Risk Evaluation and Mitigation Strategy (REMS) Document ... · Intestinal obstruction has been reported in clinical studies. In patients who develop intestinal or stomal obstruction,

Risk Evaluation and Mitigation Strategy (REMS) Document

GATTEX (teduglutide) REMS Program

I. Administrative Information

Application Number: NDA 203441Application Holder: Shire-NPS Pharmaceuticals, Inc.Initial REMS Approval: 12/2012Most Recent REMS Update: 07/2020

II. REMS Goals

The goals of the GATTEX REMS are to mitigate the risks of possible acceleration of neoplastic growth andenhancement of colon polyp growth, gastrointestinal obstruction, and biliary and pancreatic disordersassociated with GATTEX by:

1. Informing patients about the risks listed above associated with the use of GATTEX

2. Informing healthcare providers about the risks listed above associated with GATTEX

III. REMS Requirements

Shire-NPS Pharmaceuticals, Inc. must provide training to healthcare providers who prescribeGattex.The training includes the following educational materials: Prescribing Information, Medication Guide, DearHealthcare Professional Letter, Prescriber Education Slide Deck, Post-Training Knowledge AssessmentQuestions, and Patient and Caregiver Counseling Guide. The training must be available online via theREMS website www.GATTEXREMS.com, by calling the REMS Program Call Center, during prescriber visitsby Shire representatives, at professional society meetings, and at medical educational venues where Shirehas a presence. In addition, the Prescriber Education Slide Deck must be part of training/educationalprograms provided by medical science liaisons.

Target Audience Communication Materials & Dissemination PlansHealthcare providerswho are likely toprescribe GATTEX

REMS Letter: Dear Healthcare Professional Letter with attachment:Prescriber Education Slide Deck

1. Mail or email to prescribers within 60 calendar days of their initialprescription who are identified as untrained, and again 12 and24 months later.

2. Mail or email to healthcare providers who inquire about how tobecome trained and request hard copies of the training materials.

3. Mail or email to healthcare providers who have not written aprescription for GATTEX within 12 months of completing the REMStraining.

Reference ID: 4640332

To support REMS Program operations, Shire-NPS Pharmaceuticals, Inc. must:

1. Establish and maintain a REMS Program website, www.GATTEXREMS.com. The REMS Programwebsite must include the capability to complete prescriber training online, and the option to printthe Prescribing Information, Medication Guide, and REMS materials. All product websites forconsumers and healthcare providers must include prominent REMS-specific links to the REMSProgram website. The REMS Program website must not link back to the promotional productwebsite(s).

2. Make the REMS Program website fully operational and all REMS materials available through theREMS website and REMS call center within 60 calendar days of REMS modification.

3. Establish and maintain a REMS Program call center for REMS participants at 1-855-5GATTEX(1-855-542-8839).

4. Establish and maintain a validated, secure database of all healthcare providers who havecompleted training for the GATTEX REMS Program.

5. Ensure healthcare providers are able to report completion of training by fax at 1-855-359-3393and online.

IV. REMS Assessment Timetable

Shire-NPS Pharmaceuticals, Inc. must submit REMS Assessments at 12 months from the date of the initialREMS (12/21/2012) and annually thereafter. To facilitate inclusion of as much information as possiblewhile allowing reasonable time to prepare the submission, the reporting interval covered by eachassessment should conclude no earlier than 60 calendar days before the submission date for thatassessment. Shire-NPS Pharmaceuticals, Inc. must submit each assessment so that it will be received bythe FDA on or before the due date.

V. REMS Materials

The following materials are part of the GATTEX REMS:

Training and Educational MaterialsPrescriber:

1. Prescriber Education Slide Deck2. Dear Healthcare Professional Letter3. Post-Training Knowledge Assessment Questions

Patient:4. Patient and Caregiver Counseling Guide

Other Materials5. REMS website


Shire

-NPS

Pha

rmac

eutic

als,

Inc.

300

Shire

Way

, Lex

ingt

on, M

A 0

2421

GATT

EX®

(tedu

glut

ide)

REM

S Pr

escr

iber

Educ

atio

n Sl

ide D

eck

A RE

MS

(Risk

Eva

luat

ion

and

Miti

gatio

n St

rate

gy) i

s a p

rogr

am re

quire

d by

the

FDA

to m

anag

e kn

own

or p

oten

tial

serio

us ri

sks a

ssoc

iate

d w

ith a

dru

g pr

oduc

t. Th

e Pr

escr

iber

Edu

catio

n Sl

ide

Deck

is re

quire

d by

the

FDA

as p

art o

f th

e GA

TTEX

REM

S.

MM

/YY


Tabl

e of

Con

tent

s

Topi

cSl

ide

Indi

catio

n3

Ove

rvie

w:I

mpo

rtan

t Adv

erse

Rea

ctio

ns o

f Spe

cial

Inte

rest

4Po

ssib

le A

ccel

erat

ion

of N

eopl

astic

Gro

wth

5

Enha

nced

Gro

wth

of C

olor

ecta

l Pol

yps

7In

test

inal

Obs

truc

tion

10Ga

llbla

dder

and

Bilia

ry T

ract

Dise

ase

13Pa

ncre

atic

Dise

ase

15Fl

uid

Ove

rload

18In

crea

sed

Abso

rptio

n of

Con

com

itant

Ora

l Med

icat

ion

22

2


Indi

catio

n

GLP-

2, g

luca

gon-

like

pept

ide-

2

GA

TTEX

® (t

edug

lutid

e) fo

r inj

ectio

n is

indi

cate

d fo

r the

tr

eatm

ent o

f adu

lts a

nd p

edia

tric

pat

ient

s 1ye

ar o

f age

and

ol

der w

ith S

hort

Bow

el S

yndr

ome

(SBS

) who

are

dep

ende

nt o

n pa

rent

eral

supp

ort.

