Drug Use Research & Management Program

OHA Division of Medical Assistance Programs

500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

*Agenda items will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

Oregon Drug Use Review / Pharmacy & Therapeutics Committee

Thursday, April 26, 2012 1:00-4:00 PM Clackamas Community Training Center

29353 SW Town Center Loop East Wilsonville, OR 97070

MEETING AGENDA

NOTE: Any agenda items discussed by the DUR/P&T Committee may result in changes to coverage, PDL composition, or utilization control recommendations to the OHA. I. CALL TO ORDER 1:00 pm – 1:05 pm

a. Roll Call & Introductions B. Origer (Chair) b. Conflict of Interest Declaration R. Citron (OSU) c. Approval of Agenda and Minutes B. Origer (Chair)

II. ProDUR 1:05 pm – 1:40 pm

a. New Drug Evaluation* (10 min) A. Burns (OSU) 1. Kalydeco® (ivacaftor) 2. Public comment 3. Discussion of clinical recommendations to OHA

b. 15-day Initial Supplies* (15 min) R. Citron (OSU) 1. Proposed List of Medications 2. Public Comment 3. Discussion of clinical recommendations to OHA

c. New Drug Evaluation* (10 min) M. Herink (OSU) 1. Egrifta® (tesamorelin) 2. Public Comment 3. Discussion of clinical recommendations to OHA

III. NEW BUSINESS 1:40 pm – 2:00 pm

a. Diabetes Medications Class Update* (20 min) K. Sentena (OSU) 1. Updated PA Criteria 2. Tradjenta® (linagliptin) 3. Bydureon® (exenatide) 4. Public comment 5. Discussion of clinical recommendations to OHA

BREAK 2:00 pm – 2:10 pm

III. NEW BUSINESS (continued) 2:10 pm – 3:30 pm b. New Drug Evaluation* (15 min) M. Herink (OSU)

1. Dificid® (fidaxomicin) 2. Public comment 3. Discussion of clinical recommendations to OHA

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Agenda items with an asterisk will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

c. Antidepressant New Drug Reviews* (15 min) A. Wheeler (OSU) 1. Viibryd® (vilazodone) 2. Public Comment 3. Discussion of clinical recommendations to OHA

d. Smoking Cessation Class Update* (15 min) A. Burns (OSU) 1. Proposed PDL/Step Therapy 2. Public comment 3. Discussion of clinical recommendations to OHA

e. Drug Class Scans* (15 min) M. Herink (OSU) 1. Pulmonary Arterial HTN 2. Oral Hypoglycemics/TZDs 3. Insulins 4. Public Comment 5. Discussion of clinical recommendations to OHA

IV. OLD BUSINESS a. Hepatitis B* (15 min) M. Herink (OSU) 1. Introduction of Ad-Hoc Expert

2. Proposed PA criteria & PDL Placement 3. Public Comment 4. Discussion of clinical recommendations to OHA

V. EXECUTIVE SESSION 3:25 pm VI. RECONVENE for PUBLIC RECOMMENDATIONS VII. ADJOURN

2 of 108

Drug Use Research & Management Program

OHA Division of Medical Assistance Programs

500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

Agenda items with an asterisk will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

Oregon Drug Use Review / Pharmacy & Therapeutics Committee

Thursday, March 29, 2012 1:00-4:00 PM Hewlett-Packard Building

4070 27th Ct SE Salem, OR 97302

MEETING MINUTES

NOTE: Any agenda items discussed by the DUR/P&T Committee may result in changes to coverage, PDL composition, or utilization control recommendations to the OHA. Members Present: Tracy Klein, PhD, FNP; William Origer, MD; Stacy Ramirez, PharmD; Zahia Esber, MD Members Present by Phone: Andris Antoniskis, MD; Joshua Bishop, PharmD; Phillip Levine, PhD Staff Present: Roger Citron, RPh; Megan Herink, PharmD, BCPS; Kathy Ketchum, RPh, MPA:HA; Valerie Smith; Richard Holsapple, RPh; Ralph Magrish, MPA; Ann Hamer, PharmD; Bing-Bing Liang, PharmD; Staff Present by Phone: Brandy Fouts, PharmD Audience Present: Jim Graves (BMS); Jeff Forshey (Shire); Ben Davidson (Physician); Deron Grothe (Teva); Deborah Crawford (Acorda); Lauren Letzenberger (Janssen Scientific Affairs); Craig Black (Biogen Idec); Jeana Colabianchi (Sunovion); Lyle Laird (Sunovion); Paul Sparks; Kimberly Langmeier (BMS); Lori Howarth (Bayer); Bruce Howard (Acorda); Rosalynde Finch (Biogen Idec); Kathy Kirk (OPMC); Elaine Thomas (Bayer); Don Stetcher (Novartis); John Brokars; Mary Kemhus; Denise Poole; Rob Pearson; Deborah Wafe; Diann Matthews; Angela Hamman; Paul Nielsen; James Matthucci; Amy Tice; Canan Shumann I. CALL TO ORDER

a. The meeting was called to order at approximately 1:20pm b. Conflict of interest declarations were reviewed and no new conflicts were reported c. The February 23, 2012 meeting minutes were reviewed.

ACTION: Approved as is. II. OLD BUSINESS

a. Hepatitis C criteria were brought back with the addition of steps 5-9 after consulting with a Hepatologist.

*ACTION: Approved as amended from the last meeting. b. Dose optimization concept was presented by Mr. Citron.

ACTION: Approved as amended to remove drugs that required titration (e.g. hypertention drugs, lamotrigine, quetiapine). Staff directed to identify drugs to target for this policy based upon past claim data. . III. NEW BUSINESS

a. Dr. Williams presented on Short Acting Opioids and recommended using the same criteria for Short Acting Opioids as Long Acting Opioids.

*ACTION: Approved as is after Executive Session. Staff directed to implement with educational component and adequate notice to providers. Also recommended butorphanol NS non-preferred, oxycodone 5mg capsule non-preferred, oxycodone concentrate non-preferred, oxycodone 2.5mg/APAP non preferred, Conzip® non-preferred.

3 of 108

Agenda items with an asterisk will be discussed by Committee members for the purpose of making recommendations to the Oregon Health Plan for adoption into Oregon Administrative Rules 410-121-0030 & 410-121-0040 as required by 414.325(9)

b. Dr. Herink presented on Multiple Slerosis drug class including new drug reviews for fingolimod and dalfampridine. It was recommended that finolimod be made non-preferred with a trial of interferon first. Dalfampridine was recommended to be managed with prior authorization criteriaand it was referred to HERC for cost-effectiveness evaluation in comparison to non-pharmacological treatments. Dr. Ben Davidson presented public comment on MS drug class in general. Elaine Thomas from Bayer presented public comment on Betaseron®. Rosalynde Finch from Biogen Idec presented public comment on Avonex®. Mary Kenhus from Novartis presented public comment on Gilenya®. Deborah Crawford from Acorda presented public comment on Ampyra®.

*ACTION: Approved as presented after Executive Session. c. Dr. Hamer presented on Antipsychotic drug class recommending education outreach to

promote appropriate utilization and minimize inappropriate off-label use and making lurasidone non-preferred. Lyle Laird from Sunvion presented public comment on Latuda®. Written testimony was provided by Dr. Lisa Boy on Latuda®. Mary Kemhus from Novartis presented public comment on Fanapt®.

*ACTION: Approved as presented after Executive Session. It was also recommended to review class pricing again in three months and to have staff to present a specific educational proposal.

d. Dr. Liang presented the Statin drug class update recommending that quantity limits be implemented on 80mg simvastatin, and making pitavastatin non-preferred.

*ACTION: Approved as presented after Executive Session and recommended revisiting pricing in three months.

e. Dr. Fouts presented the new drug evaluation and recommended implementing dose limits, age restrictions, and diagnosis documentation on icatibant.

*ACTION: Committee deferred action and asked staff for more information regarding current utilization of this class and icatibant’s place in therapy.

f. Dr. Williams presented the ADHD drug class update recommending not considering extended release forms of clonidine and guanfacine superior to other stimulant and non-stimulant ADHD treatments for PDL placement. John Brokers from Eli Lilly presented public comment on Stratera.

*ACTION: After Executive Session it was recommended Kapvay®, Daytrana®, generic methamphetamine and Concerta® and its generic equivalent be made non-preferred. It was recommended Intuniv® be listed preferred after successful contract negotiations.

g. Dr. Herink presented drug class scans. 1. Sedative Hypnotics – recommend no further research or review at this time.

Make Silenor® and Edular® non-preferred. 2. Skeletal Muscle Relaxants – recommend no further research or review at this

time. 3. Triptans – recommend no further research or review at this time.

*ACTION: After executive session the Sedative Hypnotic recommendations were approved and it was recommended to make all Skeletal Muscle Relaxant agents non-preferred except baclofen, cyclobenzaprine and tizanidine.

IV. EXECUTIVE SESSION V. RECONVENE for PUBLIC RECOMMENDATIONS* VI. The meeting adjourned at 4:45pm.

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© Copyright 2012 Oregon State University. All Rights Reserved

Drug Use Research & Management Program

Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

1

Kalydeco (ivacaftor) –

Indication: Ivacaftor was FDA approved in January 2012 for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551D mutation on at least one Cystic Fibrosis Transmembrane Regulator (CFTR) allele.

1,2If the

patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the G551D mutation.

Limitations of use:

Ivacaftor is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.

Ivacaftor has not been studied in other populations of patients with CF.

Efficacy: FDA approval of ivacaftor was based on two randomized, double blind, placebo-controlled, phase III trials submitted by Vertex pharmaceuticals including ENVISION (unpublished) and STRIVE (published).

2, 3Both were designed

to assess the efficacy and safety of 24 weeks of treatment with ivacaftor 150 mg PO twice daily in patients age 12 years and older (STRIVE) and 6 to 11 years (ENVISION). Placebo-controlled treatment was continued through 48 weeks to confirm response. All eligible patients who completed the prior 48-week randomized, controlled trials including patients previously receiving placebo were rolled over into the open-label extension study (PERSIST) which is currently ongoing.

2

Both trials demonstrated a statistically significant improvement in the primary outcome of FEV1 after 24 weeks with a treatment difference from baseline FEV1 of 10.6% in STRIVE and 12.5% in ENVISION (p<0.001).

2,3The STRIVE trial

also showed an increased proportion of patients free from pulmonary exacerbations (67% vs. 41%, HR 0.46, p=0.0012).

While these trials evaluated subjects with specifically a G551D-CFTR mutation, data from the DISCOVER trial evaluated the efficacy of ivacaftor in CF patients who are homozygous for the F508del mutation in the CFTR gene in patients aged 12 years and older.

4Through 16 weeks, no statistically significant differences from placebo were observed in change from

baseline FEV1 (treatment difference 1.7%, p=0.15), risk for pulmonary exacerbation, CF respiratory symptoms, or weight gain.

4

Safety: The most common adverse reactions in 353 patients with CF were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%). No serious adverse events known.

Conclusions: CF affects about 30,000 people in the United States and only about 4 percent of those with CF are believed to have the G551D mutation. Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of ivacaftor in CF patients with the G551D mutation. Both showed significant improvements in the primary outcome of change in FEV1 from baseline through week 24. There remains insufficient evidence to determine the ongoing gains in FEV1 beyond 48 weeks, or its effects on structural lung disease. Data from one study demonstrated ivacaftor to lack efficacy in patients with CF who are homozygous for the F508del mutation in the CFTR gene, which is the most prevalent disease-causing mutation and the drug has not been studied in any other CF patient populations. Until a more detailed evidence-based review is conducted, it is recommended to implement a prior authorization for ivacaftor to limit use to its FDA indication and in patients in which it has been studied for efficacy and safety.

5 of 108

2

Ivacaftor (Kalydeco)

Goal(s):

To ensure appropriate drug use and limit to patient populations in which the drug has been shown to be effective and safe.

Length of Authorization: One year.

Approval Criteria

1. What is the diagnosis? Record ICD-9 code

2. Does the client have a diagnosis of cystic fibrosis and is 6 years of age or older?

Yes: Go to #3. No: Pass to RPH; Deny (medical appropriateness)

3. Does the patient have a documented G551D mutation in the CFTR gene?

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the G551D mutation.

Yes: Go to #4. No: Pass to RPH; Deny (medical appropriateness)

4. Is the prescription for ivacaftor 150mg twice daily, once daily or twice-a-week?

Yes: Approve for one year.

No: Pass to RPH; Deny (medical appropriateness)

Limitations of Use:

• Ivacaftor is not effective in patients with Cystic Fibrosis who are homozygous for the F508del mutation in the CFTRgene.

• Ivacaftor has not been studied in other populations of patients with Cystic Fibrosis.

