Dosing Guidelines for Precedex®

Nonintubated Procedural Sedation

and

ICU Sedation

0\1 Precedex® '=1 (dexmedetomidile HCIInjection)

Petition for Inter Partes Review of US 8,455,527 Amneal Pharmaceuticals LLC- Exhibit 1063- Page 1

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Precede~ O

verv

iew

•

Pre

cede

x is

indi

cate

d fo

r se

datio

n o

f ini

tially

intu

bate

d a

nd

me

cha

nic

ally

ven

tilat

ed p

atie

nts

du

rin

g tr

ea

tme

nt

in a

n in

ten

sive

ca

re s

ettin

g a

nd

for

seda

tion

of

noni

ntub

ated

pa

tien

ts p

rio

r to

an

d/o

r d

uri

ng

sur

gica

l a

nd

oth

er

proc

edur

es.1

• P

rece

dex

sho

uld

be

ad

min

iste

red

by

cont

inuo

us in

fusi

on

n

ot t

o e

xcee

d 2

4 h

ours

.

• P

rece

dex

sho

uld

be

ad

min

iste

red

onl

y b

y p

ers

on

s sk

illed

in

the

ma

na

ge

me

nt o

f pa

tien

ts in

the

inte

nsiv

e ca

re o

r op

erat

ing

room

set

ting.

1

• D

ue t

o th

e kn

own

ph

arm

aco

log

ic e

ffect

s o

f Pre

cede

x,

pa

tien

ts s

houl

d b

e c

on

tinu

ou

sly

mon

itore

d.1

• Th

e m

ost

co

mm

on

ad

vers

e r

eact

ions

with

Pre

cede

x (i

nci

de

nce

>2%

) ar

e hy

pote

nsio

n, b

rady

card

ia a

nd

dry

mo

uth

.1

• D

ue t

o th

e in

crea

sed

inci

denc

e of

bra

dyca

rdia

an

d

hypo

tens

ion

in th

e e

lder

ly,

and

the

pot

entia

l fo

r red

uced

cl

eara

nce

in p

atie

nts

with

im

pair

ed h

epat

ic o

r re

nal f

unct

ion,

do

se r

educ

tions

sho

uld

be

con

side

red

in t

hese

pat

ient

type

s.1

Ple

ase

see

en

clo

sed

fu

ll P

resc

rib

ing

Info

rma

tion

.

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Pre

cede

x®

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oo)

2

Wh

at t

o E

xpec

t C

ard

iova

scu

lar

Eff

ects

• C

linic

ally

sig

nifi

can

t e

pis

od

es

of b

rady

card

ia a

nd

sin

us

arr

est

hav

e be

en a

ssoc

iate

d w

ith P

rece

dex

adm

inis

trat

ion

in y

oung

, h

ea

lthy

volu

ntee

rs w

ith h

igh

vag

al t

one

or

with

di

ffer

ent r

oute

s o

f adm

inis

trat

ion,

suc

h a

s ra

pid

intr

ave

no

us

infu

sion

or b

olu

s ad

min

istr

atio

n.1

• Mo

de

rate

he

art

rate

and

blo

od p

ress

ure

red

uctio

ns s

houl

d b

e a

ntic

ipat

ed w

ith P

rece

dex.

2

• If

med

ical

inte

rven

tion

is r

equi

red

for

Pre

cede

x-in

duce

d hy

pote

nsio

n o

r bra

dyca

rdia

, tr

ea

tme

nt

may

incl

ud

e1 •3:

-D

ecre

asin

g o

r st

oppi

ng t

he in

fusi

on o

f Pre

cede

x -

Incr

easi

ng t

he

rat

e o

f IV

flui

d ad

min

istr

atio

n -

Ele

vatio

n o

f lo

we

r ext

rem

ities

-

Use

of p

ress

or

agen

ts,

such

as

glyc

opyr

rola

te,

atro

pine

or

ep

he

dri

ne

• Be

cau

se P

rece

dex

de

cre

ase

s sy

mp

ath

etic

ne

rvo

us

syst

em

activ

ity,

hypo

tens

ion

an

d/o

r bra

dyca

rdia

ma

y b

e e

xpec

ted

to b

e m

ore

pron

ounc

ed in

hyp

ovol

emic

pat

ient

s an

d in

p

atie

nts

with

dia

bete

s m

ellit

us o

r ch

roni

c hy

pert

ensi

on,

as

wel

l as

in th

e el

derly

. 1

• B

eca

use

Pre

cede

x h

as

the

pot

entia

l to

au

gm

en

t bra

dyca

rdia

in

duce

d b

y va

gal s

timul

i, cl

inic

ian

s sh

ould

be

pre

pare

d to

inte

rven

e w

ith a

ntic

holin

ergi

c a

ge

nts

(e.g

., at

ropi

ne,

glyc

opyr

rola

te o

r ep

hedr

ine)

to m

od

ify v

agal

ton

e.1 •3

• Cau

tion

sho

uld

be

exe

rcis

ed w

hen

ad

min

iste

rin

g P

rece

dex

to p

atie

nts

with

adv

ance

d h

ea

rt b

lock

an

d/o

r sev

ere

ven

tric

ula

r dy

sfun

ctio

n.1

• U

se w

ith c

autio

n w

he

n c

oa

dm

inis

teri

ng

with

oth

er

vaso

dila

tors

or

nega

tive

chro

no

tro

pic

ag

en

ts d

ue

to a

dd

itive

p

ha

rma

cod

yna

mic

effe

cts.

1

• Tra

nsie

nt h

yper

tens

ion

ha

s b

ee

n o

bse

rve

d p

rim

ari

ly d

uri

ng

th

e lo

adin

g d

ose

in a

sso

cia

tion

with

th

e in

itial

per

iphe

ral

vaso

con

stri

ctiv

e e

ffect

s o

f P

rece

dex.