Te

dugl

utid

e is

a re

com

bina

nt a

nalo

g of

GLP

-2.

3


Ove

rvie

wIm

port

ant A

dver

se R

eact

ions

of S

peci

al In

tere

st

Sa

fety

risk

s with

GAT

TEX

–Po

ssib

le a

ccel

erat

ion

of n

eopl

astic

gro

wth

–En

hanc

ed g

row

th o

f col

orec

tal p

olyp

s

–In

test

inal

obs

truc

tion

–Ga

llbla

dder

, bili

ary

trac

t and

pan

crea

tic d

iseas

e

–In

crea

sed

abso

rptio

n of

flui

ds le

adin

g to

flui

d ov

erlo

ad in

pa

tient

s with

car

diov

ascu

lar d

iseas

e

–In

crea

sed

abso

rptio

n of

ora

l med

icat

ions

4


Poss

ible

Acc

eler

atio

n of

Neo

plas

tic G

row

th

GL

P-2

rece

ptor

s are

loca

lized

mai

nly

in th

e GI

trac

t.1

GA

TTEX

pro

mot

es g

row

th o

f int

estin

al e

pith

elia

l cel

ls in

the

GI tr

act.

It

cann

ot b

e ex

clud

ed th

at G

ATTE

X pr

omot

es g

row

th o

f exi

stin

g ne

opla

sms i

n th

e GI

trac

t.

3

adul

t pat

ient

s on

GATT

EX w

ere

repo

rted

to h

ave

neop

lasm

s:*

–2 c

ases

of l

ung

canc

er w

ith e

xten

sive

smok

ing

hist

ory

–1 c

ase

of G

I met

asta

tic a

deno

carc

inom

a (u

nkno

wn

orig

in)

follo

win

g ab

dom

inal

radi

atio

n fo

r Hod

gkin

’s di

seas

e

N

o GA

TTEX

-trea

ted

pedi

atric

pat

ient

s wer

e re

port

ed to

hav

e ne

opla

sms i

n th

e pe

diat

ric c

linic

al st

udie

s.**

1.M

unro

e DG

et a

l. P

roc

Nat

l Aca

d Sc

i. 19

99; 9

6:15

69-1

573.

*

As o

f 24

Janu

ary

2013

; **

As o

f 24

July

201

85


Poss

ible

Acc

eler

atio

n of

Neo

plas

tic G

row

thGA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Poss

ible

Acc

eler

atio

n of

Neo

plas

tic G

row

th–

Base

d on

the

phar

mac

olog

ic a

ctiv

ity a

nd fi

ndin

gs in

ani

mal

s, G

ATTE

X ha

s the

pot

entia

l to

caus

e hy

perp

last

ic c

hang

es in

clud

ing

neop

lasia

.–

In p

atie

nts a

t inc

reas

ed ri

sk fo

r mal

igna

ncy,

the

clin

ical

dec

ision

to u

se

GATT

EX sh

ould

be

cons

ider

ed o

nly

if th

e be

nefit

s out

wei

gh th

e ris

ks.

–In

pat

ient

s who

dev

elop

act

ive

gast

roin

test

inal

mal

igna

ncy

(GI t

ract

, he

pato

bilia

ry, p

ancr

eatic

) whi

le o

n GA

TTEX

, disc

ontin

ue G

ATTE

X tr

eatm

ent.

–In

pat

ient

s who

dev

elop

act

ive

non-

gast

roin

test

inal

mal

igna

ncy

whi

le

on G

ATTE

X, th

e cl

inic

al d

ecisi

on to

con

tinue

GAT

TEX

shou

ld b

e m

ade

base

d on

risk

-ben

efit

cons

ider

atio

ns.

–Ba

sed

on tu

mor

find

ings

in th

e ra

t and

mou

se c

arci

noge

nici

ty st

udie

s,

patie

nts s

houl

d be

mon

itore

d cl

inic

ally

for s

mal

l bow

el n

eopl

asia

. If a

be

nign

neo

plas

m is

foun

d, it

shou

ld b

e re

mov

ed. I

n ca

se o

f sm

all

bow

el c

ance

r, GA

TTEX

ther

apy

shou

ld b

e di

scon

tinue

d.

6


GA

TTEX

’s m

echa

nism

of a

ctio

n an

d no

nclin

ical

dat

a ar

e co

nsist

ent w

ith a

po

tent

ial t

o en

hanc

e gr

owth

of p

olyp

s.

In

the

adul

t clin

ical

stud

ies,

14

patie

nts w

ith S

BS w

ere

diag

nose

d w

ith

poly

ps o

f the

GI t

ract

aft

er in

itiat

ion

of st

udy

trea

tmen

t.