DUR Board Action: Revision(s): Initiated:

References:1. Kalydeco [package insert]. Vertex Pharmaceuticals Inc., Cambridge, MA; January 2012.

http://pi.vrtx.com/files/uspi_ivacaftor.pdf. 2. Kalydeco™” (ivacaftor) for the Management of Cystic Fibrosis. Formulary Submission Dossier. Vertex

Pharmaceuticals. February 2012. 3. Ramsey B., Davies J., McElvaney G., et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D

Mutation. N Engl J Med 365;18. November 3, 20114. Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the

F508del-CFTR mutation. Chest. 2012 Mar 1. [Epub ahead of print]

6 of 108

Drug Use Research & Management Program

OHA Division of Medical Assistance Programs

500 Summer Street NE, E35; Salem, OR 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

Proposed Fifteen Day Initial Prescription List Drugs that have been identified with high side effect profiles, high discontinuation rates, or frequent dose

adjustments are proposed to be limited to a 15-day initial supply. The initial prescription supply limit ensures cost effectiveness without waste of unused medications.

ANTIDEPRESSANTS- SELECTED SSRI'S ANTISPASMODICS- LONG ACTING Aplenzin Detrol LA Bupropion Enablex Bupropion SR Gelnique Cymbalta Oxybutynin Chloride ER Effexor XR Oxytrol Fluoxetine HCl Tablets (PMDD) Sanctura XR Fluvomaxine Maleate Toviaz Lexapro Vesicare Luvox CR Maprotiline CHOLINERGIC Nefazodone Bethanechol Chloride OleptroParoxetine ER STIMULANTSPexeva Desoxyn Pristiq Procentra SarafemSavella STIMULANTS-AMPHETAMINES-LONG ACTING Venlafaxine Adderall XR Venlafaxine ER Dexedrine Viibryd Vyvanse

ANTIPSYCHOTICS-ATYPICALS STIMULANTS-AMPHETAMINES-SHORT ACTING Abilify Amphetamine-Dextroamphetamine Fanapt Dextroamphetamine Sulfate Geodon Invega STIMULANTS-METHYLPHENIDATE Latuda Focalin Risperdal Methylin chew Risperidone Methylphenidate HCl solution Saphris Seroquel STIMULANTS-METHYLPHENIDATE-LONG ACTING Zyprexa Concerta

Focalin XR ANTISPASMODICS MetadateDetrol Methylphenidate HCl SR FlavoxateHCl Ritalin LA Sanctura Ritalin SR

STIMULANTS-OTHER /LIKE STIMULANTS IntunivKapvayNuvigilProvigilStrattera

7 of 108

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cera

l a

dip

ose

tis

sue

is

ass

oci

ate

d w

ith

im

pro

ve

d m

ed

ica

tio

n a

dh

ere

nce

, m

orb

idit

y o

r m

ort

ali

ty i

n H

IV-i

nfe

cte

d p

ati

en

ts w

ith

lip

od

yst

rop

hy.

Te

sam

ore

lin

als

o r

eq

uir

es

da

ily s

ub

cuta

ne

ou

s a

dm

inis

tra

tio

n a

nd

th

e e

ffe

ct i

s n

ot

ma

inta

ine

d f

oll

ow

ing

dis

con

tin

ua

tio

n.

Re

com

me

nd

ati

on

s: R

eq

uir

e a

pri

or

au

tho

riza

tio

n f

or

ap

pro

ve

d O

HP

dia

gn

ose

s o

nly

.

BA

CK

GR

OU

ND

/CU

RR

EN

T L

AN

DS

CA

PE

:

H

igh

ly

act

ive

a

nti

retr

ovir

al

the

rap

ies

(HA

AR

T)

are

co

nsi

de

red

th

e

sta

nd

ard

o

f ca

re

in

HIV

-in

fect

ed

p

ati

en

ts

wh

o

req

uir

e

tre

atm

en

t.

Tre

atm

en

t w

ith

HA

AR

T h

as

cle

arl

y d

em

on

stra

ted

sig

nif

ica

nt

red

uct

ion

s in

HIV

-ass

oci

ate

d m

orb

idit

y a

nd

mo

rta

lity

bu

t is

no

t w

ith

ou

t a

dve

rse

eff

ect

s.

Pa

tie

nts

re

ceiv

ing

tr

ea

tme

nt

wit

h

HA

AR

T,

an

d

esp

eci

all

y

pro

tea

se

inh

ibit

ors

, a

re

at

hig

h

risk

fo

r d

eve

lop

me

nt

of

HIV

-ass

oci

ate

d

lip

od

yst

rop

hy,

wh

ich

is

cha

ract

eri

zed

by c

ha

ng

es

in l

ipid

co

mp

osi

tio

n,

insu

lin

re

sist

an

ce,

dia

be

tes

me

llit

us,

an

d f

at

red

istr

ibu

tio

n.3

-6 T

he

re i

s n

o

sta

nd

ard

ize

d d

efi

nit

ion

fo

r d

iag

no

sin

g H

IV-a

sso

cia

ted

lip

od

yst

rop

hy,

so e

stim

ati

on

s o

f it

s p

reva

len

ce r

an

ge

fro

m 5

-83

% o

f p

ati

en

ts u

sin

g p

rote

ase

inh

ibit

ors

. D

ise

ase

pre

va

len

ce f

or

pa

tie

nts

usi

ng

nu

cle

osi

de

re

ve

rse

tra

nsc

rip

tase

in

hib

ito

rs i

s n

ot

ava

ila

ble

.

T

he

lo

ng

-te

rm i

mp

lica

tio

ns

of

lip

od

yst

rop

hy a

re n

ot

kn

ow

n,

bu

t th

ere

is

con

cern

th

at

an

in

cre

ase

lip

id a

bn

orm

aliti

es

is l

inke

d t

o a

n i

ncr

ea

se

in t

he

ris

k o

f ca

rdio

va

scu

lar

dis

ea

se.

Th

ere

ha

ve

be

en

so

me

stu

die

s th

at

sug

ge

st t

he

re i

s a

re

lati

on

ship

be

twe

en

th

e d

eg

ree

of

coro

na

ry a

rte

ry

dis

ea

se a

nd

th

e a

mo

un

t o

f vis

cera

l fa

t d

ep

osi

tio

n,

bu

t n

on

e o

f th

ese

stu

die

s w

ere

co

nd

uct

ed

in

HIV

-po

siti

ve

pa

tie

nts

usi

ng

HA

AR

T,

an

d m

an

y o

f th

e

stu

die

s in

clu

de

d

pa

tie

nts

w

ho

h

ad

a

dd

itio

na

l ri

sk

fact

ors

fo

r ca

rdio

va

scu

lar

dis

ea

se

(e.x

. d

iab

ete

s,

imp

air

ed

g

luco

se

tole

ran

ce,

hyp

erc

ho

lest

ero

lem

ia).

No

ne

the

less

, th

ere

is

no

cle

ar

ass

oci

ati

on

be

twe

en

lip

od

yst

rop

hy i

n H

IV-i

nfe

cte

d p

ati

en

ts a

nd

ca

rdio

va

scu

lar

dis

ea

se. 1

, 3

-6

U

nti

l th

e

ap

pro

va

l o

f te

sam

ore

lin

, th

ere

w

as

no

F

DA

-ap

pro

ve

d

tre

atm

en

t fo

r li

po

dyst

rop

hy

in

HIV

-in

fect

ed

p

ati

en

ts.

Pa

tie

nts

w

ho

de

ve

lop

ed

in

tole

rab

le f

at

dis

trib

uti

on

ma

y h

ave

be

en

sw

itch

ed

to

an

alt

ern

ati

ve

HA

AR

T r

eg

ime

n.

Hyp

ert

rig

lyce

rid

em

ia m

ay b

e t

rea

ted

wit

h a

fib

rate

or

pe

roxi

som

e p

roli

fera

tor-

act

iva

ted

re

cep

tor

(PP

AR

) a

go

nis

t. G

HR

H h

as

lip

oly

tic

pro

pe

rtie

s a

nd

stu

die

s h

ave

sh

ow

n p

osi

tive

ch

an

ge

s in

fa

t

dis

trib

uti

on

in

HIV

-in

fect

ed

pa

tie

nts

, h

ow

eve

r a

ny i

mp

rove

me

nt

see

n o

n f

at

dis

trib

uti

on

wa

s re

ve

rse

d u

po

n d

isco

nti

nu

ati

on

of

gro

wth

ho

rmo

ne

.

Te

sam

ore

lin

is

a s

yn

the

tic

gro

wth

ho

rmo

ne

-re

lea

sin

g f

act

or

an

alo

g t

ha

t h

as

be

en

ap

pro

ve

d f

or

the

use

of

HIV

in

fect

ed

pa

tie

nts

wit

h l

ipo

dyst

rop

hy.1

9 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

3

Bra

nd

y F

outs

, P

har

mD

CLI

NIC

AL

PH

AR

MA

CO

LOG

Y:

T

esa

mo

relin

act

s o

n p

itu

ita

ry c

ell

s in

th

e b

rain

to

sti

mu

late

th

e s

yn

the

sis

an

d r

ele

ase

of

en

do

ge

no

us

gro

wth

ho

rmo

ne

, ca

usi

ng

in

cre

ase

s in

insu

lin

-lik

e g

row

th f

act

or

I a

nd

in

suli

n-l

ike

gro

wth

fa

cto

r b

ind

ing

pro

tein

3.1

CO

MP

AR

AT

IVE

CLI

NIC

AL

EF

FIC

AC

Y:

Re

lev

an

t E

nd

po

ints

:

1)

Mo

rta

lity

2)

Ma

jor

card

iova

scu

lar

eve

nts

3)

Co

mp

lia

nce

wit

h a

nti

-re

tro

vir

al th

era

py m

ea

sure

d b

y t

he

pro

po

rtio

n o

f d

ays

cove

red

(P

DC

) ra

tio

.

4)

Ra

te o

f tr

ea

tme

nt

rela

ted

ad

ve

rse

eve

nts

Stu

dy

En

dp

oin

ts:

1)

Pri

ma

ry e

nd

po

int:

Pe

rce

nt

cha

ng

e i

n t

he

vis

cera

l a

dip

ose

tis

sue

(V

AT

) fr

om

ba

selin

e t

o w

ee

k 2

6.

2)

Pe

rce

nt

cha

ng

e in

in

sulin

-lik

e g

row

th f

act

or

1 (

IGF-I

)

3)

Bo

dy i

ma

ge

– d

ete

rmin

ed

by q

ue

stio

nn

air

e in

wh

ich

su

bje

cts

rate

th

eir

be

lly s

ize

, b

ell

y i

ma

ge

dis

tre

ss,

an

d b

ell

y p

rofi

le.

4)

Pe

rce

nt

cha

ng

e in

bio

che

mic

al

ind

ice

s –

Lip

id l

eve

ls [

trig

lyce

rid

es,

to

tal

cho

lest

ero

l (T

C),

hig

h-d

en

sity

lip

op

rote

in (

HD

L) c

ho

lest

ero

l],

glu

cose

,

insu

lin

an

d f

ree

te

sto

ste

ron

e.

Ext

en

sio

n p

ha

se:

1)

Pri

ma

ry e

nd

po

int

wa

s sa

fety

2)

Se

con

da

ry e

ffic

acy

en

dp

oin

ts:

52

-we

ek e

ffic

acy

en

dp

oin

ts (

% c

ha

ng

e i

n V

AT

, IG

F-I

, b

ioch

em

ica

l in

dic

es

an

d b

od

y im

ag

e s

urv

ey s

core

s).

10 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

4

Bra

nd

y F

outs

, P

har

mD

Ev

ide

nce

Ta

ble

Re

f./

Stu

dy

De

sig

n1

Dru

g

Re

gim

en

s

Pa

tie

nt

Po

pu

lati

on

N

Du

rati

on

E

ffic

acy

Re

sult

s2

(CI,

p-v

alu

es)

AR

R /

NN

T3

Sa

fety

Re

sult

s^

(CI,

p-v

alu

es)

AR

R

/

NN

H3

Qu

ali

ty R

ati

ng

4;

Co

mm

en

ts

1.F

alu

tz

20

07

7,8

RC

T,

DB

,

PC

, M

C

1.

Te

sam

or

eli

n 2

mg

SQ

da

ily

2.

Pla

ceb

o

HIV

+ p

ati

en

ts s

tab

le

on

AR

T f

or !"!

we

ek

s w

ith

ev

ide

nce

of

ab

do

min

al

fat

acc

um

ula

tio

n

de

fin

ed

as

a w

ais

t

circ

um

fere

nce

of !

95

cm

an

d a

wa

ist-

to-h

ip r

ati

o o

f !