Tre

atm

ent

ha

s g

en

era

lly n

ot

been

nec

essa

ry,

alth

ou

gh

red

uctio

n o

f the

lo

ad

ing

infu

sion

rat

e m

ay

be

des

irabl

e.1

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..,

ICU

Sed

atio

n

•In

two

piv

otal

Pha

se I

ll cl

inic

al t

ria

ls o

f IC

U p

atie

nts

trea

ted

with

Pre

cede

x®,

the

larg

est m

ea

n d

ecr

ea

se in

he

art

rat

e w

as a

pp

roxi

ma

tely

7%

an

d th

e la

rges

t m

ean

de

cre

ase

s in

sy

stol

ic a

nd

dia

stol

ic b

loo

d p

ress

ure

s w

ere

10%

an

d 1

1%,

resp

ectiv

ely.

2

Pro

ced

ura

l S

edat

ion

4

• P

rece

dex

ha

s be

en s

tudi

ed in

tw

o p

ivot

al P

ha

se I

ll cl

inic

al tr

ials

of n

on

intu

ba

ted

pat

ient

s re

ceiv

ing

mon

itore

d a

ne

sth

esi

a c

are

(M

AC

) se

datio

n fo

r a

vari

ety

of

surg

ical

pr

oced

ures

as

wel

l as

patie

nts

un

de

rgo

ing

aw

ake

fiber

optic

in

tuba

tion.

1

• Th

e t

able

on

page

5 s

ho

ws

the

fre

qu

en

cy a

t w

hich

P

rece

dex-

seda

ted

pa

tien

ts u

nder

goin

g M

AC

se

da

tion

may

ex

peri

ence

hyp

oten

sion

or b

rady

card

ia a

nd

the

freq

uenc

y a

t wh

ich

ce

rta

in t

ype

s o

f in

terv

entio

ns m

ay

be

nee

ded

to

ma

na

ge

thes

e ad

vers

e ev

ents

.

Inci

de

nce

an

d I

nte

rve

nti

on

s fo

r H

ypo

ten

sio

n, B

rad

yca

rdia

in

Pa

tien

ts U

nd

erg

oin

g P

roce

du

ral

Se

da

tion

3

Ove

rall

Inci

denc

e

Inte

rven

tion

No

Inte

rven

tion

Req

uire

d In

terv

entio

n R

equi

red

Type

of I

nter

vent

ion

Whe

n R

equi

red*

E

phed

rine

or P

heny

leph

rine

Gly

copy

rro

late

A

tropi

ne

Calc

ium

Chl

orid

e D

opam

ine

IV F

luid

Adm

inis

trat

ion

Pre

cede

x D

ose

Red

uced

P

rece

dex

Dis

cont

inue

d

173

(54%

)

(n=

173)

11

3 (6

5%)

60

(35

%)

(n=

173)

55

(32

%)

2 (1

%)

1 (<

1%)

16

(9%

) 9

(5%

) 1

(<1%

)

45 (

14%

)

(n=

45)

33 (

73%

) 12

(27

0fo)

(n=

45)

1 (2

%)

7 (1

6%)

1 (2

%)

1 (

20fo

)

•Hyp

oten

sion

was

def

ined

in p

ivot

al tr

ial p

roto

cols

in a

bsol

ute

and

rela

tive

tenm

s as

SB

P <

80 m

m H

g, D

BP

<50

mm

Hg

or >

30

% d

ecre

ase

from

pre

stud

y dr

ug

infu

sion

val

ues.

tBra

dyca

rdia

was

def

ined

in p

ivot

al tr

ial p

roto

cols

as

<4

0 b

eats

per

min

ute

or >

30%

dec

reas

e fro

m p

rest

udy

drug

infu

sion

val

ues.

*Oth

er p

ossi

ble

inte

rven

tions

indu

ded

elev

atio

n of

low

er e

xtre

miti

es.

Pat

ient

s m

ay h

ave

rece

ived

mul

tiple

form

s of

inte

rven

tion.

Ple

ase

se

e e

ncl

ose

d f

ull

Pre

scri

bin

g I

nfo

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tio

n.

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Tre

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ent

Op

tio

ns

for

Dru

g-i

nd

uce

d B

rad

ycar

dia

o

r H

ypo

ten

sio

n

In P

rece

dex®

clin

ical

tria

ls,

atro

pine

, gl

ycop

yrro

late

an

d

ephe

drin

e w

ere

effe

ctiv

e in

the

tre

atm

en

t of

mo

st e

pis

od

es

of P

rece

dex-

indu

ced

brad

ycar

dia.

How

ever

, in

so

me

pat

ient

s w

ith s

ign

ifica

nt c

ard

iova

scu

lar d

ysfu

nctio

n, m

ore

adva

nced

re

susc

itativ

e m

ea

sure

s w

ere

requ

ired.

1 •3

Gly

cop

yrro

late

Do

sin

g f

or

Dru

g­

ind

uce

d B

rad

ycar

dia

or

Hyp

ote

nsi

on

Gly

copy

rrol

ate

Inje

ctio

n m

ay

be

use

d d

urin

g su

rge

ry to

co

un

tera

ct d

rug

-in

du

ced

or

vaga

l re

flexe

s an

d th

eir

ass

ocia

ted

arrh

ythm

ias

(e.g

., br

adyc

ardi

a).

It s

houl

d b

e a

dmin

iste

red

intr

aven

ousl

y a

s si

ng

le d

ose

s o

f 0.1

mg

(0.5

ml)

an

d r

epea

ted,

a

s ne

eded

, a

t int

erva

ls o

f 2 to

3 m

inut

es.4

Atr

op

ine

Do

sin

g f

or

Dru

g-i

nd

uce

d

Bra

dyc

ard

ia o

r H

ypo

ten

sio

n

Initi

al s

ing

le d

ose

s in

ad

ults

va

ry fr

om a

rou

nd

0.5

mg

to 1

mg

(5

-10

ml

of a

0.1

mg

/ml s

olut

ion)

. Adm

inis

trat

ion

of l

ess

tha

n

0.5

mg

can

prod

uce

a pa

rado

xica

l br

adyc

ardi

a b

eca

use

of t

he

cent

ral

or

peri

pher

al p

ara

sym

pa

tho

mim

etic

effe

cts

of l

ow

do

ses

in a

dults

.5

Whe

n th

e re

curr

ent u

se o

f atr

opin

e is

ess

entia

l in

pa

tien

ts w

ith

coro

na

ry a

rte

ry d

isea

se,

the

tota

l d

ose

sho

uld

be

res

tric

ted

to 2

to

3 m

g (m

axim

um 0

.03

to 0

.04

mg

/kg

) to

avo

id t

he d

etr

ime

nta

l ef

fect

s o

f atr

opin

e-in

duce

d ta

chyc

ardi

a on

myo

card

ial o

xyge

n

6

dem

and.