In

the

pedi

atric

clin

ical

stud

ies (

up to

69

wee

ks o

f exp

osur

e) th

ere

was

one

ca

se o

f cec

alpo

lyp

that

was

not

bio

psie

d an

d w

as n

ot se

en o

n re

peat

co

lono

scop

y.**

Enha

nced

Gro

wth

of C

olor

ecta

l Pol

yps

* As

of 2

4 Ja

nuar

y 20

13; *

* As

of 2

4 Ju

ly 2

018

7

•12

GAT

TEX-

trea

ted

patie

nts (

12/1

73; 6

.9%

) in

the

exte

nsio

n st

udie

s:*

–2

colo

rect

al v

illou

s ade

nom

as–

2 hy

perp

last

ic p

olyp

s–

4 co

lore

ctal

tubu

lar a

deno

ma

–1

serr

ated

ade

nom

a–

1 re

ctal

infla

mm

ator

y po

lyp

–1

colo

rect

al p

olyp

bio

psy

not d

one

–1

smal

l duo

dena

l pol

yp

•2

patie

nts i

n th

e SB

S-pl

aceb

o-co

ntro

lled

stud

ies:

2 c

olor

ecta

l vill

ous a

deno

mas

–1

patie

nt (1

/59;

2%

) on

plac

ebo

with

an

infla

mm

ator

y st

omal

pol

yp

afte

r 3 m

onth

s–

1 pa

tient

(1/1

09; 1

%) o

n GA

TTEX

0.

05 m

g/kg

/day

with

a h

yper

plas

tic

sigm

oida

l pol

yp a

fter

5 m

onth

s


Colo

rect

al P

olyp

s in

adul

ts

–Co

lono

scop

y of

the

entir

e co

lon

with

rem

oval

of p

olyp

s sh

ould

be

done

with

in 6

mon

ths p

rior t

o st

artin

g tr

eatm

ent

with

GAT

TEX.

–A

follo

w-u

p co

lono

scop

y (o

r alte

rnat

e im

agin

g) is

re

com

men

ded

at th

e en

d of

1 y

ear o

f GAT

TEX.

–Su

bseq

uent

col

onos

copi

es sh

ould

be

done

eve

ry 5

yea

rs o

r m

ore

ofte

n as

nee

ded.

If a

pol

yp is

foun

d, a

dher

ence

to

curr

ent p

olyp

follo

w-u

p gu

idel

ines

is re

com

men

ded.

–In

cas

e of

dia

gnos

is of

col

orec

tal c

ance

r, GA

TTEX

ther

apy

shou

ld b

e di

scon

tinue

d.

Enha

nced

Gro

wth

of C

olor

ecta

l Pol

yps

GATT

EX L

abel

–W

arni

ngs a

nd P

reca

utio

ns

8


Colo

rect

al P

olyp

s in

child

ren

and

adol

esce

nts

–Fe

cal o

ccul

t blo

od te

stin

g pr

ior t

o in

itiat

ing

trea

tmen

t with

GA

TTEX

shou

ld b

e do

ne.

–Co

lono

scop

y/sig

moi

dosc

opy

is re

quire

d if

ther

e is

unex

plai

ned

bloo

d in

the

stoo

l.

–Su

bseq

uent

feca

l occ

ult b

lood

test

ing

annu

ally

in c

hild

ren

and

adol

esce

nts s

houl

d be

per

form

ed w

hile

they

are

re

ceiv

ing

GATT

EX.

–Co

lono

scop

y/sig

moi

dosc

opy

is re

com

men

ded

for a

ll ch

ildre

n an

d ad

oles

cent

s afte

r 1 y

ear o

f tre

atm

ent,

ever

y 5

year

s th

erea

fter

whi

le o

n co

ntin

uous

trea

tmen

t with

GAT

TEX,

and

if

they

hav

e ne

w o

r une

xpla

ined

gas

troi

ntes

tinal

ble

edin

g.

Enha

nced

Gro

wth

of C

olor

ecta

l Pol

yps

GATT

EX L

abel

–W

arni

ngs a

nd P

reca

utio

ns

9


Inte

stin

al O

bstr

uctio

n

12

adu

lt pa

tient

s wer

e re

port

ed to

hav

e on

e or

mor

e ep

isode

s of s

erio

us in

test

inal

ob

stru

ctio

n/st

enos

is ev

ents

*

–6

in S

BS p

lace

bo-c

ontr

olle

d st

udie

s

•3/

77 (3

.9%

) on

GATT

EX, 0

.05

mg/

kg/d

ay

•3/

32 (9

.4%

) on

GATT

EX, 0

.10

mg/

kg/d

ay**

•N

one

in p

lace

bo-g

roup

•O

nset

1 d

ay to

6 m

onth

s

•2/

6 pa

tient

s had

recu

rren

ce o

f int

estin

al o

bstr

uctio

n in

the

exte

nsio

n st

udie

s

–6

addi

tiona

l pat

ient

s in

the

exte

nsio

n st

udie

s (al

l on

GATT

EX, 0

.05

mg/

kg/d

ay)

•O

nset

6 d

ays t

o 19

mon

ths

–O

f all

8 pa

tient

s with

an

episo

de o

f int

estin

al o

bstr

uctio

n/st

enos

is in

the

exte

nsio

n st

udie

s, 2

pat

ient

s req

uire

d en

dosc

opic

dila

tatio

n an

d 1

requ

ired

surg

ical

inte

rven

tion

* As

of 2

4 Ja

nuar

y 20

13; *

* N

ote

that

as p

er th

e GA

TTEX

Pre

scrib

ing

Info

rmat

ion,

the

reco

mm

ende

d do

sage

of G

ATTE

X fo

r bot

h ad

ult a

nd p

edia

tric

pat

ient

s is

0.05

mg/

kg/d

ay10


Inte

stin

al O

bstr

uctio

n

1

pedi

atric

pat

ient

was

repo

rted

to h

ave

a se

rious

reac

tion

of

obst

ruct

ion

that

was

ass

esse

d as

rela

ted

to te

dugl

utid

e in

the

pedi

atric

clin

ical

stud

ies.