0.9

4 f

or

me

n a

nd

a

wa

ist

circ

um

fere

nce

of !#$!%&!'()!'!

wa

ist-

to-h

ip r

ati

o o

f

*+""!,-.!/-&0(+

Mo

re p

ati

en

ts i

n

the

te

sam

ore

lin

gro

up

ha

d r

ece

ive

d

no

n-n

ucl

eo

sid

e

rev

ers

e-

tra

nsc

rip

tase

inh

ibit

ors

(5

3.7

vs

41

.6,

p=

0.0

3)

Ex

clu

sio

n C

rite

ria

:

Ty

pe

1 o

r 2

dia

be

tes,

se

rum

cre

ati

nin

e >

1.5

,

ele

va

ted

liv

er

en

zym

es,

his

tory

of

ma

lig

na

ncy

,

un

tre

ate

d

hy

po

thy

roid

ism

or

hy

pe

rte

nsi

on

N=

41

2

Ra

nd

om

ize

d 2

:1,

tesa

mo

reli

n:p

lac

eb

o (

PB

O)

Tx:

n=

27

5

PB

O:

n=

13

7

Ext

en

sio

n P

ha

se

(ra

nd

om

ize

d

3:1

)

T-T

: n

=1

54

T-P

: n

=5

0

RC

T –

26

we

ek

s

Ext

en

sio

n p

ha

se

(6 m

on

ths)

–

sub

ject

s w

ho

rem

ain

ed

in

th

e

tria

l fo

r th

e

ext

en

sio

n p

ha

se

we

re r

e-

ran

do

miz

ed

3:1

to

rece

ive

tesa

mo

reli

n o

r

pla

ceb

o.

!"!#$%

Tx:

-1

5.2

%

PB

O:

5.0

%

Dif

f -3

2.9

%,

95

% C

I (-

40

.7 t

o -

25

)

p<

0.0

01

!"!!&'(

-I

Tx:

81

PB

O:-

5.0

Dif

f: 1

25

; 9

5%

CI

(10

5 t

o 1

46

)

p<

0.0

01

!"

To

tal

cho

lest

ero

l

Tx:

-3

.3

PB

O:

-0.7

p=

0.0

2

!"

fa

stin

g g

luco

se

Tx:

3.7

PB

O:

1.6

p=

0.2

8

EX

TE

NS

ION

PH

AS

E

!"!#$%

T-T

: 1

7.5

% p

<0

.00

1

T-P

: 1

.3%

p=

0.4

32

NA

NA

NA

NA

NA

% p

ati

en

ts

exp

eri

en

cin

g

an

y A

E:

Tx:

82

.8

PB

O:7

5.2

p=

0.0

9

% p

ati

en

ts

exp

eri

en

ce

tre

atm

en

t-

rela

ted

AE

:

Tx:

53

.8

PB

O:

36

.5

p=

0.0

01

Wit

hd

raw

als

du

e t

o a

dv

ers

e

ev

en

ts:

Tx:

12

.1

PB

O:

2.9

p=

0.0

02

EX

TE

NS

ION

PH

AS

E:

# w

ith

dra

wn

du

e t

o a

dv

ers

e

ev

en

ts:

T-T

: 2

pa

tie

nts

T-P

: 4

pa

tie

nts

NA

AR

R:

17

.3%

NN

H:

6

AR

R:

9.2

%

NN

H:

11

Th

e s

tud

y l

ack

ed

a t

ho

rou

gh

de

scri

pti

on

of

ran

do

miz

ati

on

.

Ra

tes

of

ad

ve

rse

ev

en

ts w

ere

hig

h i

n b

oth

stu

dy

gro

up

s, b

ut

ma

y b

e a

ttri

bu

ted

to

th

e

na

ture

of

the

dis

ea

se o

f p

ati

en

ts i

ncl

ud

ed

in t

he

tri

al.

Tre

atm

en

t g

rou

ps

ha

d s

ign

ific

an

tly

dif

fere

nt

HA

AR

T r

eg

ime

ns

at

ba

seli

ne

.

Eff

ica

cy e

nd

po

ints

fo

r V

AT

an

d c

ho

lest

ero

l

rem

ain

ed

sig

nif

ica

ntl

y s

up

eri

or

to p

lace

bo

aft

er

con

tro

llin

g f

or

incr

ea

sed

NN

RT

I u

se i

n

the

tre

atm

en

t g

rou

p.

An

tib

od

ies

de

ve

lop

ed

in

50

% o

f

tesa

mo

reli

n t

rea

ted

pa

tie

nts

, th

e l

on

g-

term

im

pli

cati

on

s o

f th

is a

re u

nk

no

wn

.

Th

e p

rim

ary

en

dp

oin

t is

use

d a

s a

surr

og

ate

ma

rke

r o

f ca

rdio

va

scu

lar

ou

tco

me

s, f

or

wh

ich

th

ere

is

lim

ite

d

ev

ide

nce

to

su

pp

ort

.

Pa

tie

nts

in

tole

ran

t to

te

sam

ore

lin

lik

ely

dis

con

tin

ue

d t

rea

tme

nt

pri

or

to r

e-

ran

do

miz

ati

on

fo

r th

e e

xte

nsi

on

ph

ase

.

Th

is m

ay

co

ntr

ibu

te t

o t

he

lo

w w

ith

dra

wa

l

rate

se

en

in

th

e e

xte

nsi

on

ph

ase

.

LOC

F u

sed

fo

r su

bje

cts

wh

o d

idn

’t

com

ple

te t

he

stu

dy

Init

ial

ph

ase

, d

rop

-ou

t ra

tes:

22

.7%

fo

r te

sam

ore

lin

16

.1%

fo

r p

lace

bo

11 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

5

Bra

nd

y F

outs

, P

har

mD

Fa

lutz

, e

t

al9

RC

T,

DB

,

PC

1.

Te

sam

o

reli

n

2m

g S

Q

da

ily

2.

Pla

ceb

o

Ext

en

sio

n

Ph

ase

:

1)

Te

sam

or

eli

n 2

mg

SQ

da

ily

(T-T

)

2)

Pla

ceb

o

(T-P

)

HIV

+ p

ati

en

ts s

tab

le

on

AR

T f

or !"!

we

ek

s w

ith

ev

ide

nce

of

ab

do

min

al

fat

acc

um

ula

tio

n

de

fin

ed

as

a w

ais

t

circ

um

fere

nce

of !

95

cm

an

d a

wa

ist-

to-h

ip r

ati

o o

f !

0.9

4 f

or

me

n a

nd

a

wa

ist

circ

um

fere

nce

of !#$!%&!'()!'!

wa

ist-

to-h

ip r

ati

o o

f

*+""!,-.!/-&0(+

Ba

seli

ne

cha

ract

eri

stic

s

sim

ila

r b

etw

ee

n

gro

up

s.

Exc

lusi

on

s C

rite

ria

:

Ty

pe

1 o

r 2

dia

be

tes,

se

rum

cre

ati

nin

e >

1.5

,

ele

va

ted

liv

er

en

zym

es,

his

tory

of

ma

lig

na

ncy

,

un

tre

ate

d

hy

po

thy

roid

ism

or

hy

pe

rte

nsi

on

N=

40

4

Ra

nd

om

ize

d 2

:1,

tesa

mo

reli

n:P

BO

Tx:

n=

27

0

PB

O:

n=

12

6

Ext

en

sio

n P

ha

se

(ra

nd

om

ize

d

1:1

)

T-T

: n

=9

2

T-P

: n

=8

5

RC

T –

26

we

ek

s

Ext

en

sio

n

ph

ase

(6

mo

nth

s) –

sub

ject

s w

ho

rem

ain

ed

in

the

tri

al

for

the

ext

en

sio

n

ph

ase

we

re r

e-

ran

do

miz

ed

3:1

to

re

ceiv

e

tesa

mo

reli

n o

r

pla

ceb

o.

!"!#$%

Tx:

-1

0.9

%

PB

O:

-0.6

%

p<

0.0

01

!"!!&'(

-I

Tx:

85

.8

PB

O:5

.6

p<

0.0

01

!"

To

tal

cho

lest

ero

l

Tx:

2.1

PB

O:

3.9

p=

0.1

0

!"

fa

stin

g g

luco

se

Tx:

3.2

PB

O:

2.7

p=

0.1

5

EX

TE

NS

ION

PH

AS

E

!"!#$%

T-T

: 1

7.5

% p

<0

.00

1

T-P

: 1

.3%

p=

0.4

32

NA

%

pa

tie

nts

exp

eri

en

cin

g

an

y A

E:

Tx:

74

.1

PB

O:6

9.8

p=

0.3

98

% p

ati

en

ts

exp

eri

en

ce

tre

atm

en

t-

rela

ted

AE

:

Tx:

53

PB

O:

37

.3

p=

0.0

05

% W

ith

dra

wa

ls

du

e t

o a

dv

ers

e

ev

en

ts:

Tx:

10

PB

O:

8.7

p=

0.8

55

EX

TE

NS

ION

PH

AS

E:

% p

ati

en

ts

exp

eri

en

cin

g

an

y A

E:

T-T

: 7

3.9

%

T-P

:57

.6%

Wit

hd

raw

als

du

e t

o a

dv

ers

e

ev

en

ts:

T-T

: 2

.2%

T-P

: 4

.7%

NA

AR

R:

15

.7%

NN

H:

7

NA

De

spit

e t

he

re

du

ctio

n i

n V

AT

, g

luco

se

lev

els

we

re n

ot

imp

rov

ed

. T

he

au

tho

r

sug

ge

sts

this

is

du

e t

o p

oss

ible

dis

rup

tio

n o

f in

suli

n f

un

ctio

na

lity

bu

t

this

is

cou

nte

rba

lan

ced

by

th

e

imp

rov

em

en

t in

VA

T.

Th

ere

wa

s n

o s

ign

ific

an

t im

pa

ct o

n

trig

lyce

rid

e l

ev

els

as

see

n i

n p

rev

iou

s

tria

ls.

Th

is c

ou

ld b

e r

ela

ted

to

lo

we

r

ba

seli

ne

TR

G l

ev

els

or

va

ria

tio

n i

n d

iets

for

pa

tie

nts

tre

ate

d a

t E

uro

pe

an

cen

ters

.

Th

ere

is

no

ev

ide

nce

to

sh

ow

th

at

imp

rov

ed

bo

dy

im

ag

e d

istr

ess

corr

ela

tes

wit

h i

mp

rov

ed

ad

he

ren

ce.

Th

e p

rim

ary

en

dp

oin

t is

use

d a

s a

surr

og

ate

ma

rke

r o

f ca

rdio

va

scu

lar

ou

tco

me

s, f

or

wh

ich

th

ere

is

lim

ite

d

ev

ide

nce

to

su

pp

ort

.

Ad

ve

rse

ev

en

t ra

tes

we

re s

imil

ar

in t

he

ext

en

sio

n p

ha

se a

nd

in

th

e p

rim

ary

ph

ase

.

Pa

tie

nts

in

tole

ran

t to

te

sam

ore

lin

lik

ely

dis

con

tin

ue

d t

rea

tme

nt

pri

or

to r

e-

ran

do

miz

ati

on

fo

r th

e e

xte

nsi

on

ph

ase

.

Th

is m

ay

co

ntr

ibu

te t

o t

he

lo

w

wit

hd

raw

al

rate

se

en

in

th

e e

xte

nsi

on

ph

ase

.

Init

ial

ph

ase

, d

rop

-ou

t ra

tes:

25

% f

or

tesa

mo

reli

n

27

% f

or

pla

ceb

o

1S

tud

y d

esi

gn

ab

bre

via

tio

ns:

DB

= d

ou

ble

-bli

nd

, R

CT

= r

an

do

miz

ed

tri

al,

PC

= p

lace

bo

-co

ntr

oll

ed

, P

G =

pa

rall

el

-gro

up

, X

O =

cro

sso

ve

r.

2R

esu

lts

ab

bre

via

tio

ns:

RR

R =

re

lati

ve

ris

k r

ed

uct

ion

, R

R =

rela

tiv

e r

isk

, O

R=

Od

ds

Ra

tio

, H

R =

Ha

zard

Ra

tio

, A

RR

= a

bso

lute

ris

k r

ed

uct

ion

,

NN

T =

nu

mb

er

ne

ed

ed

to

tre

at,

NN

H =

nu

mb

er

ne

ed

ed

to

ha

rm,

CI

= c

on

fid

en

ce i

nte

rva

l 3N

NT

/NN

H a

re r

ep

ort

ed

on

ly f

or

sta

tist

ica

lly

sig

nif

ica

nt

resu

lts

4Q

ua

lity

Ra

tin

g:

(Go

od

- li

ke

ly v

ali

d,

Fa

ir-

lik

ely

va

lid

/po

ssib

ly v

ali

d,

Po

or-

fa

tal

fla

w-n

ot

va

lid

)

12 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

6

Bra

nd

y F

outs

, P

har

mD

Su

mm

ary

of

Fin

din

gs

–

Te

sam

ore

lin

wa

s st

ud

ied

in

tw

o p

ha

se 3

tri

als

th

at

we

re id

en

tica

l in

stu

dy d

esi

gn

. E

ach

ra

nd

om

ize

d,

pla

ceb

o-c

on

tro

lle

d t

ria

l in

clu

de

d p

ati

en

ts w

ith

HIV

wh

o w

ere

sta

ble

on

an

tire

tro

vir

al

the

rap

y f

or

at

lea

st 8

we

eks,

an

d r

an

do

miz

ed

th

em

3:1

to

re

ceiv

e t

esa

mo

reli

n 2

mg

su

bcu

tan

eo

usl

y d

ail

y o

r

pla

ceb

o f

or

26

we

eks.