Fo

r pa

tien

ts w

ith b

rady

asys

tolic

car

diac

arr

est,

a 1

mg

do

se o

f atr

opin

e is

adm

inis

tere

d in

trav

enou

sly

and

is r

epea

ted

eve

ry 3

to

5 m

inu

tes

if a

syst

ole

pers

ists

. Th

ree

mill

igra

ms

(0.0

4 m

g/k

g)

give

n IV

is a

ful

ly v

agol

ytic

do

se in

mo

st p

atie

nts.

T

he

adm

inis

trat

ion

of t

his

do

se o

f atr

opin

e sh

ould

be

res

erve

d fo

r pa

tien

ts w

ith b

rady

asys

tolic

car

diac

arr

est.

End

otra

chea

l ad

min

istr

atio

n o

f atr

op

ine

can

be

use

d in

pa

tien

ts w

itho

ut

IV a

cces

s. T

he

re

com

me

nd

ed

ad

ult

do

se o

f atr

op

ine

for

en

do

tra

che

al a

dm

inis

tra

tion

is 1

to 2

mg

dilu

ted

to a

tot

al

no

t to

exc

eed

10 m

l of

ster

ile w

ater

or

no

rma

l sa

line.

5

Ep

hed

rin

e D

osi

ng

fo

r D

rug

-in

du

ced

B

rad

ycar

dia

or

Hyp

ote

nsi

on

Ep

he

dri

ne

is in

dica

ted

to c

ount

erac

t th

e h

ypot

ensi

ve e

ffect

s o

f sp

ina

l or

oth

er t

ype

s of

non

topi

cal c

ondu

ctio

n an

esth

esia

. D

ep

en

din

g o

n th

e c

linic

al c

ircu

mst

ance

s, E

ph

ed

rin

e S

ulfa

te

Inje

ctio

n m

ay

be

giv

en s

ubcu

tane

ousl

y, i

ntra

mus

cula

rly

or

intr

aven

ousl

y. U

sua

l ad

ult

dos

e: 2

5 to

50

mg

(ra

nge

10 t

o 5

0 m

g) i

njec

ted

sub

cuta

ne

ou

sly

or

intr

amus

cula

rly

(equ

ival

ent

to 0

.2 to

1 m

l of 5

% s

olu

tion

) is

usu

ally

ade

quat

e to

pre

ven

t or

min

imiz

e hy

pote

nsio

n se

con

da

ry to

spi

nal a

nest

hesi

a. R

ep

ea

t d

ose

s sh

ould

be

gov

ern

ed

by

bloo

d p

ress

ure

res

pons

es.

Ab

sorp

tion

(o

nse

t of a

ctio

n) b

y th

e in

tra

mu

scu

lar

rout

e is

mo

re

rapi

d (w

ithin

10

to 2

0 m

inut

es)

than

by

sub

cuta

ne

ou

s in

ject

ion.

T

he

intr

ave

no

us

rout

e m

ay

be

use

d if

an

imm

ed

iate

eff

ect

is d

esir

ed.6

Ple

ase

se

e e

ncl

ose

d f

ull

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scri

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g I

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Precede~ a

nd

C

on

com

itan

t M

edic

atio

ns

to E

ffec

t C

oa

dm

inis

tra

tion

of P

rece

de

x w

ith a

nest

hetic

s, s

edat

ives

, hy

pnot

ics

an

d o

pio

ids

can

en

ha

nce

the

ph

arm

aco

dyn

am

ic

effe

cts

of t

hese

age

nts.

Spe

cific

stu

die

s ha

ve c

onfir

med

the

se

effe

cts

with

sev

oflu

rane

, is

oflu

rane

, pr

opof

ol,

alfe

ntan

il a

nd

m

idaz

olam

. A d

ecr

ea

se in

the

do

sag

e o

f P

rece

dex

or

the

co

nco

mita

nt a

ge

nt m

ay

be

req

uire

d.1

Th

ese

eff

ect

s h

ave

be

en

de

mo

nst

rate

d in

ph

arm

aco

dyn

am

ic

stu

die

s o

f he

alt

hy

sub

ject

s a

nd

in p

ati

en

ts u

nd

erg

oin

g

sed

ati

on

wh

ile ta

kin

g t

he

me

dic

ati

on

s lis

ted

be

low

.

Th

ese

clin

ical

tri

als

are

of d

iffer

ent d

esi

gn

s in

a v

ari

ety

of

pa

tien

t pop

ulat

ions

. B

eca

use

clin

ical

tri

als

are

con

duct

ed u

nd

er

wid

ely

vary

ing

cond

ition

s, r

ates

obs

erve

d m

ay

no

t be

dir

ectly

co

mpa

red

to o

the

r tri

als

an

d m

ay

no

t alw

ays

refle

ct t

he

rat

es

obse

rved

in p

ract

ice.

8

asev

oflu

rane

. D

exm

ed

eto

mid

ine

0.7

ng

/ml d

ecr

ea

sed

the

MA

C

of s

evof

lu ra

ne b

y 1

7%

in p

atie

nts

und

ergo

ing

elec

tive

surg

ery.

7

blso

flura

ne. L

ow-

an

d h

igh

-do

se in

fusi

ons

of d

exm

ed

eto

mid

ine

de

crea

sed

the

end

-tid

al i

soflu

ran

e c

once

ntra

tion

by

31

%-5

0%

, re

spec

tivel

y, n

ece

ssa

ry to

elic

it th

e d

esir

ed r

esp

on

se in

5

0%

of h

ea

lthy

subj

ects

.8

clso

flura

ne.