**

–GA

TTEX

was

tem

pora

rily

with

held

, the

obs

truc

tion

reso

lved

w

ithou

t add

ition

al in

terv

entio

n, a

nd th

ere

was

no

recu

rren

ce

once

GAT

TEX

was

rest

arte

d.

** A

s of 2

4 Ju

ly 2

018

11


Inte

stin

al O

bstr

uctio

n GA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Inte

stin

al O

bstr

uctio

n

–In

test

inal

obs

truc

tion

has b

een

repo

rted

in c

linic

al st

udie

s an

d po

stm

arke

ting.

–In

pat

ient

s who

dev

elop

inte

stin

al o

r sto

mal

obs

truc

tion,

GA

TTEX

shou

ld b

e te

mpo

raril

y di

scon

tinue

d w

hile

the

patie

nt is

clin

ical

ly m

anag

ed.

–GA

TTEX

may

be

rest

arte

d w

hen

the

obst

ruct

ive

pres

enta

tion

reso

lves

, if c

linic

ally

indi

cate

d.

12


Gallb

ladd

er a

nd B

iliar

y Tr

act D

iseas

e

* As

of 2

4 Ja

nuar

y 20

13; *

*As o

f 24

July

201

813

13

/173

(7.5

%) o

f GAT

TEX-

trea

ted

adul

t pat

ient

s wer

e re

port

ed to

ha

vebi

liary

eve

nts,

incl

udin

g ch

olec

ystit

is an

d ga

llsto

nes/

sludg

e in

po

oled

Pha

se II

I SBS

stud

ies*

–5

adul

t pat

ient

s had

a h

istor

y of

bili

ary

dise

ase

–N

one

of th

ese

even

ts re

sulte

d in

stud

y w

ithdr

awal

N

o GA

TTEX

-trea

ted

pedi

atric

pat

ient

s wer

e re

port

ed to

hav

ebi

liary

eve

nts r

elat

ed to

tedu

glut

ide

in th

e pe

diat

ric c

linic

al

stud

ies.

**


Gallb

ladd

er a

nd B

iliar

y Tr

act D

iseas

eGA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Gallb

ladd

er a

nd B

iliar

y Tr

act D

iseas

e

–Ch

olec

ystit

is, c

hola

ngiti

s, a

nd c

hole

lithi

asis

have

bee

n re

port

ed in

clin

ical

stud

ies a

nd p

ostm

arke

ting.

–Pa

tient

s sho

uld

unde

rgo

labo

rato

ry a

sses

smen

t of b

iliru

bin

and

alka

line

phos

phat

ase

with

in 6

mon

ths p

rior t

o st

artin

g GA

TTEX

.

–Su

bseq

uent

labo

rato

ry a

sses

smen

ts a

re re

com

men

ded

at

leas

t eve

ry 6

mon

ths w

hile

on

GATT

EX. I

f clin

ical

ly

mea

ning

ful c

hang

es a

re se

en, f

urth

er e

valu

atio

n in

clud

ing

imag

ing

of th

e ga

llbla

dder

and

/or b

iliar

y tr

act i

s re

com

men

ded.

Rea

sses

s the

nee

d fo

r con

tinue

d GA

TTEX

tr

eatm

ent.

14


Panc

reat

ic D

iseas

e

3/

173

(1.7

%) o

f GAT

TEX-

trea

ted

adul

t pat

ient

s wer

e re

port

ed

to h

ave

panc

reat

itis i

n po

oled

Pha

se II

I SBS

stud

ies.

*

–Al

l 3 p

atie

nts h

ad a

hist

ory

of p

ancr

eatit

is

–N

one

of th

ese

even

ts re

sulte

d in

stud

y w

ithdr

awal

N

o GA

TTEX

-trea

ted

patie

nts w

ere

repo

rted

to h

ave

panc

reat

ic

adve

rse

even

ts re

late

d to

tedu

glut

ide

in th

e pe

diat

ric c

linic

al

stud

ies.

**

* As

of 2

4 Ja

nuar

y 20

13; *

*As o

f 24

July

201

815


Panc

reat

ic D

iseas

e GA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Panc

reat

ic D

iseas

e

–Pa

ncre

atiti

s has

bee

n re

port

ed in

adu

lt cl

inic

al st

udie

s.

–Pa

tient

s sho

uld

unde

rgo

labo

rato

ry a

sses

smen

t of

lipas

e an

d am

ylas

e w

ithin

6 m

onth

s prio

r to

star

ting

GATT

EX.

–Su

bseq

uent

labo

rato

ry a

sses

smen

ts a

re re

com

men

ded

at

leas

t eve

ry 6

mon

ths w

hile

on

GATT

EX; i

f clin

ical

ly

mea

ning

ful c

hang

es a

re se

en, f

urth

er e

valu

atio

n su

ch a

s im

agin

g of

the

panc

reas

is re

com

men

ded;

reas

sess

the

need

fo

r con

tinue

d GA

TTEX

trea

tmen

t.

16


Post

-mar

ketin

g Da

ta S

ourc

e: In

test

inal

Obs

truc

tion,

Bi

liary

and

Pan

crea

tic D

iseas

e

Al

l pos

t mar

ketin

g da

ta a

re re

view

ed o

n an

ong

oing

bas

is.

No

new

saf

ety

findi

ngs h

ave

been

unc

over

ed re

gard

ing

inte

stin

al o

bstr

uctio

n, b

iliar

y or

pan

crea

tic d

iseas

e.