A

fte

r 2

6 w

ee

ks,

pa

tie

nts

we

re r

e-r

an

do

miz

ed

to

te

sam

ore

lin

or

pla

ceb

o f

or

a 2

6 w

ee

k e

xte

nsi

on

ph

ase

. F

or

bo

th s

tud

ies,

th

e

pri

ma

ry e

ffic

acy

en

dp

oin

t w

as

the

ch

an

ge

in

vis

cera

l a

dip

ose

tis

sue

(V

AT

) fr

om

ba

seli

ne

to

we

ek 2

6,

me

asu

red

by c

om

pu

teri

zed

to

mo

gra

ph

ic (

CT

)

sca

n.

A s

eco

nd

ary

en

dp

oin

t w

as

the

im

pa

ct o

n b

od

y im

ag

e p

erc

ep

tio

n m

ea

sure

d b

y a

qu

est

ion

na

ire

in

wh

ich

su

bje

cts

rate

d t

he

ir b

ell

y s

ize

[fr

om

th

inn

er

(-1

00

) to

mu

ch b

igg

er

(+1

00

)],

be

lly i

ma

ge

dis

tre

ss [

ext

rem

ely

dis

tre

ssin

g (

0)

to e

xtre

me

ly e

nco

ura

gin

g (

10

0)]

, a

nd

be

lly p

rofi

le b

y c

ho

osi

ng

fro

m 6

silh

ou

ett

es.

Oth

er

seco

nd

ary

en

dp

oin

ts i

ncl

ud

ed

ch

an

ge

s in

lip

id l

eve

ls a

nd

bio

che

mic

al m

ea

sure

s su

ch a

s In

suli

n-l

ike

gro

wth

fa

cto

r I

(IG

F-I

) a

nd

blo

od

glu

cose

. T

he

go

al o

f th

e e

xte

nsi

on

ph

ase

wa

s to

ass

ess

th

e lo

ng

te

rm s

afe

ty o

f te

sam

ore

lin

an

d e

va

lua

ted

eff

ect

s o

n g

luco

se,

insu

lin

, a

nd

bo

dy i

ma

ge

.

Bo

th s

tud

ies

saw

a s

tati

stic

all

y s

ign

ific

an

t ch

an

ge

in

VA

T i

n p

ati

en

ts t

rea

ted

wit

h t

esa

mo

relin

(-1

5.2

% a

nd

-1

0.9

%)

com

pa

red

to

pla

ceb

o (

+5

.0%

an

d

-0.6

%,

p<

0.0

01

fo

r b

oth

tri

als

).

Eff

ica

cy e

nd

po

ints

fro

m t

he

ext

en

sio

n p

ha

ses

ind

ica

te t

ha

t th

is d

ecr

ea

se i

n V

AT

is

no

t m

ain

tain

ed

aft

er

tre

atm

en

t

dis

con

tin

ua

tio

n a

nd

th

ese

re

sult

s w

ere

no

t se

en

in

pa

tie

nts

sw

itch

ed

to

pla

ceb

o in

th

e e

xte

nsi

on

arm

. B

oth

stu

die

s a

lso

fo

un

d n

o s

ign

ific

an

t

dif

fere

nce

in

th

e c

ha

ng

e in

bo

dy m

ass

in

de

x (B

MI)

aft

er

26

we

eks

wh

en

co

mp

ari

ng

pa

tie

nts

tre

ate

d w

ith

te

sam

ore

lin

ve

rsu

s p

lace

bo

. In

on

e s

tud

y

(20

10

), t

he

BM

I sl

igh

tly in

cre

ase

d i

n p

ati

en

ts t

rea

ted

wit

h t

esa

mo

relin

(+

0.6

%).

Th

e im

pa

ct o

f te

sam

ore

lin

on

lip

id le

ve

ls s

lig

htl

y v

ari

ed

be

twe

en

th

e t

wo

stu

die

s. I

n t

he

ea

rlie

r st

ud

y,

the

re w

as

a s

ign

ific

an

t d

iffe

ren

ce in

th

e

cha

ng

e in

tri

gly

ceri

de

s w

he

n c

om

pa

rin

g t

esa

mo

reli

n t

o p

lace

bo

(-7

.5%

vs

+1

1.6

%,

p<

0.0

01

). A

dd

itio

na

lly,

the

ch

an

ge

in

th

e r

ati

o o

f to

tal

cho

lest

ero

l to

HD

L ch

ole

ste

rol

wa

s -4

.7%

in

th

e t

esa

mo

relin

gro

up

co

mp

are

d t

o +

6.1

in

th

e p

lace

bo

gro

up

, p

<0

.00

1).

In

th

e s

eco

nd

stu

dy,

the

cha

ng

e in

tri

gly

ceri

de

s w

as

no

t si

gn

ific

an

t w

he

n c

om

pa

red

to

pla

ceb

o (

+2

.8%

vs

+7

.6%

, p

=0

.10

), a

nd

pa

tie

nts

in

th

e t

esa

mo

reli

n g

rou

p a

ctu

all

y s

aw

a s

lig

ht

incr

ea

se i

n t

rig

lyce

rid

e l

eve

ls.

Th

ere

wa

s a

lso

no

dif

fere

nce

in

th

e c

ha

ng

e i

n r

ati

o o

f to

tal ch

ole

ste

rol to

HD

L ch

ole

ste

rol

(+1

.5%

in

th

e

tesa

mo

reli

n g

rou

p v

s +

5.0

% i

n t

he

pla

ceb

o g

rou

p,

p=

0.1

0).

De

spit

e a

ve

ry s

ma

ll c

ha

ng

e in

wa

ist

circ

um

fere

nce

in

eit

he

r st

ud

y (

-2.2

cm a

nd

-2

.6cm

), a

s w

ell

as

no

dif

fere

nce

in

qu

est

ion

na

ire

sco

res

for

“be

lly

size

” a

fte

r 2

6 w

ee

ks,

th

ere

wa

s a

sig

nif

ica

nt

cha

ng

e i

n p

ati

en

t sc

ore

s fo

r “b

ell

y i

ma

ge

dis

tre

ss.”

Bio

che

mic

al

me

asu

res

sho

we

d t

ha

t p

ati

en

ts t

rea

ted

wit

h t

esa

mo

relin

sa

w a

n in

cre

ase

in

IG

F-I

(+

81

% a

nd

+8

5.8

%)

bu

t h

ad

lit

tle

im

pa

ct o

n f

ast

ing

glu

cose

le

ve

ls (

+3

.7%

an

d +

3.2

%).

Ove

rall

, ra

tes

of

ad

ve

rse

eve

nts

an

d a

ny

seri

ou

s a

dve

rse

eve

nts

we

re h

igh

, b

ut

sim

ila

r b

etw

ee

n t

he

tw

o t

rea

tme

nt

gro

up

s, w

hic

h m

ay b

e d

ue

to

th

e

na

ture

of

the

dis

ea

se in

th

is p

ati

en

t p

op

ula

tio

n.

In t

he

ea

rlie

r st

ud

y,

53

.8%

of

pa

tie

nts

tre

ate

d w

ith

te

sam

ore

lin

exp

eri

en

ced

tre

atm

en

t-re

late

d s

ide

eff

ect

s co

mp

are

d t

o 3

6.5

% t

rea

ted

wit

h p

lace

bo

, a

nd

12

.1%

of

tesa

mo

relin

-tre

ate

d p

ati

en

ts d

isco

nti

nu

ed

th

e s

tud

y.

Th

e m

ost

co

mm

on

ad

ve

rse

13 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

7

Bra

nd

y F

outs

, P

har

mD

eve

nts

we

re h

ea

da

che

, a

rth

ralg

ias,

in

ject

ion

-sit

e b

ruis

ing

, d

iarr

he

a,

pe

rip

he

ral e

de

ma

, m

ya

lgia

, a

nd

lim

b p

ain

. T

he

se r

esu

lts

we

re c

on

sist

en

t w

ith

safe

ty r

esu

lts

see

n in

th

e s

eco

nd

stu

dy,

wit

h t

he

exc

ep

tio

n b

ein

g t

ha

t th

ere

wa

s n

o s

ign

ific

an

t d

iffe

ren

ce in

th

e p

erc

en

t o

f p

ati

en

ts w

ho

dis

con

tin

ue

the

stu

dy d

ue

to

ad

ve

rse

eve

nts

(1

0%

te

sam

ore

lin

vs

8.7

% p

lace

bo

, p

=0

.85

5).

Aft

er

26

we

eks

of

tre

atm

en

t, t

he

me

an

Hb

A1

c w

as

hig

he

r a

mo

ng

pa

tie

nts

tre

ate

d w

ith

te

sam

ore

lin

co

mp

are

d t

o p

lace

bo

; th

e m

ea

n t

rea

tme

nt

dif

fere

nce

fo

r p

ati

en

ts r

ece

ivin

g t

esa

mo

relin

wa

s +

0.1

2%

(p

=0

.00

04

) w

hil

e t

he

Hb

A1

c o

f p

ati

en

ts in

th

e p

lace

bo

gro

up

did

no

t ch

an

ge

fro

m

ba

seli

ne

. P

ati

en

ts in

th

e t

esa

mo

reli

n g

rou

p h

ad

an

in

cre

ase

d r

isk o

f d

eve

lop

ing

dia

be

tes

com

pa

red

to

pla

ceb

o [

4.5

% v

s 1

.3%

, H

R 3

.3 (

1.4

,9.6

)].

In t

he

fir

st e

xte

nsi

on

ph

ase

, th

ere

we

re 1

54

pa

tie

nts

wh

o w

ere

tre

ate

d w

ith

te

sam

ore

lin

fo

r th

e e

nti

re 5

2 w

ee

ks.

Ra

tes

of

ad

ve

rse

eve

nts

we

re

low

er

tha

n t

ho

se s

ee

n in

th

e i

nit

ial e

ffic

acy

ph

ase

at

the

en

d o

f 2

6 w

ee

ks.

Ove

rall

, 5

7.8

% o

f p

ati

en

ts e

xpe

rie

nce

d a

ny a

dve

rse

eve

nt,

14

.3%

exp

eri

en

ced

tre

atm

en

t-re

late

d a

dve

rse

eve

nts

, a

nd

2.6

% d

isco

nti

nu

ed

th

e s

tud

y.

Th

ese

are

sim

ila

r to

th

e r

esu

lts

see

n in

th

e e

xte

nsi

on

ph

ase

of

the

seco

nd

stu

dy.

In t

his

stu

dy,

92

pa

tie

nts

we

re t

rea

ted

wit

h t

esa

mo

relin

fo

r th

e e

nti

re 5

2 w

ee

ks,

an

d 7

3.9

% e

xpe

rie

nce

d a

n a

dve

rse

eve

nt,

37

%

exp

eri

en

ced

an

ad

ve

rse

eve

nt

rela

ted

to

th

e s

tud

y t

rea

tme

nt,

bu

t o

nly

2.2

% r

esu

lte

d in

stu

dy

dis

con

tin

ua

tio

n.

Th

ese

are

sli

gh

tly l

ow

er

tha

n t

he

rate

s se

en

in

th

e i

nit

ial e

ffic

acy

ph

ase

of

the

tri

al (2

01

0).

14 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

8

Bra

nd

y F

outs

, P

har

mD

DR

UG

SA

FE

TY

:

Co

ntr

ain

dic

ati

on

s1,2

:

p

ati

en

ts w

ith

dis

rup

tio

n o

f th

e h

yp

oth

ala

mic

-pit

uit

ary

axi

s d

ue

to

hyp

op

hyse

cto

my,

hyp

op

itu

ita

rism

, o

r p

itu

ita

ry t

um

or/

surg

ery

, h

ea

d

irra

dia

tio

n o

r h

ea

d t

rau

ma

a

ctiv

e m

ali

gn

an

cy

kn

ow

n h

yp

ers

en

siti

vit

y t

o t

esa

mo

relin

an

d/o

r m

an

nit

ol

p

reg

na

ncy

Wa

rnin

gs

an

d p

reca

uti

on

s1,2

:

Ne

op

lasm

s: P

ati

en

ts w

ith

a h

isto

ry o

f n

on

-ma

lig

na

nt

ne

op

lasm

s sh

ou

ld o

nly

be

gin

te

sam

ore

lin

tre

atm

en

t a

fte

r ca

refu

l e

va

lua

tio

n o

f th

e p

ote

nti

al

be

ne

fit

of

tre

atm

en

t. T

he

de

cisi

on

to

sta

rt t

rea

tme

nt

wit

h t

esa

mo

relin

sh

ou

ld b

e c

on

sid

ere

d c

are

full

y b

ase

d o

n t

he

in

cre

ase

d b

ack

gro

un

d r

isk o

f

ma

lig

na

nci

es

in H

IV-p

osi

tive

pa

tie

nts

.

Ele

va

ted

IG

F-1

: T

he

im

pa

ct o

f e

leva

ted

IG

F-1

le

ve

ls o

n t

he

de

ve

lop

me

nt

of

ma

lig

na

nci

es

is u

nkn

ow

n.

Ca

refu

l co

nsi

de

rati

on

sh

ou

ld b

e g

ive

n t

o

dis

con

tin

uin

g t

esa

mo

relin

in

pa

tie

nts

wit

h p

ers

iste

nt

ele

va

tio

ns

in I

GF-1

le

ve

ls.

