDVWH SHUYHUVLRQ
`
`7KH IROORZLQJ VHOHFWHG DGYHUVH UHDFWLRQV ZHUH UHSRUWHG OHVV IUHTXHQWO\
`YHVLFXOREXOORXV UDVK
`I ,QFOXGHV WDVWH ORVV DQG WDVWH SHUYHUVLRQ
`
`7KH IROORZLQJ VHOHFWHG DGYHUVH UHDFWLRQV ZHUH UHSRUWHG OHVV IUHTXHQWO\
`
`*DVWURLQWHVWLQDO 'LVRUGHUV ± *DVWURLQWHVWLQDO KHPRUUKDJH
UHFWDO KHPRUUKDJH
`
`(\H 'LVRUGHUV ± &RQMXQFWLYLWLV LQFOXGLQJ ODFULPDWLRQ GLVRUGHU
`
`,PPXQH 6\VWHP ± $QJLRQHXURWLF HGHPDW\SH UHDFWLRQV LQFOXGLQJ GHOD\HG UHDFWLRQV RFFXUULQJ WZR PRQWKV
`IROORZLQJ LQLWLDWLRQ RI WKHUDS\
KDYH EHHQ REVHUYHG LQ VRPH SDWLHQWV ZKR UHFHLYHG 725,6(/ DQG $&(
`LQKLELWRUV FRQFRPLWDQWO\
`
`,QIHFWLRQV ± 3QHXPRQLD
`LQKLELWRUV FRQFRPLWDQWO\
`
`,QIHFWLRQV ± 3QHXPRQLD
XSSHU UHVSLUDWRU\ WUDFW LQIHFWLRQ
ZRXQG LQIHFWLRQSRVWRSHUDWLYH
`ZRXQG LQIHFWLRQ
`ZRXQG LQIHFWLRQ
VHSVLV
`
`*HQHUDO 'LVRUGHUV DQG $GPLQLVWUDWLRQ 6LWH &RQGLWLRQV 'LDEHWHV PHOOLWXV
`
`5HVSLUDWRU\ 7KRUDFLF DQG 0HGLDVWLQDO 'LVRUGHUV ± 3OHXUDO HIIXVLRQ
`
`9DVFXODU ± +\SHUWHQVLRQ
YHQRXV WKURPERHPEROLVP LQFOXGLQJ GHHS YH
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