As

of 3

0 Au

gust

201

8, e

stim

ated

cum

ulat

ive

wor

ldw

ide

patie

nt e

xpos

ure

to te

dugl

utid

e w

as 4

,740

pat

ient

-yea

rs.

17

Risk

Num

ber o

f Cum

ulat

ive

Post

-Mar

ketin

g Ca

ses*

Inte

stin

al O

bstr

uctio

n31

4Ga

llbla

dder

and

Bili

ary

Trac

t Dise

ase

122

Panc

reat

ic d

iseas

e43

1

*Pos

t-m

arke

ting

data

are

repo

rted

on

a vo

lunt

ary

basis

from

a p

opul

atio

n of

unc

erta

in si

ze, a

nd it

is n

ot a

lway

s pos

sible

to

obta

in re

liabl

e es

timat

e of

AE

freq

uenc

y, or

to e

stab

lish

a ca

usal

rela

tions

hip

of A

Es to

dru

g ex

posu

re.

Sour

ces:

spo

ntan

eous

cas

es, s

olic

ited

case

s , c

ases

from

Reg

istry

TED

-R13

-002


Flui

d O

verlo

ad

23

/173

(13.

3%) o

f adu

lt pa

tient

s tre

ated

with

GAT

TEX

wer

e re

port

ed to

hav

e flu

id o

verlo

ad in

poo

led

Phas

e III

SBS

st

udie

s.*

Fl

uid

over

load

shou

ld b

e co

nsid

ered

whe

n ad

min

ister

ing

GATT

EX in

pat

ient

s with

und

erly

ing

hear

t dise

ase.

N

o GA

TTEX

-tre

ated

pat

ient

s wer

e re

port

edto

hav

e se

rious

ev

ents

of f

luid

ove

rload

in th

e pe

diat

ric c

linic

al st

udie

s.**

Th

ere

was

1 p

atie

nt w

ho h

ad a

non

-ser

ious

rela

ted

adve

rse

even

t of p

erip

hera

l ede

ma

in th

e 0.

025

mg/

kg/d

ay g

roup

.†

* As

of 2

4 Ja

nuar

y 20

13; *

*As o

f 24

July

201

8†

Not

e th

at a

s per

the

GATT

EX P

resc

ribin

g In

form

atio

n, th

e re

com

men

ded

dosa

ge o

f GA

TTEX

for b

oth

adul

t and

ped

iatr

ic p

atie

nts

is 0.

05 m

g/kg

/day

18


Flui

d O

verlo

adGA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Card

iova

scul

ar D

iseas

e

–Du

e to

incr

ease

d in

test

inal

flui

d ab

sorp

tion,

pat

ient

s with

ca

rdio

vasc

ular

dise

ase,

such

as c

ardi

ac in

suffi

cien

cy a

nd

hype

rten

sion,

shou

ld b

e m

onito

red

with

rega

rd to

flui

d ov

erlo

ad, e

spec

ially

dur

ing

initi

atio

n of

ther

apy.

–Pa

rent

eral

nut

ritio

n/in

trav

enou

s (PN

/IV)

flui

d vo

lum

e sh

ould

be

reas

sess

ed re

lativ

e to

sign

s of f

luid

ove

rload

.

–In

cas

e of

a si

gnifi

cant

det

erio

ratio

n of

the

card

iova

scul

ar

dise

ase,

the

need

for c

ontin

ued

GATT

EX tr

eatm

ent s

houl

d be

reas

sess

ed.

19


PN/I

V Vo

lum

e Ad

just

men

t in

Adul

ts

20

*

PN

/IV=p

aren

tera

lnut

ritio

nan

d/or

intra

veno

usflu

ids

**

Bas

elin

eur

ine

outp

utis

vol

ume

obta

ined

durin

gst

abili

zatio

n pe

riod

befo

retre

atm

enti

sin

itiat

ed†D

ata

pres

ente

d ar

e ba

sed

on th

e S

TEP

S c

linic

al tr

ial a

nd a

re n

ot c

onta

ined

with

in th

e G

atte

x la

bel

Jepp

esen

PB

,eta

l.G

astro

ente

rolo

gy.2

012;

143:

1473

-81

48-HourUrineOutput**

PN/IV*Action

•<1

.0 L

/day

or t

arge

t bas

ed o

n st

abili

zed

urin

e ou

tput

•In

crea

se P

N/IV

* by

≥10

%

(wee

k 2)

or t

o pr

evio

us le

vel

•≥1

.0 L

/day

but

< b

asel

ine

•If

patie

nt is

deh

ydra

ted

or

inad

equa

tely

nou

rishe

d, in

crea

se

PN

/IV*

•If

not d

ehyd

rate

d m

aint

ain

PN

/IV*

•0%

to <

10%

incr

ease

ove

r bas

elin

e•

Mai

ntai

n P

N/IV

*

•≥1

0% in

crea

se o

ver b

asel

ine

•R

educ

e P

N/IV

* by

≥10

% o

f st

abili

zed

base

line

leve

l up

to a

cl

inic

ally

app

ropr

iate

am

ount

(m

axim

um o

f 30%

)

To m

inim

ize th

e ris

k of

flui

d ov

erlo

ad, t

he fo

llow

ing

adju

stm

ent a

lgor

ithm

is re

com

men

ded.