Flu

id r

ete

nti

on

: F

luid

re

ten

tio

n m

ay r

esu

lt i

n a

va

rie

ty o

f a

dve

rse

re

act

ion

s w

hic

h a

re e

ith

er

tra

nsi

en

t o

r w

ill

reso

lve

wit

h d

isco

nti

nu

ati

on

of

tre

atm

en

t.

Glu

cose

in

tole

ran

ce:

Te

sam

ore

lin

tre

atm

en

t m

ay r

esu

lt in

glu

cose

in

tole

ran

ce.

An

in

cre

ase

d r

isk o

f d

eve

lop

ing

dia

be

tes

wit

h t

esa

mo

relin

re

lati

ve

to

pla

ceb

o w

as

ob

serv

ed

in

cli

nic

al

tria

ls [

HR

3.3

(1

.4,9

.6)]

. T

he

refo

re,

glu

cose

sta

tus

sho

uld

be

ca

refu

lly e

va

lua

ted

pri

or

to i

nit

iati

ng

te

sam

ore

lin

tre

atm

en

t.

Pa

tie

nts

sh

ou

ld

be

m

on

ito

red

p

eri

od

ica

lly

for

cha

ng

es

in

glu

cose

m

eta

bo

lism

to

d

iag

no

se

tho

se

wh

o

de

velo

p

imp

air

ed

g

luco

se

tole

ran

ce o

r d

iab

ete

s.

Hyp

ers

en

siti

vit

y

rea

ctio

ns:

H

yp

ers

en

siti

vit

y

rea

ctio

ns

incl

ud

ed

p

ruri

tus,

e

ryth

em

a,

flu

shin

g,

urt

ica

ria

, a

nd

o

the

r ra

sh.

In

case

s o

f su

spe

cte

d

hyp

ers

en

siti

vit

y re

act

ion

s, p

ati

en

ts s

ho

uld

be

ad

vise

d t

o s

ee

k p

rom

pt

me

dic

al

att

en

tio

n a

nd

tre

atm

en

t sh

ou

ld b

e d

isco

nti

nu

ed

im

me

dia

tely

.

Inje

ctio

n s

ite

re

act

ion

s: R

ea

ctio

ns

incl

ud

e i

nje

ctio

n s

ite

ery

the

ma

, p

ruri

tus,

pa

in,

irri

tati

on

, a

nd

bru

isin

g.

In o

rde

r to

th

e i

nci

de

nce

of

inje

ctio

n s

ite

rea

ctio

ns,

it

is r

eco

mm

en

de

d t

o r

ota

te t

he

sit

e o

f in

ject

ion

to

dif

fere

nt

are

as

of

the

ab

do

me

n.

Acu

te c

riti

cal

illn

ess

: In

cre

ase

d m

ort

ality

wa

s se

e in

pa

tie

nts

wit

h a

cute

cri

tica

l il

lne

ss d

ue

to

co

mp

lica

tio

ns

foll

ow

ing

op

en

he

art

su

rge

ry,

ab

do

min

al

surg

ery

, o

r m

ult

iple

acc

ide

nta

l tr

au

ma

, o

r th

ose

wit

h a

cute

re

spir

ato

ry f

ail

ure

ha

s b

ee

n r

ep

ort

ed

aft

er

tre

atm

en

t w

ith

ph

arm

aco

log

ic a

mo

un

ts o

f

gro

wth

ho

rmo

ne

. T

esa

mo

reli

n h

as

no

t b

ee

n s

tud

ied

in

pa

tie

nts

wit

h a

cute

cri

tica

l il

lne

ss.

15 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

9

Bra

nd

y F

outs

, P

har

mD

To

lera

bil

ity:

Du

rin

g t

he

in

itia

l tr

ea

tme

nt

ph

ase

of

clin

ica

l tr

ials

, d

isco

nti

nu

ati

on

s a

s a

re

sult

of

ad

ve

rse

re

act

ion

s o

ccu

rre

d i

n 9

.6%

of

pa

tie

nts

rece

ivin

g t

esa

mo

relin

an

d 6

.8%

of

pa

tie

nts

re

ceiv

ing

pla

ceb

o.

Th

e m

ost

co

mm

on

re

aso

ns

for

dis

con

tin

ua

tio

n o

f te

sam

ore

lin

tre

atm

en

t w

ere

ad

ve

rse

re

act

ion

s d

ue

to

th

e e

ffe

cts

of

gro

wth

ho

rmo

ne

(4

.2%

) a

nd

lo

cal

inje

ctio

n s

ite

re

act

ion

s (4

.6%

). D

ue

ing

th

e 2

6-w

ee

k e

xte

nsi

on

ph

ase

s,

dis

con

tin

ua

tio

ns

as

a r

esu

lt o

f a

dve

rse

eve

nts

occ

urr

ed

in

2.4

% o

f p

ati

en

ts i

n t

he

T-T

gro

up

an

d 5

.2%

of

pa

tie

nts

in

th

e T

-P g

rou

p.

Pre

gn

an

cy/L

act

ati

on

ra

tin

g:

Pre

gn

an

cy c

ate

go

ry X

. V

isce

ral

ad

ipo

se t

issu

e i

ncr

ea

ses

du

rin

g p

reg

na

ncy

an

d m

od

ifyin

g t

his

off

ers

no

kn

ow

n b

en

efi

t

an

d m

ay r

esu

lt in

fe

tal

ha

rm.

Ad

min

istr

ati

on

to

ra

ts d

uri

ng

org

an

og

en

esi

s a

nd

la

cta

tio

n p

rod

uce

d h

yd

roce

ph

aly

in

off

spri

ng

at

a d

ose

2-4

x h

igh

er

tha

n t

he

clin

ica

l d

ose

.

Un

an

swe

red

sa

fety

qu

est

ion

s:

IGF

-1 i

s a

gro

wth

fa

cto

r a

nd

th

e e

ffe

ct o

f p

rolo

ng

ed

ele

va

tio

ns

in I

GF

-1 l

eve

ls o

n t

he

de

ve

lop

me

nt

or

pro

gre

ssio

n o

f m

ali

gn

an

cie

s is

un

kn

ow

n.

Ad

dit

ion

all

y,

sin

ce t

esa

mo

reli

n i

ncr

ea

ses

IGF

-1,

pa

tie

nts

wit

h d

iab

ete

s w

ho

are

re

ceiv

ing

on

go

ing

tre

atm

en

t w

ith

te

sam

ore

lin

sh

ou

ld b

e m

on

ito

red

at

reg

ula

r in

terv

als

fo

r p

ote

nti

al d

eve

lop

me

nt

of

wo

rse

nin

g o

f re

tin

op

ath

y.

Do

se I

nd

ex

(eff

ica

cy/t

oxi

c):

No

t a

pp

lica

ble

Loo

k-a

like

/ S

ou

nd

-ali

ke

(LA

/SA

) E

rro

r R

isk P

ote

nti

al

LA/S

A n

am

es

are

ass

ess

ed

du

rin

g t

he

PD

L se

lect

ion

of

dru

gs.

B

ase

d o

n c

lin

ica

l ju

dg

me

nt

an

d a

n e

va

lua

tio

n o

f LA

/SA

in

form

ati

on

fro

m f

ou

r d

ata

sou

rce

s (L

exi

-Co

mp

, U

SP

On

lin

e L

AS

A F

ind

er,

Fir

st D

ata

ba

nk,

an

d I

SM

P C

on

fuse

d D

rug

Na

me

Lis

t),

the

fo

llo

win

g d

rug

na

me

s m

ay c

au

se L

AS

A

con

fusi

on

:

NM

E D

rug

Na

me

Le

xi-

Co

mp

U

SP

On

lin

e

Fir

st D

ata

Ba

nk

IS

MP

C

lin

ica

l Ju

dg

me

nt

LA/S

A f

or

[g

en

eri

c]

te

mis

iro

lim

us

LA/S

A f

or

[b

ran

d]

16 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

10

Bra

nd

y F

outs

, P

har

mD

Inci

de

nce

of

pa

tie

nts

(%

) w

ith

ad

ve

rse

dru

g r

ea

ctio

ns

Ad

ve

rse

Ev

en

ts (

1)

(Me

dD

RA

Sy

ste

m O

rga

n C

lass

an

d P

refe

rre

d T

erm

)

Te

sam

ore

lin

C

on

tro

l

Nu

mb

er

of

Pa

tie

nts

5

43

2

63

Mu

scu

losk

ele

tal

an

d c

on

ne

ctiv

e t

issu

e d

iso

rde

rs

Art

hra

lgia

1

3.3

1

1.0

Pa

in i

n e

xtre

mit

y 6

.1

4.6

My

alg

ia

5.5

1

.9

Mu

scu

losk

ele

tal

pa

in

1.8

0

.8

Mu

scu

losk

ele

tal

stif

fne

ss

1.7

0

.4

Join

t st

iffn

ess

1

.5

0.8

Mu

scle

sp

asm

s 1

.1

0.8

Join

t sw

ell

ing

1

.1

0

Ge

ne

ral

dis

ord

ers

an

d a

dm

inis

tra

tio

n s

ite

co

nd

itio

ns

Inje

ctio

n s

ite

ery

the

ma

8

.5

2.7

Inje

ctio

n s

ite

pru

ritu

s 7

.6

0.8

Ed

em

a p

eri

ph

era

l 6

.1

2.3

Inje

ctio

n s

ite

pa

in

4.1

3

.0

Inje

ctio

n s

ite

irr

ita

tio

n

2.9

1

.1

Pa

in

1.7

1

.1

Inje

ctio

n s

ite

he

mo

rrh

ag

e

1.7

0

.4

Inje

ctio

n s

ite

urt

ica

ria

1

.7

0.4

Inje

ctio

n s

ite

sw

ell

ing

1

.5

0.4

Inje

ctio

n s

ite

re

act

ion

1

.3

0.8

Ch

est

pa

in

1.1

0

.8

Inje

ctio

n s

ite

ra

sh

1.1

0

.0

Ne

rvo

us

syst

em

dis

ord

ers

Pa

rest

he

sia

4

.8

2.3

Hy

po

est

he

sia

4

.2

1.5

Ca

rpa

l tu

nn

el

syn

dro

me

1

.5

0

Ga

stro

inte

stin

al

dis

ord

ers

17 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

11

Bra

nd

y F

outs

, P

har

mD

Na

use

a

4.4

3

.8

Vo

mit

ing

2

.6

0

Dy

spe

psi

a

1.7

0

.8

Ab

do

min

al

pa

in u

pp

er

1.1

0

.8

Ca

rdia

c d

iso

rde

rs

Pa

lpit

ati

on

s 1

.1

0.4

Psy

chia

tric

dis

ord

ers

De

pre

ssio

n

2.0

1

.5

Sk

in a

nd

su

bcu

tan

eo

us

tiss

ue

dis

ord

ers

Ra

sh

3.7

1

.5

Pru

ritu

s 2

.4

1.1

Nig

ht

swe

ats

1

.1

0.4

Va

scu

lar

dis

ord

ers

Hy

pe

rte

nsi

on

1

.3

0.8

Inju

ry,

po

iso

nin

g a

nd

pro

ced

ura

l co

mp

lica

tio

ns

Mu

scle

str

ain

1.1

0

Inv

est

iga

tio

ns

Blo

od

cre

ati

ne

ph

osp

ho

kin

ase

in

cre

ase

d

1.5

0

.4

DO

SE

& A

VA

ILA

BIL

ITY

:1,2

ST

RE

NG

TH

F

OR

M

RO

UT

E

FR

EQ

UE

NC

Y

RE

NA

L

AD

J

HE

PA

TIC

AD

J

Pe

dia

tric

Do

se

Eld

erl

y

Do

se

OT

HE

R D

OS

ING

CO

NS

IDE

RA

TIO

NS

1m

g

via

l S

Q

2m

g o

nce

da

ily

N/A

N

/A

No

t st

ud

ied

N

ot

stu

die

d

No

ne

PH

AR

MA

CO

KIN

ET

ICS

:1,2

Pa

ram

ete

r R

esu

lt

Bio

ava

ila

bil

ity

4%

Cm

ax

28

22

.3 p

g/m

L

Pro

tein

Bin

din

g

No

t re

po

rte

d

Eli

min

ati

on

N

ot

rep

ort

ed

Ha

lf-L

ife

3

8 m

inu

tes

in H

IV-i

nfe

cte

d p

ati

en

ts

Me

tab

oli

sm

No

t st

ud

ied

in

hu

ma

ns

18 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

12

Bra

nd

y F

outs

, P

har

mD

ALL

ER

GIE

S/I

NT

ER

AC

TIO

NS

:1,2

Dru

g-D

rug

:

Po

ssib

le i

nte

ract

ion

s w

ith

CY

P P

45

0 m

eta

bo

lize

d d

rug

s. M

on

ito

r d

uri

ng

co

ncu

rre

nt

use

wit

h t

esa

mo

reli

n.