De

xme

de

tom

idin

e d

ecr

ea

sed

the

MA

C o

f iso

flura

ne

by

47

% in

pa

tien

ts w

ho a

lso

rece

ived

thi

open

tal a

nd

alfe

ntan

il a

s in

du

ctio

n a

gent

s.9

dMid

azol

am.

In h

ea

lthy

subj

ects

, th

e e

ffec

t of m

ida

zola

m in

co

mbi

natio

n w

ith d

exm

edet

omid

ine

on s

edat

ion

was

syn

ergi

stic

, w

ith g

rea

ter d

egre

es o

f sy

nerg

y oc

curr

ing

at l

ow

er l

evel

s o

f se

datio

n. A

t hi

gher

deg

rees

of s

edat

ion,

th

e a

ugm

enta

tion

of th

e

effe

ct o

f dex

med

etom

idin

e on

mid

azol

am w

as le

ss p

rono

unce

d.8

epro

pofo

l. In

hea

lthy

subj

ects

, d

exm

ed

eto

mid

ine

red

uced

the

pr

opof

ol c

once

ntra

tions

req

uire

d fo

r se

da

tion

an

d s

up

pre

ssio

n

of m

oto

r re

spon

se b

y ap

prox

imat

ely

on

e h

alf.

Pro

pofo

l do

ses

requ

ired

for

seda

tion

an

d in

duct

ion

of a

nest

hesi

a m

ay h

ave

to b

e

redu

ced

in th

e p

rese

nce

of d

exm

edet

omid

ine.

10

'Mo

rph

ine

. A s

ingl

e IV

do

se o

f 1

meg

/kg

de

xme

de

tom

idin

e g

iven

10

min

utes

be

fore

ind

uct

ion

red

uced

pos

tope

rativ

e m

orp

hin

e

cons

umpt

ion

by

28

% a

t ide

ntic

al p

ain

scor

es c

ompa

red

to

cont

rol.

11

9Aife

ntan

il. I

n th

e pr

esen

ce o

f de

xmed

etom

idin

e, l

ess

alfe

ntan

il is

ne

ed

ed

to p

rod

uce

the

sam

e d

eg

ree

of p

ain

relie

f; th

us,

the

im

pa

ct o

n r

espi

rato

ry f

un

ctio

n c

an

be

less

en

ed

by

redu

cing

al

fent

anil

wh

en

coa

dmin

iste

red

with

Pre

cede

x.8

Ple

ase

se

e e

ncl

ose

d f

ull

Pre

scri

bin

g I

nfo

rma

tio

n.

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edeto

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tljecti

oo) 9

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,

Coa

dmin

istr

atio

n o

f P

rece

dex®

with

ane

sthe

tics,

se

dativ

es,

hypn

otic

s a

nd

opi

oids

can

en

ha

nce

th

e p

ha

rma

cod

yna

mic

effe

cts

of t

he

se a

gent

s.

Sp

eci

fic s

tudi

es h

ave

conf

irm

ed t

he

se e

ffect

s w

ith

sevo

flura

ne,

isof

lura

ne,

prop

ofol

, al

fent

anil

an

d

mid

azol

am. A

dec

reas

e in

the

dos

age

of P

rece

dex

or th

e co

ncom

itant

age

nt m

ay

be r

equi

red.

1

In P

hase

Ill

plac

ebo-

cont

rolle

d pi

vota

l tri

als,

pat

ient

s w

ere

adm

inis

tere

d th

e s

tud

y d

rug

as

wel

l as

a r

escu

e se

dativ

e a

s n

ee

de

d to

ach

ieve

an

equ

ival

ent d

ep

th o

f se

datio

n. P

atie

nts

also

rec

eive

d co

nco

mita

nt

mo

rph

ine

or f

enta

nyl

as n

eede

d to

co

ntro

l pa

in.

Diff

eren

ces

in c

oadm

inis

tere

d d

osa

ge

s of

res

cue

seda

tive

and

anal

gesi

cs a

re s

ho

wn

in th

e ta

ble

on p

ag

e 1

1 fo

r pa

tien

ts r

ecei

ving

Pre

ced

ex

an

d p

atie

nts

in th

e pl

aceb

o co

ntro

l gr

oup.

10

Mea

n to

tal

do

sag

es

of c

oa

dm

inis

tere

d s

ed

ati

ves

an

d/o

r m

orp

hin

e in

th

ree

pla

ceb

o-c

on

tro

lled

Ph

ase

Ill p

ivo

tal

tria

ls o

f P

rece

dex

in s

urg

ica

iiCU

pa

tie

nts

an

d p

ati

en

ts

un

de

rgo

ing

MA

C s

ed

ati

on

.1 •12

Stud

y 1

ICU

Seda

tion

Prop

ofol

(m

g)

Stud

y 2

ICU

Seda

tion

Mid

azol

am (

mg)

Stud

y 1

ICU

Seda

tion

Mor

phin

e (m

g/hr

)

Stud

y 2

ICU

Seda

tion

Mor

phin

e (m

g/hr

)

Stud

y 3

MA

C Se

datio

n Fe

ntan

yl (

meg

)

513

19

4.1

0.89

0.83

151

72

5

0.9

to 1

.4*

0.43

0.47

as to

as·

Pat

ient

s in

eac

h st

ud

y w

ere

titra

ted

to a

chie

ve a

n e

quiv

alen

t le

vel o

f sed

atio

n, e

ithe

r a

Ra

msa

y S

edat

ion

Sco

re ;?

:3 o

r a

n

OA

A/S

sco

re ::

;4.1

Pat

ient

s re

ceiv

ed e

ithe

r mo

rph

ine

or f

enta

nyl

as n

ee

de

d t

o m

aint

ain

ad

eq

ua

te a

nalg

esia

.1 •12

'Tw

o P

rece

dex

stre

ngth

s w

ere

used

in th

e tri

al (

1 m

eg/k

g lo

adin

g do

se a

nd 0

.5 m

eg/k

g lo

adin

g do

se,

resp

ectiv

ely,

ove

r 10

miru

tes

and

titra

ted

to e

ffect

).

Ple

ase

se

e e

ncl

ose

d f

ull

Pre

scri

bin

g I

nfo

rma

tio

n.