PN/I

V Vo

lum

e Ad

just

men

t in

Child

ren

and

Adol

esce

nts

To m

inim

ize th

e ris

k of

flui

d ov

erlo

ad o

r deh

ydra

tion,

the

follo

win

g nu

triti

onal

supp

ort a

djus

tmen

t alg

orith

m is

sugg

este

d:

–Cl

inic

visi

ts e

very

1-2

wee

ks d

urin

g th

e fir

st 6

wee

ks o

f tre

atm

ent

–Ev

alua

te h

ydra

tion

stat

us a

t eve

ry c

linic

visi

t, w

hich

may

incl

ude:

•

Wei

ght t

raje

ctor

y•

Urin

e so

dium

(tar

get >

20

meq

/L)

•U

rine

outp

ut (t

arge

t 25-

50 m

l/kg/

day)

•Ph

ysic

al e

xam

find

ings

of h

ydra

tion

stat

us–

Adju

st P

N/I

V vo

lum

e in

incr

emen

ts/d

ecre

men

ts o

f 10%

-30%

to

avoi

d flu

id o

verlo

ad o

r deh

ydra

tion

–At

eve

ry c

linic

visi

t, ev

alua

te g

row

th tr

ajec

tory

, ent

eral

inta

ke, a

nd

seve

rity

of d

iarr

hea

–If

grow

th tr

ajec

tory

is a

dequ

ate

and

diar

rhea

is m

anag

eabl

e,

cons

ider

redu

cing

PN

cal

orie

s and

incr

easin

g en

tera

l nut

ritio

n

21


Incr

ease

d Ab

sorp

tion

of C

onco

mita

nt O

ral M

edic

atio

ns

Ba

sed

on th

e ph

arm

acod

ynam

ic e

ffect

of G

ATTE

X, th

ere

is a

pote

ntia

l for

incr

ease

d ab

sorp

tion

of c

onco

mita

nt o

ral

med

icat

ions

Co

nsid

erat

ions

shou

ld b

e gi

ven

for d

osag

e ad

just

men

t of

conc

omita

nt o

ral m

edic

atio

ns re

quiri

ng ti

trat

ion

or th

at h

ave

a na

rrow

ther

apeu

tic in

dex

22


Incr

ease

d Ab

sorp

tion

of C

onco

mita

nt O

ral M

edic

atio

n GA

TTEX

Lab

el –

War

ning

s and

Pre

caut

ions

Risk

s res

ultin

g fr

om in

crea

sed

abso

rptio

n of

con

com

itant

ora

l m

edic

atio

ns

–Al

tere

d m

enta

l sta

tus i

n as

soci

atio

n w

ith G

ATTE

X ha

s bee

n ob

serv

ed in

pat

ient

s on

benz

odia

zepi

nes i

n ad

ult c

linic

al

stud

ies.

–Pa

tient

s on

conc

omita

nt o

ral m

edic

atio

ns (e

.g.,

benz

odia

zepi

nes,

phe

noth

iazin

es) r

equi

ring

titra

tion

or

with

a n

arro

w th

erap

eutic

inde

x m

ay re

quire

a re

duct

ion

in

dosa

ge o

f the

con

com

itant

dru

g w

hile

on

GATT

EX.

23


IMPORTANT DRUG WARNING FDA-Required REMS Safety Information

Dear Healthcare Professional:

The purpose of this letter is to remind you about the serious risks associated with GATTEX® (teduglutide) for Injection and the need for ongoing monitoring for these risks.

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of GATTEX outweigh the potential risks.

Serious Risks:

Acceleration of neoplastic growth and enhancement of colon polyp growth

Possible Acceleration of Neoplastic Growth

Based on the pharmacologic activity and findings in animals, GATTEX has the potential to cause hyperplastic changes including neoplasia.

Possible Small Bowel Neoplasia

Based on benign tumor findings in the mouse and rat carcinogenicity studies, patients should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued.

Colorectal Polyps

Colorectal polyps were identified during the clinical studies. In adults, colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. In children and adolescents, fecal occult blood testing should be performed prior to initiating treatment with GATTEX. Colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. Perform subsequent fecal occult blood testing annually in children and adolescents while they are receiving GATTEX. Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, every 5 years thereafter while on continuous treatment with GATTEX, and if they have new or unexplained gastrointestinal bleeding.

Risks associated with GATTEX:Possible acceleration of neoplastic growth and enhancement of colon polyp growthGI obstruction Biliary and pancreatic disorders

Rev 05/19


Gastrointestinal obstruction

Intestinal obstruction has been reported in clinical studies. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued while the patient is clinically managed and restarted when the obstructive presentation resolves, if clinically indicated.

Biliary and pancreatic disorders

Gallbladder and Biliary Tract Disease

Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed.

Pancreatic Disease

Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed.

Appropriate Patient Selection, Counseling, and Monitoring

Prescribers should select the appropriate patients to receive GATTEX in accordance with the approved Prescribing Information (PI), discuss the benefits and risks of GATTEX with patients or caregivers, and monitor patients as specified in the approved (PI). The Patient and Caregiver Counseling Guide is available for use in discussing GATTEX with patients. The guide can be accessed via www.GATTEXREMS.com or by contacting 1-855-5GATTEX (1-855-542-8839).

GATTEX Healthcare Provider Training

As part of the REMS, healthcare providers who intend to prescribe GATTEX, should access www.GATTEXREMS.com to review the Prescriber Education Slide Deck and complete the Post-Training Knowledge Assessment Questions. Training can be completed either online or through a paper-based process:

1) Online: visit www.GATTEXREMS.com to review the REMS materials and follow the instructions to complete the Post-Training Knowledge Assessment Questions online.

2) Paper-based: review the REMS materials and fax the completed Post-Training Knowledge Assessment Questions to 1-855-359-3393.

Indication

GATTEX is indicated for the treatment of adults and pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral support.