Pa

tie

nts

re

ceiv

ing

glu

coco

rtic

oid

re

pla

cem

en

t fo

r h

yp

oa

dre

na

lism

ma

y r

eq

uir

e a

n i

ncr

ea

se i

n m

ain

ten

an

ce o

r st

ress

do

ses

foll

ow

ing

in

itia

tio

n o

f

tesa

mo

reli

n.

Fo

od

-Dru

g:

No

ne

All

erg

y/C

ross

Re

act

ive

Su

bst

an

ces:

No

ne

19 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

13

Bra

nd

y F

outs

, P

har

mD

Su

gg

est

ed

PA

Te

sa

mo

reli

n (

Eg

rift

a)

Go

al(

s):

C

over

for

only

OH

P c

overe

d d

iagn

oses.

R

estr

ict to

ind

ications s

upp

ort

ed b

y m

edic

al lit

era

ture

.

Len

gth

of

Au

tho

rizati

on

: 6 m

on

ths

Ap

pro

val

Cri

teri

a

1. W

hat is

the d

iag

nosis

?

Record

IC

D9 c

od

e

2.Is

the

dia

gnosis

are

duction o

f excess

abdom

ina

l fa

t in

HIV

-infe

cte

d p

atients

with

lipod

ystr

oph

y?

Yes: G

o t

o #

3N

o: P

ass to R

PH

; D

en

y (

medic

al a

ppro

pri

ate

ness).

3. Is

the

dia

gnosis

an O

HP

covere

d d

iag

nosis

?Y

es:

Appro

ve f

or

6 m

onth

sN

o: P

ass to

RP

H; D

en

y, (N

otcovere

d b

yth

e O

HP

).

20 of 108

Gen

eric

Nam

e: T

esam

ore

lin

Rev

iew

Dat

e: M

arch

201

2

14

Bra

nd

y F

outs

, P

har

mD

RE

FE

RE

NC

ES

:

1.1

. “E

gri

fta

Pre

scri

bin

g I

nfo

rmat

ion”.

Rock

ford

, M

A. T

her

atec

hnolo

gie

s, N

ovem

ber

2010.

2.

3.2.“F

DA

Sum

mar

y R

evie

w:

Tes

amore

lin”.

Cen

ter

for

Dru

g E

val

uat

ion a

nd R

esea

rch,

Novem

ber

9, 2

010.

3. Q

aqis

h, R

.B., E

. F

ish

er, J.

Ruble

in, an

d D

.A.

Wohl.

“H

IV-a

ssoci

ated

Lip

od

yst

roph

y S

yndro

me.

” P

ha

rma

coth

era

py

20, no.

1 (

2000):

13–22.

4. 4. N

akam

ura

, T

., H

. K

ob

ayas

hi,

K. Y

anag

i, T

. N

akag

awa,

M.

Nis

hid

a, S

. K

ihar

a,H

. H

irao

ka,

et

al.

“Im

po

rtan

ce o

f In

tra-

abdom

inal

Vis

cera

l F

at

Acc

um

ula

tion t

o C

oro

nar

y A

ther

osc

lero

sis

in H

eter

ozygous

Fam

ilia

l H

yp

erch

ole

ster

ola

emia

.” I

nte

rnati

onal

Journ

al

of

Obes

ity

21, no. 7 (

1997):

580–586.

5. M

azzo

ne,

T., P

.M. M

eyer

, G

.T. K

ondos,

M.H

. D

avid

son, S

.B. F

einst

ein, R

.B. D

’Agost

ino, A

. P

erez

, an

d S

.M. H

affn

er. “R

elat

ionsh

ip o

f T

radit

ional

and N

ontr

adit

ional

Car

dio

vas

cula

r R

isk F

acto

rs t

o C

oro

nar

y A

rter

y C

alci

um

in T

ype

2 D

iab

etes

.” D

iabet

es56, no. 3 (

2007):

849–855.

6. M

orr

icone,

L., C

. D

on

ati,

T. H

assa

n, P

. C

ioff

i, a

nd F

. C

avie

zel.

“R

elat

ionsh

ip o

f V

isce

ral

Fat

Dis

trib

uti

on t

o A

ngio

gra

phic

ally

Ass

esse

d C

oro

nar

y

Art

ery D

isea

se:

Res

ult

s in

Subje

cts

wit

h o

r W

ithout

Dia

bet

es o

r Im

pai

red G

luco

se T

ole

rance

.” N

utr

itio

n, M

etaboli

sm, and C

ard

iova

scula

r D

isea

ses:

NM

CD

12, no. 5 (

2002):

275.

7. F

alutz

, J.

, S

. A

llas

, K

. B

lot,

D. P

otv

in, D

. K

otl

er, M

. S

om

ero, D

. B

erger

, et

al.

“M

etab

oli

c E

ffec

ts o

f a

Gro

wth

Ho

rmone–

Rel

easi

ng F

acto

r in

Pat

ien

ts w

ith

HIV

.” N

ew E

ngla

nd J

ourn

al

of

Med

icin

e357, no. 23 (

2007):

2359–2370.

8. F

alutz

, J.

, S

. A

llas

, J.

C. M

amputu

, D

. P

otv

in, D

. K

otl

er, M

. S

om

ero, D

. B

erger

, et

al.

“L

on

g-t

erm

Saf

ety a

nd E

ffec

ts o

f T

esam

ore

lin, a

Gro

wth

Horm

one-

rele

asin

g F

acto

r A

nal

ogu

e, i

n H

IV P

atie

nts

wit

h A

bd

om

inal

Fat

Acc

um

ula

tion.”

Aid

s22,

no. 14 (

2008):

1719.

9. F

alutz

, J.

, D

. P

otv

in, J.

C. M

amputu

, H

. A

ssaa

d,

M. Z

olt

ow

ska,

S.E

. M

ich

aud, D

. B

erger

, et

al.

“E

ffec

ts o

f T

esam

ore

lin, a

Gro

wth

Horm

one-

Rel

easi

ng F

acto

r, i

n H

IV-I

nfe

cted

Pat

ien

ts W

ith

Ab

do

min

al F

at A

ccu

mu

lati

on:

A R

andom

ized

Pla

cebo-C

ontr

oll

ed T

rial

Wit

h a

Saf

ety E

xte

nsi

on.”

JAID

S J

ourn

al

of

Acq

uir

ed I

mm

un

e D

efic

ien

cy S

yndro

mes

53, no. 3 (

2010):

311.

21 of 108

Amylin Analog

Initiative: To optimize the correct use of amylin analogs.Length of Authorization: Up to 1 year

Preferred Alternatives: Listed at: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml

Requires PA: Pramlintide (Symlin®).

Approval Criteria

1. Does the patient have a diagnosis of Type1 diabetes and is taking mealtime insulin?

Yes: Approve for 1 year No: Go to #2

2. Does the patient have Type 2 diabetes andis taking mealtime insulin?

Yes: Go to #3 No: Pass to RPH; Deny (medical appropriateness)

3. Will the prescriber consider a change to a preferred product?Message:

Preferred products do not require PA.

Preferred products are evidence-based reviewed for comparative effectiveness & safety by the Health Resources Commission (HRC).

Reports are available at:http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class.

http://www.dhs.state.or.us/policy/healthplan/guides/pharmacy/main.

html

No: Go to #4.

4. Has the patient tried and failed metformin and sulfonylurea therapy or have contraindications to these treatments?Contraindications include:

- Renal disease or renal dysfunction- Know hypersensitivity to metformin- Acute or chronic metabolic acidosis- Patients at increased risk of lactic

acidosis (CHF, advanced age, impaired hepatic function)

Contraindications to sulfonylureas: - Known hypersensitivity

Yes: Approve for up to 1 year. No: Pass to RPH; Deny (medical appropriateness).Recommend trial of metformin or sulfonylurea.See below for metformin titration schedule.

Initiating Metformin

1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day.

2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 mg, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner).

3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time.

4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used.

Nathan, et al. Medical Management of Hyperglycemia in Type 2 Diabetes; A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31;1-11, 2008.

DUR Board Action: 3/17/11(KS), 4/26/12 (KS)Revision(s): 1/31/12 (KS)Initiated:

22 of 108

Incretin Enhancers

Initiative: Optimize the safety and efficacy of incretin enhancer use.

Length of Authorization: Up to 1 year

Preferred Alternatives: Listed at: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml

Requires PA: sitagliptin (Januvia®), sitagliptin/metformin (Janumet®), saxagliptin (Onglyza®) and saxagliptin/metformin (Kombiglyze XR®), linagliptin (Tradjenta®), linagliptin/metformin (Jentadueto®).

Approval Criteria

1. Does the patient have a diagnosis of type 2 diabetes?

Yes: Go to #2 No: Pass to RPH; Deny (medical appropriateness)

2. Will the prescriber consider a change to a preferred product?Message:

Preferred products do not require PA.

Preferred products are evidence-based reviewed for comparative effectiveness & safety by the Health Resources Commission (HRC).

Reports are available at:http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class.

http://www.dhs.state.or.us/policy/healt

hplan/guides/pharmacy/main.html

No: Go to #3.

3. Has the patient tried and failed metformin and sulfonylurea therapy or havecontraindications to these treatments?

Contraindications to metformin:- Known hypersensitivity- Renal disease or renal dysfunction- Acute or chronic metabolic acidosis- Increased risk of lactic acidosis (CHF,

advanced age, impaired hepatic function)

Contraindications to sulfonylureas: - Known hypersensitivity

Yes: Approve for up to 1 year. No: Pass to RPH; Deny (medical appropriateness)Recommend trial of metformin or sulfonylurea. See below for metformintitration schedule.

Initiating Metformin

1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day.

2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 mg, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner).

3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time.

4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used.

Nathan, et al. Medical Management of Hyperglycemia in Type 2 Diabetes; A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31;1-11, 2008.

DUR Board Action: 3/17/11 (KS), 4/26/12 (KS)Revision(s): Initiated: 10/26/11 (KS)

23 of 108

Incretin Mimetics

Initiative: To optimize the correct use of insulin mimetics.

Length of Authorization: Up to 1 year

Preferred Alternatives: Listed at: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml

Requires PA: Exenatide (Byetta®) and Liraglutide (Victoza®), Exenatide Extended-Release (Bydureon®)

Approval Criteria

1. Does the patient have a diagnosis of Type 2 diabetes?

Yes: Go to #2 No: Pass to RPH; Deny (medical appropriateness)

2. Will the prescriber consider a change to a preferred product?Message:

Preferred products do not require PA.

Preferred products are evidence-based reviewed for comparative effectiveness & safety by the Health Resources Commission (HRC).

Reports are available at:http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class.

http://www.dhs.state.or.us/policy/healthplan/guides/pharmacy/main.html

No: Go to #3.

3. Has the patient tried and failed metformin and sulfonylurea therapy or have contraindications to these treatments?Contraindications to metformin:

- Known hypersensitivity- Renal disease or renal dysfunction- Acute or chronic metabolic acidosis- Increased risk of lactic acidosis (CHF,

advanced age, impaired hepatic function)

Contraindications to sulfonylureas: - Known hypersensitivity

Yes: Go to #4. No: Pass to RPH; Deny (medical appropriateness).Recommend trial of metformin or sulfonylurea. See below for metformin titration schedule.

4. Is the patient currently taking insulin? Yes: Go to #5 No: Approve for up to 1 year.

5. Is the patient requesting exentatide (Byetta) and is taking insulin glargine?

Yes: Approve for up to 1 year. No: Pass to RPH; Deny (medical appropriateness). The safety and efficacy of other insulin formations and GLP-1 Agonists have not been studied.

Initiating Metformin

1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day.

2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 mg, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner).

3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time.

4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may

24 of 108

limit the dose that can be used. Nathan, et al. Medical Management of Hyperglycemia in Type 2 Diabetes; A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31;1-11, 2008.

DUR Board Action: 3/17/11 (KS), 4/26/12 (KS)Revision(s): 1/31/12 (KS)Initiated:

25 of 108

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bru

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ric

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me

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ina

glip

tin

B

ran

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am

e (

Ma

nu

fact

ure

r):

Tra

dje

nta

(B

oe

hri

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er

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eim

)

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ssie

r re

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:

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s

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Me

tfo

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, su

lfo

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lita

zon

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Pre

ferr

ed

Ag

en

ts:

me

tfo

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lim

ep

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glip

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bu

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tid

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ne

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refe

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ge

nts

: s

ita

gli

pti

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saxa

gli

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exe

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EX

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UT

IVE

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MM

AR

Y:

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pp

rove

d I

nd

ica

tio

ns:

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na

glip

tin

is

a d

ipe

pti

dyl

pe

pti

da

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(D

PP

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Inh

ibit

or

use

d a

s a

n a

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nct

to

die

t a

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exe

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mp

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cem

ic

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ad

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s w

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typ

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tes.

1

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ckg

rou

nd

: O

ral

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tid

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eti

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e s

tan

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f ca

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aft

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dif

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, to

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n p

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in is

wid

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t fo

r p

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eq

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mm

en

da

tio

ns

for

tie

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ag

en

ts in

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su

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rea

s a

nd

ba

sal in

suli

n.