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tf (

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edeto

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e HCi

tljecti

oo) 11

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Sed

ativ

e P

rofi

le

Pre

cede

x® h

as

a di

ffer

ent m

ech

an

ism

of a

ctio

n th

an o

the

r IV

se

dativ

es,

an

d t

he s

edat

ive

pro

file

ma

y d

iffe

r fro

m t

ha

t of o

the

r IV

se

da

tive

s yo

u ar

e m

ore

acc

ust

om

ed

to u

sing

.1

In p

ivot

al c

linic

al tr

ials

, pa

tient

s w

ere

titra

ted

to a

chie

ve

an

equ

ival

ent

leve

l of s

ed

atio

n u

sing

Pre

ced

ex

alo

ne

or

in

com

bina

tion

with

mid

azol

am,

prop

ofol

, m

orp

hin

e o

r fen

tany

l. A

ll pa

tient

s w

ere

titra

ted

to a

chie

ve e

ithe

r a

Ra

msa

y S

edat

ion

Sco

re ~3 o

r an

OA

A/S

sco

re ::

;4. H

owev

er,

whe

n st

imul

ated

, so

me

pa

tien

ts w

ere

repo

rted

as

aro

usa

ble

an

d a

lert

.1

Th

is is

imp

ort

an

t for

clin

icia

ns

an

d c

areg

iver

s to

und

erst

and

be

cau

se th

e a

bili

ty to

be

aw

aken

ed w

hile

sed

ated

with

P

rece

dex

shou

ld n

ot b

e c

onsi

dere

d a

s e

vid

en

ce o

f a l

ack

of

effic

acy

in t

he a

bse

nce

of o

the

r cl

inic

al s

ign

s an

d sy

mpt

oms.

1

Th

e d

eci

sio

n to

ad

min

iste

r ad

ditio

nal a

nalg

esic

s o

r se

dativ

e m

edic

atio

ns s

houl

d n

ot b

e b

ased

so

lely

on

the

ab

ility

to

aro

use

a p

atie

nt s

ed

ate

d w

ith P

rece

dex.

Th

e a

dditi

ve

ph

arm

aco

dyn

am

ic e

ffect

s of

sed

ativ

e/hy

pnot

ic a

gent

s w

ith

opio

id a

nalg

esic

s m

ay

prod

uce

unw

ante

d si

de

effe

cts.

1

Qu

est

ion

the

pa

tien

t pri

or t

o a

dmin

istr

atio

n o

f add

ition

al

me

dic

atio

ns

to a

sse

ss a

ccur

atel

y th

e s

tatu

s o

f th

e p

atie

nt

befo

re d

eter

min

ing

the

need

for

add

ition

al a

na

lge

sics

or

seda

tive

med

icat

ions

.

Tim

e to

On

set

Fol

low

ing

infu

sion

, P

rece

dex

exhi

bits

a r

apid

dis

trib

utio

n ph

ase

with

a h

alf-

life

of a

bo

ut 6

min

utes

. 1

Bas

ed o

n se

datio

n sc

ores

, a

load

ing

infu

sion

of o

ne

meg

/kg

ove

r a 1

0-m

inut

e p

eri

od

pro

vide

s cl

inic

ally

effe

ctiv

e o

nse

t o

f sed

atio

n g

en

era

lly w

ithin

10

to 1

5 m

inu

tes

aft

er

the

sta

rt o

f th

e in

fusi

on.13

If a

loa

din

g d

ose

is n

ot u

sed,

tim

e to

on

set o

f the

se

dativ

e ef

fect

ma

y b

e e

xten

ded.

Th

e te

rmin

al e

limin

atio

n ha

lf-lif

e o

f P

rece

dex

is a

pp

roxi

ma

tely

2

hour

s.1

12

Tim

e to

Se

da

tive

On

set w

ith

Pre

ced

ex

in H

ea

lth

y N

orm

al

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bje

cts13

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ll ~ if ~ "5l

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)

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meg

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llow

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y a

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sion

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lthy

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l su

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ute

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na

nce

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sion

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hr,

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e R

amsa

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ed

atio

n S

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to

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wa

s ac

hiev

ed a

fter

15

to 3

3 m

inut

es.13

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ase

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ull

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From

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er IV

Sed

ativ

e A

gen

ts

Tra

nsiti

onin

g to

Pre

cede

x in

volv

es m

ain

tain

ing

a b

ala

nce

b

etw

ee

n a

dd

ing

Pre

cede

x a

nd

de

cre

asi

ng

oth

er p

reex

istin

g se

da

tive

s a

nd

/or

op

ioid

s d

ue

to t

he a

dd

itive

ph

arm

aco

dyn

am

ic

effe

cts.

Th

is is

im

po

rta

nt t

o kn

ow

so

tha

t pre

exis

ting

seda

tive

ag

en

ts a

re n

ot t

itrat

ed d

ow

nw

ard

too

qu

ickl

y be

fore

the

se

da

tive

ef

fect

s o

f P

rece

dex

are

ob

serv

ed

, o

r to

o sl

owly

, su

ch th

at

pa

tien

ts a

re o

vers

edat

ed.1

14

• G

en

era

lly in

itiat

e P

rece

dex

ma

inte

na

nce

infu

sio

n a

t 0

.4 m

eg/k

g/hr

. Th

e ti

trat

ion

ran

ge

for

Pre

cede

x in

th

e IC

U

is 0

.2 t

o 0

.7 m

cg/k

g/hr

.1

• Titr

ate

dow

n o

the

r co

nco

mita

nt s

ed

ativ

es

as

pe

r th

eir

di

ffer

ent p

ha

rma

coki

ne

tic/p

ha

rma

cod

yna

mic

pro

files

. •

Ful

l sed

ativ

e ef

fect

of P

rece

dex

is g

en

era

lly n

ot s

ee

n fo

r 2

0 to

30

min

utes

.13

• Adj

ustin

g th

e P

rece

dex

do

se to

o ra

pidl

y (i.

e.,

less

tha

n

20

to 3

0 m

inut

es)

ma

y n

ot a

llow

Pre

cede

x to

rea

ch it

s fu

ll se

da

tive

effe

cts

afte

r ea

ch d

osa

ge

adj

ustm

ent.