Rev 05/19


Reporting Adverse Events

Report all suspected adverse events associated with the use of GATTEX, at1-855-5GATTEX (1-855-542-8839); or to the FDA MedWatch program at 1-800-FDA-1088 (1-800-332-1088), or via the website at https://www.fda.gov/Safety/MedWatch/default.htm

Please see the enclosed PI for GATTEX for additional safety information.

Enclosures:

Prescriber Education Slide DeckPost-Training Knowledge Assessment QuestionsGATTEX Prescribing InformationMedication Guide

Rev 05/19


Asse

ssm

ent Q

uest

ion:

Po

ssib

le A

ccel

erat

ion

of N

eopl

astic

Gro

wth

Base

d on

the

phar

mac

olog

ic a

ctiv

ity a

nd fi

ndin

gs in

ani

mal

s,

GATT

EX h

as th

e po

tent

ial t

o ca

use

hype

rpla

stic

cha

nges

incl

udin

g ne

opla

sia.

In p

atie

nts a

t inc

reas

ed ri

sk fo

r mal

igna

ncy

or th

ose

with

act

ive

non-

gast

roin

test

inal

mal

igna

ncy,

the

clin

ical

dec

isio

n to

con

tinue

GAT

TEX

shou

ld b

e m

ade

base

d on

risk

-ben

efit

cons

ider

atio

ns. G

ATTE

X sh

ould

be

disc

ontin

ued

in p

atie

nts w

ith

activ

e ga

stro

inte

stin

al m

alig

nanc

y (G

I tra

ct, h

epat

obili

ary,

pa

ncre

atic

).

A.Tr

ue

B.Fa

lse


Asse

ssm

ent Q

uest

ion:

In

test

inal

Obs

truc

tion

Inte

stin

al o

bstr

uctio

n ha

s bee

n re

port

ed in

clin

ical

stud

ies.

W

hich

of t

he fo

llow

ing

stat

emen

ts re

gard

ing

obst

ruct

ion

is

true

: A.

Patie

nts w

ith sy

mpt

oms s

ugge

stiv

e of

thes

e co

nditi

ons s

houl

d be

per

man

ently

disc

ontin

ued

from

GAT

TEX.

B.

In p

atie

nts w

ho d

evel

op in

test

inal

or s

tom

al o

bstr

uctio

n,

GATT

EX sh

ould

be

tem

pora

rily

disc

ontin

ued

whi

le th

e pa

tient

is

clin

ical

ly m

anag

ed. G

ATTE

X m

ay b

e re

star

ted

whe

n th

e ob

stru

ctiv

e pr

esen

tatio

n re

solv

es, i

f clin

ical

ly in

dica

ted.

C.

GATT

EX sh

ould

be

disc

ontin

ued

if m

ucos

al h

yper

trop

hy a

t a

stom

a is

obse

rved

.

2


Asse

ssm

ent Q

uest

ion:

Ga

llbla

dder

, Bili

ary

Trac

t, an

d Pa

ncre

atic

Dis

ease

Bi

liary

dis

ease

(cho

lecy

stiti

s, ch

olan

gitis

, cho

lelit

hias

is) a

nd

panc

reat

ic d

isea

se (p

ancr

eatit

is) h

ave

been

repo

rted

in c

linic

al

stud

ies.

Wha

t is t

he re

com

men

ded

sche

dule

for a

sses

smen

ts fo

r bi

lirub

in, a

lkal

ine

phos

phat

ase,

lipa

se a

nd a

myl

ase?

A.

With

in 6

mon

ths f

ollo

win

g in

itiat

ion

of G

ATTE

X, a

nd e

very

6 m

onth

s th

erea

fter.

B.

With

in 6

mon

ths p

rior t

o st

artin

g GA

TTEX

, and

subs

eque

ntly

at l

east

eve

ry

6 m

onth

s whi

le o

n GA

TTEX

, or m

ore

freq

uent

ly if

nee

ded.

Imag

ing

is re

com

men

ded

if th

ere

are

clin

ical

ly m

eani

ngfu

l cha

nges

in b

iliar

y or

pa

ncre

atic

func

tiona

l mar

kers

. C.

At th

e tim

e GA

TTEX

is st

arte

d (w

ithin

2 w

eeks

), an

d th

en a

nnua

lly. I

mag

ing

is re

com

men

ded

for a

pos

sible

obs

truc

tion

if th

ere

are

clin

ical

ly m

eani

ngfu

l el

evat

ions

bili

ary

or p

ancr

eatic

func

tiona

l mar

kers

.

3


Asse

ssm

ent Q

uest

ion:

En

hanc

ed G

row

th o

f Col

orec

tal P

olyp

s

Colo

rect

al p

olyp

s wer

e id

entif

ied

durin

g th

e cl

inic

al st

udie

s in

adul

ts. I

n ad

ults

, col

onos

copy

shou

ld b

e do

ne a

ccor

ding

to w

hich

of

the

follo

win

g sc

hedu

les:

A.

Colo

nosc

opy

(or a

ltern

ate

imag

ing)

of t

he e

ntire

colo

n w

ith re

mov

al o

f po

lyps

at t

he e

nd o

f 1 y

ear o

f GAT

TEX

ther

apy,

and

subs

eque

ntly

eve

ry

5 ye

ars.

B.Co

lono

scop

y (o

r alte

rnat

e im

agin

g) o

f the

ent

ire co

lon

with

rem

oval

of

poly

ps w

ithin

6 m

onth

s prio

r to

star

ting

GATT

EX, s

ubse

quen

tly e

very

5

year

s.