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lid

ine

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com

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ag

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g a

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, a

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esp

ite

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ts f

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to

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et

Hb

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c g

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as

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lip

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is

the

th

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en

t in

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wh

ich

als

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es

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ag

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s a

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for

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ep

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ase

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as

a l

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en

ce o

f h

yp

og

lyce

mia

. S

ita

glip

tin

an

d s

axa

gli

pti

n r

eq

uir

e a

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stm

en

ts f

or

ren

al fu

nct

ion

bu

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qu

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ble

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ag

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rt d

ura

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lar

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me

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26 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

2

Auth

or:

Kat

hy S

ente

na

Issu

es:

Ke

y Q

ue

stio

ns:

1

. I

s li

na

gli

pti

n m

ore

eff

ect

ive

th

an

cu

rre

ntl

y a

va

ila

ble

pre

ferr

ed

ag

en

ts f

or

the

tre

atm

en

t o

f ty

pe

2 d

iab

ete

s?

2

. I

s li

na

gli

pti

n b

ett

er

tole

rate

d t

ha

n c

urr

en

tly a

vail

ab

le p

refe

rre

d a

ge

nts

?

3

. A

re t

he

re s

pe

cifi

c p

op

ula

tio

ns

wh

ich

lin

ag

lip

tin

wo

uld

be

be

tte

r to

lera

ted

or

mo

re e

ffe

ctiv

e?

Eff

ica

cy:

Mo

st s

tud

ies

of

ora

l a

nti

dia

be

tic

dru

gs

eva

lua

te i

nte

rme

dia

te o

utc

om

es,

su

ch a

s H

bA

1c

an

d w

eig

ht.

Id

ea

lly,

he

alt

h o

utc

om

es

such

as

mo

rta

lity

an

d m

acr

ova

scu

lar

an

d m

icro

va

scu

lar

eve

nts

wo

uld

be

in

clu

de

d.

In

th

e l

ina

gli

pti

n s

tud

ies

the

pri

ma

ry o

utc

om

e w

as

the

ad

just

ed

me

an

cha

ng

e f

rom

ba

selin

e H

bA

1c,

ca

ptu

red

at

24

we

eks.

Se

ve

n t

ria

ls w

ere

su

bm

itte

d t

o t

he

FD

A f

or

eva

lua

tio

n o

f e

ffic

acy

, tw

o s

tud

ies

com

pa

rin

g l

ina

gli

pti

n t

o p

lace

bo

an

d f

ive

stu

die

s co

mp

ari

ng

th

e

ad

dit

ion

of

lin

ag

lip

tin

to

oth

er

an

tid

iab

eti

c th

era

pie

s.4

, 5

, 6

, 7

, 8

Fo

ur

ph

ase

III

, fa

ir q

ua

lity

pu

bli

she

d s

tud

ies

are

ava

ila

ble

fo

r th

e e

va

lua

tio

n o

f e

ffic

acy

of

lin

ag

lip

tin

.4,

5,

6,

7 T

he

oth

er

thre

e s

tud

ies

we

re n

ot

pu

bli

she

d a

nd

th

ere

fore

we

re n

ot

pe

er

revie

we

d a

nd

co

uld

no

t b

e a

pp

rais

ed

fo

r ri

sk o

f b

ias

an

d q

ua

lity

bu

t w

ill

be

dis

cuss

ed

bri

efl

y in

th

e c

lin

ica

l e

ffic

acy

se

ctio

n.

Th

e fo

ur,

fa

ir q

ua

lity

pu

bli

she

d t

ria

ls c

om

pa

rin

g lin

ag

lip

tin

to

pla

ceb

o a

s m

on

oth

era

py o

r a

s a

dd

-on

th

era

py h

ad

sim

ila

r st

ud

y d

esi

gn

s; p

ati

en

ts

wit

h t

ype

2 d

iab

ete

s w

ith

me

an

ba

seli

ne

A1

Cs

be

twe

en

8.0

%-8

.6%

an

d a

me

an

ag

e 5

6-5

8 y

ea

rs.4

,5,6

,7 Li

na

glip

tin

wa

s st

ud

ied

as

mo

no

the

rap

y a

nd

fou

nd

to

be

su

pe

rio

r to

pla

ceb

o w

ith

an

ad

just

ed

me

an

ch

an

ge

fro

m b

ase

lin

e A

1C

of

-0.6

9 (

95

% C

I -0

.73

to

-0

.50

, p

<0

.00

01

).5

In t

he

ad

d-o

n t

ria

ls

lin

ag

lip

tin

wa

s co

mp

are

d t

o p

lace

bo

wh

en

ad

de

d t

o m

etf

orm

in,

me

tfo

rmin

an

d a

su

lfo

nylu

rea

, o

r p

iog

lita

zon

e.

All

stu

die

s fo

un

d a

dd

-on

lin

ag

lip

tin

to b

e s

up

eri

or

to p

lace

bo

ad

d-o

n w

ith

ad

just

ed

me

an

tre

atm

en

t e

ffe

ct o

n H

bA

1c

ran

gin

g f

rom

-0

.51

% t

o -

0.6

4%

fo

r li

na

glip

tin

.4,6

,7

Lin

ag

lip

tin

de

cre

ase

d p

ost

-pra

nd

ial g

luco

se (

PP

G)

leve

ls m

ore

th

an

pla

ceb

o.5

,6

Lin

ag

lip

tin

wa

s w

eig

ht

ne

utr

al

in a

ll s

tud

ies

wit

h t

he

exc

ep

tio

n o

f th

e s

tud

y b

y

Go

mis

, e

t a

l.,

wh

ich

th

e c

om

bin

ati

on

of

pio

glita

zon

e a

nd

lin

ag

lip

tin

re

sult

ed

in

a m

ea

n w

eig

ht

ga

in o

f 1

.1kg

ove

r p

iog

lita

zon

e a

nd

pla

ceb

o.4

Lip

id

pa

ram

ete

rs w

ere

min

ima

lly a

ffe

cte

d b

y lin

ag

lip

tin

wit

h c

ha

ng

es

sim

ila

r o

r le

ss t

ha

n p

lace

bo

.1

Th

ere

is

no

da

ta o

n t

he

re

lati

ve

eff

ica

cy a

nd

sa

fety

of

lin

ag

lip

tin

co

mp

are

d t

o s

ita

glip

tin

or

saxa

gli

pti

n.

Th

e F

DA

su

mm

ary

re

ite

rate

s th

e

ob

serv

ati

on

th

at

Hb

A1

c lo

we

rin

g w

as

gre

ate

r w

ith

me

tfo

rmin

an

d s

ulf

on

ylu

rea

s (g

lim

ep

irid

e)

tha

n w

ith

lin

ag

lip

tin

.8

Sa

fety

: L

ina

gli

pti

n w

as

we

ll t

ole

rate

d w

ith

lo

w l

eve

ls o

f d

isco

nti

nu

ati

on

ra

tes

du

e t

o a

dve

rse

eff

ect

s.

Se

rio

us

ad

ve

rse

eve

nts

we

re s

imil

ar

in t

he

lin

ag

lip

tin

an

d p

lace

bo

gro

up

s, 2

.8%

an

d 2

.7%

, re

spe

ctiv

ely

.9 T

he

mo

st c

om

mo

n a

dve

rse

re

act

ion

s th

at

we

re g

rea

ter

for

lin

ag

lip

tin

co

mp

are

d t

o

pla

ceb

o w

ere

na

sop

ha

ryn

git

is (

5.9

% a

nd

5.1

%)

an

d c

ou

gh

(1

.7%

an

d 1

.0%

).

Ra

tes

of

hyp

og

lyce

mia

we

re s

imil

ar

to p

lace

bo

an

d <

1%

in

mo

no

the

rap

y s

tud

ies.

H

igh

er

rate

s o

f h

yp

og

lyce

mia

we

re e

xpe

rie

nce

d in

ad

d-o

n s

tud

ies

wit

h t

he

gre

ate

st i

nci

de

nce

occ

urr

ing

wit

h t

he

com

bin

ati

on

of

lin

ag

lip

tin

an

d a

su

lfo

nylu

rea

, 2

2.7

% a

nd

14

.8%

, re

spe

ctiv

ely

.7

Infe

ctio

n r

isk w

as

sim

ila

r o

r le

ss t

ha

n p

lace

bo

. N

o d

osa

ge

ad

just

me

nt

is r

eq

uir

ed

in

re

na

l o

r h

ep

ati

c im

pa

irm

en

t.

27 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

3

Auth

or:

Kat

hy S

ente

na

Co

ncl

usi

on

s:

Th

ere

is

mo

de

rate

le

ve

l o

f e

vid

en

ce t

o s

ug

ge

st t

ha

t li

na

gli

pti

n i

s su

pe

rio

r to

pla

ceb

o f

or

glu

cose

lo

we

rin

g a

s d

em

on

stra

ted

by c

ha

ng

es

in H

bA

1c

leve

ls.

Th

ere

is

mo

de

rate

le

ve

l o

f e

vid

en

ce t

ha

t li

na

glip

tin

is

we

ll t

ole

rate

d w

ith

a l

ow

in

cid

en

ce o

f h

yp

og

lyce

mia

an

d w

ith

dra

wa

ls d

ue

to

ad

ve

rse

eff

ect

s. T

he

re a

re n

o p

ub

lish

ed

he

ad

-to

-he

ad

tri

als

on

co

mp

ara

tive

eff

ica

cy a

nd

sa

fety

of

lin

ag

lip

tin

to

oth

er

an

tid

iab

eti

c m

ed

ica

tio

ns.

Th

e e

ffic

acy

an

d s

afe

ty e

va

lua

tio

n o

f lin

ag

lip

tin

wa

s li

mit

ed

by s

tud

ies

of

sho

rt t

erm

du

rati

on

. L

on

ge

r-te

rm s

tud

ies

eva

lua

tin

g d

ire

ct o

utc

om

es

such

as

all

-ca

use

mo

rta

lity

, m

acr

ova

scu

lar

an

d m

icro

va

scu

lar

eve

nts

wo

uld

be

he

lpfu

l. A

dd

itio

na

lly,

allo

cati

on

co

nce

alm

en

t a

nd

ra

nd

om

iza

tio

n d

eta

ils

we

re i

nco

mp

lete

su

gg

est

ing

th

e p

ote

nti

al fo

r se

lect

ion

bia

s.

Lin

ag

lip

tin

de

mo

nst

rate

d r

ed

uce

d e

ffic

acy

co

mp

are

d t

o e

sta

bli

she

d o

ral

an

tid

iab

eti

c a

ge

nts

bu

t p

rove

s to

be

an

ap

pro

pri

ate

ch

oic

e in

th

ose

wh

om

ha

ve

co

ntr

ain

dic

ati

on

s to

me

tfo

rmin

an

d/o

r a

re c

on

cern

ed

wit

h h

ypo

gly

cem

ia o

r w

eig

ht

ga

in a

sso

cia

ted

wit

h o

the

r o

ral

an

tid

iab

eti

c tr

ea

tme

nts

.

Re

com

me

nd

ati

on

s:

It i

s re

com

me

nd

ed

to

use

cli

nic

al p

rio

r a

uth

ori

zati

on

cri

teri

a t

o l

imit

th

e u

se o

f li

na

glip

tin

to

pa

tie

nts

th

at

ha

ve

tri

ed

an

d f

aile

d o

ral

an

tid

iab

eti

c

tre

atm

en

ts t

ha

t h

ave

a p

rove

n h

isto

ry o

f sa

fety

an

d e

ffic

acy

as

ou

tlin

ed

in

th

e P

A c

rite

ria

fo

r In

cre

tin

En

ha

nce

rs (

ap

pe

nd

ix).

BA

CK

GR

OU

ND

/CU

RR

EN

T L

AN

DS

CA

PE

Th

ree

wid

ely

use

d c

lin

ica

l g

uid

eli

ne

s a

re a

va

ila

ble

to

gu

ide

th

e m

ed

ica

l m

an

ag

em

en

t o

f ty

pe

2 d

iab

ete

s. T

he

AD

A i

nco

rpo

rate

s st

ud

y r

evie

w a

nd

clin

ica

l ju

dg

me

nt,

wit

h a

n e

mp

ha

sis

on

glu

cose

-lo

we

rin

g a

bil

ity a

nd

co

st,

into

de

term

inin

g w

he

the

r tr

ea

tme

nts

are

we

ll-v

alid

ate

d v

ers

us

less

we

ll-

va

lid

ate

d t

he

rap

ies.

In

th

e 2

01

2 A

DA

Sta

nd

ard

s o

f M

ed

ica

l C

are

in

Dia

be

tes

Ad

dit

ion

s a

nd

Re

vis

ion

s, l

eve

ls o

f e

vid

en

ce w

ere

in

clu

de

d w

ith

reco

mm

en

da

tio

ns,

wh

ich

use

d t

he

ir o

wn

gra

din

g s

yst

em

ra

nkin

g e

vid

en

ce A

th

rou

gh

E.