13

•In

crea

sing

Pre

ced

ex

do

sag

es

too

rap

idly

cou

ld le

ad

to

over

seda

tion

and

an

incr

ease

d po

tent

ial f

or

side

effe

cts.

1

• D

ecre

asin

g/di

scon

tinui

ng t

he

pat

ient

's p

revi

ous

IV s

edat

ive

the

rap

y p

rio

r to

th

e o

nse

t of

Pre

cede

x co

uld

lea

d t

o p

eri

od

s of

un

de

rse

da

tion

an

d a

n i

ncre

ased

pot

entia

l fo

r ag

itatio

n.

Imp

ort

ant

Ph

arm

aco

dyn

amic

Pro

per

ties

o

f P

rece

dex

to U

nd

erst

and

Wh

en

Tra

nsi

tio

nin

g f

rom

Oth

er IV

Sed

ativ

es

Coa

dmin

istr

atio

n of

ane

sthe

tics,

sed

ativ

es,

hypn

otic

s a

nd

op

ioid

s w

ith P

rece

dex

can

enha

nce

the

pha

rmac

odyn

amic

ef

fect

s of

the

se a

gent

s a

nd

a d

ecr

ea

se in

th

e d

osag

e of

P

rece

dex

or t

he

con

com

itant

med

icat

ion

ma

y b

e re

quire

d w

hen

initi

atin

g P

rece

dex.

Spe

cific

stu

dies

hav

e co

nfir

med

thes

e ef

fect

s w

ith s

evof

lura

ne,

isof

lura

ne,

prop

ofol

, al

fent

anil

and

mid

azol

am.1

Be

cau

se o

f the

pot

entia

l for

en

ha

nce

d p

ha

rma

cod

yna

mic

ef

fect

s o

f P

rece

dex

in c

om

bin

atio

n w

ith o

the

r IV

se

da

tive

s it

is

espe

cial

ly im

po

rta

nt t

o w

ait

20

to 3

0 m

inut

es a

fter

eac

h d

osa

ge

tit

ratio

n to

de

term

ine

the

exte

nt o

f ea

ch d

osa

ge

mo

difi

catio

n s

o

as

to a

void

ove

rsed

atio

n a

nd

po

ten

tial f

or in

crea

sed

inci

de

nce

o

f sid

e e

ffect

s. 1 •13

With

Pre

cede

x th

e ti

me

to o

nse

t of

so

me

sed

ativ

e ef

fect

is

ge

ne

rally

10

to 1

5 m

inut

es w

hen

a 1

meg

/kg

load

ing

do

se is

ad

min

iste

red

ove

r a

10 m

inu

te p

erio

d. H

owev

er,

if a

loa

din

g

do

se is

no

t us

ed, t

he

initi

atio

n o

f a s

ed

ativ

e e

ffec

t ma

y ex

tend

be

yond

15

min

utes

. 13

Ple

ase

se

e e

ncl

ose

d f

ull

Pre

scri

bin

g I

nfo

rma

tio

n.

{]'\)

Precedex~

tf (

dexm

edeto

midi'l

e HCi

tljecti

oo) 15

)>

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)

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,

Do

sin

g i

n S

pec

ial

Pat

ien

t P

op

ula

tio

ns1

Pre

gn

ancy

Th

ere

are

no

ad

eq

ua

te a

nd w

ell-

cont

rolle

d st

ud

ies

in p

reg

na

nt

wom

en.

Pre

cede

x® s

houl

d b

e u

sed

du

rin

g p

reg

na

ncy

onl

y if

the

po

tent

ial b

en

efit

s ju

stify

the

pote

ntia

l ri

sk to

the

fetu

s.

Lab

or

and

Del

iver

y

Th

e s

afe

ty o

f P

rece

dex

du

rin

g la

bo

r and

de

live

ry h

as

no

t be

en

st

udie

d. T

here

fore

, P

rece

de

x is

no

t re

com

me

nd

ed

dur

ing

lab

or

an

d d

eliv

ery

incl

ud

ing

ces

area

n se

ctio

n d

eliv

erie

s.

Nu

rsin

g M

oth

ers

It is

no

t kn

own

wh

eth

er

Pre

cede

x is

exc

rete

d in

hu

ma

n m

ilk.

Rad

io-l

abel

ed P

rece

dex

adm

inis

tere

d su

bcu

tan

eo

usl

y to

la

ctat

ing

fem

ale

rat

s w

as e

xcre

ted

in m

ilk. B

eca

use

ma

ny

dru

gs

are

excr

eted

in h

um

an

milk

, ca

utio

n sh

ould

be

exe

rcis

ed w

hen

Pre

cede

x is

adm

inis

tere

d to

a n

ursi

ng w

oman

.

Ped

iatr

ic U

se

The

re h

ave

be

en

no

clin

ical

stu

die

s to

est

ablis

h th

e s

afe

ty a

nd

ef

ficac

y o

f Pre

cede

x in

pe

dia

tric

pa

tien

ts b

elo

w 1

8 ye

ars

of a

ge.

The

refo

re,

Pre

cede

x sh

ould

no

t be

use

d in

th

is p

opul

atio

n.

Ger

iatr

ic U

se

Pre

cede

x is

kn

ow

n to

be

sub

sta

ntia

lly e

xcre

ted

by

the

kidn

ey,

and

the

risk

of

adve

rse

reac

tions

to

this

dru

g m

ay

be

gre

ate

r in

pa

tient

s w

ith im

pair

ed r

enal

fun

ctio

n. B

eca

use

eld

erl

y pa

tient

s ar

e m

ore

like

ly to

hav

e d

ecr

ea

sed

ren

al f

unct

ion,

car

e sh

ou

ld

be

take

n in

do

se s

elec

tion

in e

lde

rly

patie

nts,

an

d it

ma

y be

us

eful

to m

on

itor

rena

l fun

ctio

n.

16

Hep

atic

Imp

airm

ent

Sin

ce P

rece

dex

cle

ara

nce

de

cre

ase

s w

ith s

eve

rity

of h

ep

atic

im

pa

irm

en

t, d

ose

red

uctio

n sh

ould

be

con

side

red

in p

atie

nts

w

ith im

pair

ed h

ep

atic

func

tion.