C.Co

lono

scop

y (o

r alte

rnat

e im

agin

g) o

f the

ent

ire co

lon

with

rem

oval

of

poly

ps w

ithin

6 m

onth

s prio

r to

star

ting

GATT

EX.

A fo

llow

-up

colo

nosc

opy

(or a

ltern

ate

imag

ing)

is re

com

men

ded

at th

e en

d of

1 y

ear

of tr

eatm

ent.

If n

o po

lyp

is fo

und,

subs

eque

nt co

lono

scop

ies s

houl

d be

do

ne e

very

5 y

ears

or m

ore

ofte

n as

nee

ded.

If a

pol

yp is

foun

d,

adhe

renc

e to

cur

rent

pol

yp fo

llow

-up

guid

elin

es is

reco

mm

ende

d.

4


Asse

ssm

ent Q

uest

ion:

En

hanc

ed G

row

th o

f Col

orec

tal P

olyp

s

In c

hild

ren

and

adol

esce

nts,

col

onos

copy

shou

ld b

e do

ne

acco

rdin

g to

whi

ch o

f the

follo

win

g sc

hedu

les:

A.

Colo

nosc

opy

(or a

ltern

ate

imag

ing)

of t

he e

ntire

colo

n w

ith re

mov

al o

f po

lyps

with

in 6

mon

ths p

rior t

o st

artin

g GA

TTEX

, and

subs

eque

ntly

eve

ry

5 ye

ars.

B.Pe

rform

feca

l blo

od te

stin

g pr

ior t

o in

itiat

ing

trea

tmen

t. Co

lono

scop

y/sig

moi

dosc

opy

is re

quire

d if

ther

e is

unex

plai

ned

bloo

d in

th

e st

ool.

Perfo

rm su

bseq

uent

feca

l occ

ult b

lood

test

ing

annu

ally

whi

le

rece

ivin

g GA

TTEX

. Co

lono

scop

y/sig

moi

dosc

opy

is re

com

men

ded

for a

ll ch

ildre

n an

d ad

oles

cent

s afte

r 1 y

ear o

f tre

atm

ent,

ever

y 5

year

s th

erea

fter w

hile

on

cont

inuo

us tr

eatm

ent w

ith G

ATTE

X, a

nd if

they

hav

e ne

w o

r une

xpla

ined

gas

troi

ntes

tinal

ble

edin

g.

C.N

o co

lono

scop

y is

requ

ired

for c

hild

ren

and

adol

esce

nts.

Onl

y fe

cal

occu

lt bl

ood

test

ing

is re

quire

d pr

ior t

o in

itiat

ing

trea

tmen

t with

GAT

TEX

and

annu

ally

ther

eafte

r.

5


Asse

ssm

ent Q

uest

ion:

Fl

uid

Ove

rload

Flui

d ov

erlo

ad a

nd co

nges

tive

hear

t fai

lure

hav

e be

en

obse

rved

in c

linic

al st

udie

s, w

hich

wer

e de

emed

to b

e re

late

d to

enh

ance

d flu

id a

bsor

ptio

n as

soci

ated

with

GA

TTEX

. Wha

t is t

he re

com

men

ded

man

agem

ent f

or

patie

nts r

egar

ding

flui

d ov

erlo

ad?

A.

Patie

nts s

houl

d be

mon

itore

d w

ith re

gard

to fl

uid

over

load

, esp

ecia

lly

durin

g in

itiat

ion

of th

erap

y.

B.If

fluid

ove

rload

occ

urs,

par

ente

ral s

uppo

rt sh

ould

be

adju

sted

and

th

e ne

ed fo

r con

tinue

d GA

TTEX

trea

tmen

t sho

uld

be re

asse

ssed

.

C.If

signi

fican

t car

diac

det

erio

ratio

n de

velo

ps w

hile

on

GATT

EX, t

he

need

for c

ontin

ued

GATT

EX tr

eatm

ent s

houl

d be

reas

sess

ed.

D.Al

l of t

he a

bove

.

6


Asse

ssm

ent Q

uest

ion:

In

crea

sed

Abso

rptio

n of

Con

com

itant

Ora

l Med

icat

ion

GATT

EX m

ay in

crea

se a

bsor

ptio

n of

con

com

itant

ora

l med

icat

ions

. Al

tere

d m

enta

l sta

tus i

n as

soci

atio

n w

ith G

ATTE

X ha

s bee

n ob

serv

ed in

pat

ient

s on

benz

odia

zepi

nes i

n cl

inic

al st

udie

s. W

hich

of

the

follo

win

g st

atem

ents

is tr

ue?

A.Pa

tient

on

conc

omita

nt o

ral d

rugs

requ

iring

titr

atio

n or

with

a n

arro

w

ther

apeu

tic in

dex

may

requ

ire d

ose

adju

stm

ent w

hile

on

GATT

EX.

B.O

ral m

edic

atio

ns re

quiri

ng ti

trat

ion

or th

at h

ave

a na

rrow

th

erap

eutic

inde

x sh

ould

be

disc

ontin

ued

prio

r to

star

ting

GATT

EX.

C.N

o do

se a

djus

tmen

t con

sider

atio

ns a

re n

eede

d, b

ut p

atie

nts o

n or

al

med

icat

ions

shou

ld b

e m

onito

red

care

fully

.

7












Documents

Risk Evaluation and Mitigation Strategy (REMS) Document ... · Intestinal obstruction has been reported in clinical studies. In patients who develop intestinal or stomal obstruction,