Ren

al I

mp

airm

ent

Pre

cede

x p

ha

rma

coki

ne

tics

(Cm

ax,

T m

ax, A

UC

, t1

12, C

L, a

nd

Vss

) w

ere

no

t sig

nific

antly

diff

eren

t in

pa

tien

ts w

ith s

ever

e re

nal

imp

air

me

nt (

crea

tinin

e cl

eara

nce:

<3

0 m

Um

in)

com

pa

red

to

hea

lthy

subj

ects

. H

owev

er,

the

ph

arm

aco

kin

etic

s o

f th

e

me

tab

olit

es

of

Pre

cede

x ha

ve n

ot b

ee

n e

valu

ated

in p

atie

nts

w

ith im

pair

ed r

enal

fun

ctio

n. S

ince

the

ma

jori

ty o

f m

etab

olite

s ar

e ex

cret

ed in

the

urin

e, i

t is

po

ssib

le th

at t

he

met

abol

ites

may

a

ccu

mu

late

upo

n lo

ng-t

erm

infu

sio

ns

in p

atie

nts

with

im

pair

ed

rena

l fu

nctio

n.

Als

o s

ee

Ge

ria

tric

Use

.

Ple

ase

se

e e

ncl

ose

d f

ull

Pre

scri

bin

g I

nfo

rma

tio

n.

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cede

x®

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dexm

edeto

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e HCi

tljecti

oo) 17

)>

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w to

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on

stit

ute

P

rece

dex®

P

rece

dex

shou

ld b

e d

ilute

d in

0.9

% s

od

ium

chl

orid

e so

lutio

n p

rio

r to

adm

inis

trat

ion.

Pre

para

tion

of s

olu

tion

s is

the

sam

e

wh

eth

er

for

the

load

ing

do

se o

r m

ain

ten

an

ce in

fusi

on.1

To p

repa

re th

e in

fusi

on1 :

18

1. W

ithdr

aw 2

ml o

f Pre

cede

x.

2. A

dd

to 4

8 m

l of 0

.9%

so

diu

m c

hlor

ide

inje

ctio

n to

a t

otal

of 5

0 m

l.

3. S

hake

ge

ntly

to m

ix w

ell.

4. F

inal

co

nce

ntr

atio

n is

4 m

cg/m

l.

Co

mp

atib

ility

P

rece

dex

ha

s b

ee

n s

how

n to

be

CO

MP

AT

IBLE

whe

n ad

min

iste

red

with

the

fol

low

ing

intr

aven

ous

fluid

s: 5

%

dext

rose

in w

ater

, 0

.9%

sod

ium

ch

lori

de

in w

ate

r, la

ctat

ed

Rin

ger's

sol

utio

n. P

rece

dex

is a

lso

com

patib

le w

ith a

nu

mb

er

of a

dd

itio

na

l dru

gs.

Ple

ase

se

e fu

ll P

resc

ribin

g In

form

atio

n fo

r a

com

plet

e lis

t.1

Pre

cede

x h

as

be

en

sh

ow

n to

be

INC

OM

PA

TIB

LE w

he

n

ad

min

iste

red

with

the

follo

win

g d

rug

s: a

mp

ho

teri

cin

B,

diaz

epam

.1

~~~ =·

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~~

.E =:

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:;

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sa!:

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4<

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t.%1i

r

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as

e se

e e

ncl

os

ed f

ull

Pre

scri

bin

g I

nfo

rmat

ion

.

®P

rece

dex

®

· 0

(deXJ

redeto

micil

e OCI

ij!ctio

o) 19

)>

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. 0

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Do

sin

g f

or

No

nin

tub

ated

P

atie

nts

Req

uir

ing

S

edat

ion

fo

r S

urg

ical

o

r O

ther

Pro

ced

ure

s

20 •

Pre

cede

x® s

ho

uld

be

dilu

ted

in 0

.9%

sod

ium

chl

orid

e so

lutio

n p

rio

r to

adm

inis

trat

ion.

Pre

para

tion

of s

olut

ions

is

the

sam

e w

he

the

r fo

r th

e lo

adin

g do

se o

r m

aint

enan

ce

infu

sion

. To

pre

pa

re th

e in

fusi

on1

:

-W

ithdr

aw 2

ml o

f Pre

cede

x.

-A

dd t

o 4

8 m

l of 0

.9%

sod

ium

ch

lori

de

inje

ctio

n to

a t

otal

of 5

0 m

l.

-S

hake

ge

ntly

to m

ix w

ell.

-F

inal

con

cent

ratio

n is

4 m

cg/m

l.

• P

rece

dex

dosi

ng s

houl

d b

e in

divi

dual

ized

and

titr

ated

to

the

des

ired

clin

ical

effe

ct. 1

• P

rece

dex

is n

ot

indi

cate

d fo

r in

fusi

ons

last

ing

lon

ge

r th

an 2

4 h

ours

.1

• P

rece

dex

sho

uld

be

adm

inis

tere

d u

sin

g a

con

trol

led

infu

sion

dev

ice

(IV

pu

mp

).1

Adu

lt pa

tient

s an

d pr

oced

ures

Less

inva

sive

pr

oced

ures

(e

.g.,

opht

halm

ic)

Pat

ient

s ov

er 6

5 yr

s

Pat

ient

s w

ith

im

paire

d he

patic

or

ren

al f

unct

ion

Aw

ake

fiber

optic

in

tuba

tion

1 m

eg/k

g ov

er

10 m

inut

es*

0.5

meg

/kg

over

10

min

utes

may

be

suita

ble

0.5

meg

/kg

over

10

min

utes

A d

ose

redu

ctio

n sh

ould

be

cons

ider

ed

1 m

eg/k

g ov

er

10 m

inut

es

• Fo

llow

ed b

y 0.

6 m

cg/k

g/hr

• T

itrat

e to

effe

ct

wit

h d

oses

from

0.

2-1

mcg

/kg/

hr

• R

ate

of i

nfus

ion

shou

ld

be a

djus

ted

to a

chie

ve

targ

eted

leve

l of s

edat

ion

• A

red

uctio

n in

m

aint

enan

ce d

osag

e sh

ould

be

cons

ider

ed

• A

red

uctio

n in

m

aint

enan

ce d

osag

e sh

ould

be

cons

ider

ed

• Fo

llow

ed b

y 0.

7 m

cg/k

g/hr

u

ntil

end

otra

chea

l tub

e is

sec

ured

·coa

<tni

nist

ratio

n of

Pre

cede

x w

ith a

nest

hetic

s, s

edat

ives

, hy

pnot

ics

and

opio

ids

can

enha

nce

the

phar

mac

odyn

amic

effe

cts

of th

ese

agen

ts. S

peci

fic s

tudi

es

have

con

firm

ed th

ese

effe

cts

with

sev

oflu

rane

, is

oflu

rane

, pr

opof

ol,

alfe

ntan

il an

d m

idaz

olam

. A d

ecre

ase

in th

e do

sage

of P

rece

dex

or th

e co

ncom

itant

age

nt

may

be

requ

ired.

In p

atie

nts

alre

ady

seda

ted

with

oth

er a

nest

hetic

s, s

edat

ives

, hy

pnot

ics

or o

pioi

d an

alge

sics

, a lo

adin

g do

se m

ay n

ot b

e ne

cess

ary.

Ple

ase

see

encl

ose

d f

ull

Pre

scri

bin

g I

nfo

rmat

ion

.

{]'\)

Precedex~

tf (

dexm

edeto

midi1

e HCi

tljecti

oo) 21

Pre

cede

x® D

osin

g fo

r P

roce

dura

l S

edat

ion

B

ased

on

4 m

cg

/ml c

on

cen

tra

tion

Loa

ding

Dos

e14

Pre

cede

x is

ge

ne

rally

initi

ated

with

a l

oa

din

g i

nfu

sio

n

of

1 m

eg

/kg

ove

r 10

min

ute

s. C

oa

dm

inis

tra

tion

of P

rece

de

x w

ith a

ne

sth

etic

s, s

ed

ativ

es,

hyp

no

tics

an

d o

pio

ids

can

en

ha

nce

th

e p

ha

rma

cod

yna

mic

eff

ects

of t

he

se a

ge

nts

. S

pe

cific

stu

die

s h

ave

co

nfir

me

d t

he

se e

ffec

ts w

ith s

evo

flura

ne

, is

oflu

ran

e,

prop

ofol

, al

fent

anil

an

d m

ida

zola

m. A

de

cre

ase

in t

he

do

sag

e

of

Pre

cede

x o

r th

e c

on

com

ita

nt a

ge

nt m

ay

be

req

uire

d. I

n p

atie

nts

alr

ea

dy

sed

ate

d w

ith o

the

r an

est

he

tics,

se

da

tive

s o

r o

pio

id a

na

lge

sics

, a

loa

din

g d

ose

ma

y n

ot b

e n

ece

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ry.1

50

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12

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5

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105

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11

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8 IN

FU

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aint

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the

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draw

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to a

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50 m

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uctio

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uctio

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·coa

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atio

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Pre

cede

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ith a

nest

hetic

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edat

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enha

nce

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cts

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agen

ts. S

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firm

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cts

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atie

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cess

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itiat

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tes.

Co

ad

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istr

atio

n o

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est

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ce

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aco

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ffec

ts o

f th

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en

ts.

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fic s

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ies

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ve c

on

firm

ed

th

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ects

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se

voflu

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e,

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ntan

il a

nd

mid

azo

lam

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ecr

ea

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th

e d

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ge

of

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cede

x o

r th

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nt

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y b

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eq

uir

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12

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24.5

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28

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27

31

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81

NF

USI

ON

RAT

E (m

l/h

r) Th

e ra

te o

f the

mai

nten

ance

infu

sion

sho

uld

be a

djus

ted

from

0.2

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to a

chie

ve th

e de

sire

d ef

fect

<f) P

recedex

~ (de

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Otomi

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HCil1j

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o) 27

References:

1. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2008. 2. Data on file, #3. Hospira, Inc. 3. Data on file, #4. Hospira, Inc. 4. Robinul [package insert]. Deerfield, IL: Baxter Healthcare Corporation; 2007. 5. Atropine [package insert]. Lake Forest, IL: Hospira, Inc; 2006. 6. Ephedrine [package insert]. Lake Forest, IL: Hospira, Inc; 2004. 7. Fragen RJ, Fitzgerald PC. Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. J Clin Anesth. 1999;11 (6):466-470. 8. Karol M, Maze M. Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans. Best Pract & Res Clin Anaesthesia/. 2000; 14(2):261-269. 9. Aantaa R, Jaakola ML, Kallio A, Kanto J. Reduction of the minimum alveolar concentration of isoflurane by dexmedetomidine. Anesthesiology. 1997;86(5):1055-1060. 10. Dutta S, Karol MD, Cohen T, Jones RM, Mant T. Effect of dexmedetomidine on propofol requirements in healthy subjects. J Pharm Sci. 2001 ;90(2): 172-181. 11. Unlugenc H, Gunduz M, Guier T, Yagmur 0, lsik G. The effect of pre-anaesthetic administration of intravenous dexmedetomidine on postoperative pain in patients receiving patient-controlled morphine. Eur J Anaesthesia/. 2005;22(5):386-391. 12. Hospira Clinical Study Report 2005-005. 13. Data on file, #2. Hospira, Inc. 14. Data on file, #7. Hospira, Inc.

Robinul is a registered trademark of Wyeth.

0\J Precedex® v (deXIllE!detarin 1[1 ~)

www.precedex.com

Hospi ra, Inc. 275 North Reid Drive, Lake Forest. IL 60045 P09 -1B74-0ct, 09. Printed in the USA.

ftp Hosp1ra Afkoncing ~/ness'~~~

For more information on Advancing WellnesslM, contact your Hospi ra representative

at 1-877-9HOSPIRA (1-877-946-7747) or visit www.hospi ra.com.

Petit ion for Inter Partes Review of US 8,455,527 Amneal Pharmaceuticals LLC - Exhibit 1063 - Page 15