Th

e A

me

rica

n A

sso

cia

tio

n o

f C

lin

ica

l E

nd

ocr

ino

log

ists

(AA

CE

)/ A

me

rica

n C

oll

eg

e o

f E

nd

ocr

ino

log

y (

AC

E)

con

sid

ers

me

dic

al

lite

ratu

re a

nd

th

e j

ud

gm

en

t o

f p

an

el m

em

be

rs in

to t

he

ir r

eco

mm

en

da

tio

n,

wit

h a

fo

cus

on

be

ne

fits

ve

rsu

s ri

sks

of

tre

atm

en

ts.

No

sp

eci

fic

gra

din

g o

f e

vid

en

ce i

s in

clu

de

d.

Th

e A

me

rica

n C

oll

eg

e o

f P

hysi

cia

ns

(A

CP

)

gu

ide

lin

es

uti

lize

an

ad

ap

tati

on

of

the

GR

AD

E (

Gra

din

g o

f R

eco

mm

en

da

tio

ns,

Ass

ess

me

nts

, D

eve

lop

me

nt

an

d E

va

lua

tio

n)

wo

rkg

rou

p t

o d

ete

rmin

e

if t

he

evid

en

ce i

s o

f h

igh

, m

od

era

te o

r lo

w q

ua

lity

.

Th

e A

DA

co

nse

nsu

s p

an

el

reco

mm

en

ds

me

tfo

rmin

as

ste

p 1

th

era

py [

hig

he

st l

eve

l o

f e

vid

en

ce g

rad

e (

A)]

, fo

llo

we

d b

y e

ith

er

a s

ulf

on

ylu

rea

or

ba

sal

insu

lin

fo

r st

ep

2.

Le

ss w

ell

va

lid

ate

d t

ier

2 t

he

rap

ies

incl

ud

e t

he

ad

dit

ion

of

pio

gli

tazo

ne

, a

GLP

-1 a

go

nis

t, o

r p

iog

lita

zon

e a

nd

a s

ulf

on

ylu

rea

to s

tep

1 r

eco

mm

en

da

tio

ns.

Ste

p 3

re

com

me

nd

ati

on

s in

clu

de

th

e a

dd

itio

n o

f in

ten

sive

in

sulin

to

ste

p 1

tre

atm

en

ts.

Th

e D

PP

-4 in

hib

ito

rs a

re

con

sid

ere

d t

hir

d l

ine

by t

he

AD

A,

ba

sed

on

gly

cem

ic e

ffe

ctiv

en

ess

an

d r

ela

tive

co

st.3

T

he

AA

CE

/AC

E c

on

sen

sus

pa

ne

l co

nsi

de

rs D

PP

-4 in

hib

ito

rs

pre

ferr

ed

ag

en

ts,

aft

er

me

tfo

rmin

, a

s m

on

oth

era

py o

r a

dd

-on

th

era

py.1

0 T

he

AC

P r

eco

mm

en

ds

me

tfo

rmin

fir

st l

ine

fo

r m

on

oth

era

py.

Po

ole

d

resu

lts

sho

we

d m

od

era

te s

tre

ng

th o

f e

vid

en

ce t

ha

t m

etf

orm

in h

ad

gre

ate

r H

bA

1c

low

eri

ng

th

an

DP

P-4

in

hib

ito

rs (

me

an

dif

fere

nce

, -0

.37

%,

95

% C

I

28 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

4

Auth

or:

Kat

hy S

ente

na

-0.5

4 t

o -

0.2

0).

M

etf

orm

in w

as

als

o r

eco

mm

en

de

d f

or

com

bin

ati

on

th

era

pie

s.

Th

e g

rea

test

Hb

A1

c lo

we

rin

g w

as

fou

nd

wit

h m

etf

orm

in +

sulf

on

ylu

rea

(m

ea

n d

iffe

ren

ce,

1.0

0%

, 9

5%

CI

0.7

5 t

o 1

.25

; h

igh

-qu

ali

ty e

vid

en

ce),

fo

llo

we

d b

y m

etf

orm

in +

DP

P-4

in

hib

ito

rs (

me

an

dif

fere

nce

,

0.6

9%

, 9

5%

CI

0.5

6 t

o 0

.82

; m

od

era

te-q

ua

lity

of

evid

en

ce)

an

d l

ast

ly w

ith

me

tfo

rmin

+ t

hia

zoli

din

ed

ion

e (

me

an

dif

fere

nce

, 0

.66

%,

95

% C

I 0

.45

to

0.8

6;

hig

h-q

ua

lity

of

evid

en

ce).

11

Th

e C

och

ran

e R

evie

w o

f D

PP

-4 in

hib

ito

rs f

or

typ

e 2

dia

be

tes

me

llit

us

rep

ort

ed

no

ad

va

nta

ge

s o

f D

PP

-4 in

hib

ito

rs o

ve

r e

xist

ing

th

era

pie

s (l

ina

gli

pti

n

no

t a

pp

rove

d a

t ti

me

of

revie

w).

12

Da

ta o

n m

ort

ali

ty,

dia

be

tic

com

pli

cati

on

s a

s w

ell a

s lo

ng

te

rm c

ard

iova

scu

lar

ou

tco

me

s a

nd

sa

fety

da

ta a

re

lack

ing

. A

nim

al m

od

els

su

gg

est

be

ta-c

ell

pre

serv

ati

on

wit

h c

hro

nic

use

of

DP

P-4

in

hib

ito

rs b

ut

ad

dit

ion

al st

ud

ies

are

ne

ed

ed

to

de

term

ine

if

this

can

be

ext

rap

ola

ted

to

hu

ma

ns.

D

PP

-4 i

nh

ibit

ors

ma

y b

e a

n o

pti

on

fo

r p

ati

en

ts c

lose

to

th

eir

Hb

A1

c g

oa

l a

nd

are

un

ab

le t

o t

ole

rate

oth

er

hyp

og

lyce

mic

ag

en

ts d

ue

to

ad

ve

rse

eff

ect

s, in

clu

din

g h

yp

og

lyce

mia

.

CLI

NIC

AL

PH

AR

MA

CO

LOG

Y1

Lin

ag

lip

tin

blo

cks

the

de

gra

da

tio

n o

f D

PP

-4,

wh

ich

is

the

en

zym

e r

esp

on

sib

le f

or

de

gra

din

g t

he

in

cre

tin

ho

rmo

ne

s g

luca

go

n-l

ike

pe

pti

de

-1 (

GLP

-1)

an

d g

luco

se-d

ep

en

de

nt

insu

lin

otr

op

ic p

oly

pe

pti

de

(G

IP).

Li

na

glip

tin

in

cre

ase

s th

e a

va

ila

ble

am

ou

nt

of

act

ive

in

cre

tin

ho

rmo

ne

s a

va

ila

ble

wh

ich

stim

ula

tes

the

re

lea

se o

f in

sulin

in

a g

luco

se-d

ep

en

de

nt

ma

nn

er

an

d d

ecr

ea

ses

the

le

ve

ls o

f g

luca

go

n in

cir

cula

tio

n.1

It

is

sug

ge

ste

d t

ha

t lin

ag

lip

tin

en

ha

nce

s b

eta

-ce

ll f

un

ctio

n d

ue

to

th

e in

cre

ase

s in

GLP

-1 a

va

ila

bil

ity,

att

en

ua

tin

g lo

ss o

f g

lyce

mic

co

ntr

ol o

ve

r ti

me

, h

ow

eve

r lo

ng

-te

rm s

tud

ies

are

ne

ed

ed

.

PH

AR

MA

CO

KIN

ET

ICS

1

Pa

ram

ete

r R

esu

lt

Ora

l B

ioa

va

ila

bil

ity

30

%

Pro

tein

Bin

din

g

70

-99

% (

con

cen

tra

tio

n d

ep

en

de

nt)

Eli

min

ati

on

8

0%

en

tero

he

pa

tic

in

fe

ces

an

d 5

% u

rin

e

Ha

lf-L

ife

12

ho

urs

Me

tab

oli

sm

90

% e

xcre

ted

un

cha

ng

ed

CO

MP

AR

AT

IVE

CLI

NIC

AL

EF

FIC

AC

Y

Re

lev

an

t E

nd

po

ints

S

tud

y E

nd

po

ints

:

All

Stu

die

s:

Hb

A1

C a

nd

we

igh

t (i

nte

rme

dia

te o

utc

om

es)

A

ll S

tud

ies:

A

1C

, w

eig

ht

Mic

rova

scu

lar

Dis

ea

se

Ma

cro

va

scu

lar

Dis

ea

se

All

-ca

use

Mo

rta

lity

29 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

5

Auth

or:

Kat

hy S

ente

na

Ev

ide

nce

Ta

ble

Re

f./

Stu

dy

De

sig

n1

Dru

g

Re

gim

en

s

Pa

tie

nt

Po

pu

lati

on

N

Du

rati

on

E

ffic

acy

Re

sult

s2

(CI,

p-v

alu

es)

AR

R /

NN

T3

Sa

fety

Re

sult

s^

(CI,

p-v

alu

es)

AR

R/

NN

H3

Qu

ali

ty R

ati

ng

4;

Co

mm

en

ts

Stu

dy

15

4

Go

mis

, e

t a

l

Ph

ase

III

, P

C

RC

T,

DB

, P

G

Mu

lti-

cen

tre

7 C

ou

ntr

ies

(No

US

sit

es

1.

Pio

gli

tazo

ne

30

mg

+

lin

ag

lip

tin

5m

g

da

ily

2.

Pio

gli

tazo

ne

30

mg

+ p

lace

bo

* 6

we

ek

wa

sho

ut

for

pa

tie

nts

pre

vio

usl

y o

n

ora

l d

iab

eti

c

tre

atm

en

t

(in

clu

de

d 2

we

ek

pla

ceb

o

run

-in

)

* 2

we

ek

pla

ceb

o r

un

-

in f

or

all

pa

tie

nts

Ag

e:

58

yrs

Ma

le:

61

%

Me

an

ba

seli

ne

A1

C:

8.6

%

Incl

usi

on

:

Tre

atm

en

t n

aïv

e o

r o

n

on

e o

ral

dia

be

tic

ag

en

t,

18

-80

yr

old

s w

ith

ty

pe

2 D

M,

BM

I

40

kg

/m2

,

an

d b

ase

lin

e A

1C

7.5

%

to 1

1%

in

pre

tre

ate

d

pa

tie

nts

an

d 7

% t

o 1

0%

in t

rea

tme

nt-

na

ïve

pa

tie

nts

.

Exc

lusi

on

:

Pa

tie

nts

wit

h a

his

tory

of

usi

ng

a G

LP-1

an

alo

gu

e o

r a

go

nis

t,

insu

lin

or

an

tio

be

sity

dru

g w

ith

in 3

mo

nth

s,

he

pa

tic,

ca

rdia

c o

r

cere

bra

l v

asc

ula

r

dis

ea

se.

1.

25

9

2.

13

0

24

we

ek

s A

dju

ste

d m

ea

n c

ha

ng

e f

rom

ba

seli

ne

A1

C:

Pio

+ L

(2

52

):

-1.0

6%

Pio

+ P

(1

28

): -

0.5

6%

Ad

just

ed

me

an

tre

atm

en

t

eff

ect

: -0

.51

%

95

% C

I -0

.71

to

-0

.30

P<

0.0

00

1

Ad

just

ed

Me

an

We

igh

t G

ain

:

Pio

+ L

: 2

.3k

g

Pio

+ P

: 1

.2K

g

Dif

fere

nce

: 1

.1k

g

95

% C

I 0

.2 t

o 2

.0

P=

0.0

14

NA

Hy

po

gly

cem

ia:

P i

o +

L:

5 (

2%

)

Pio

+ P

: 0

(0

%)

Dis

con

tin

ua

tio

n

du

e t

o A

E:

Pio

+ L

: 4

(1

.5%

)

Pio

+P

: 6

(4

.6%

)

RR

: 0

.33

95

% C

I 0

.10

to

1.2

F

air

Qu

ali

ty

B

ase

lin

e A

1c

hig

he

r a

t

incl

usi

on

wh

ich

co

uld

le

nd

for

gre

ate

r A

1c

low

eri

ng

eff

ect

.

Re

sult

s sh

ow

ed

A

1C

cha

ng

es

we

re r

ed

uce

d t

o

gre

ate

st e

xte

nt

in p

t.s

wit

h

hig

he

r b

ase

lin

e A

1C

va

lue

s

P

ote

nti

al

for

ass

ess

me

nt

bia

s d

ue

to

lim

ite

d

info

rma

tio

n o

n p

rov

ide

r a

nd

ass

ess

or

bli

nd

ing

R

esc

ue

tre

atm

en

t n

ee

de

d

in

7.9

% o

f P

io

+ L

an

d

14

.1%

in

Pio

+P

N

o r

ep

ort

s o

f se

ve

re

hy

po

gly

cem

ia

Stu

dy

16

5

De

l P

rato

S,

et

al

1.

Lin

ag

lip

tin

5m

g Q

D

Ag

e:

56

yrs

Ma

le:

48

%

Me

an

ba

seli

ne

A1

C:

8%

1.

33

6

24

we

ek

s A

dju

ste

d m

ea

n c

ha

ng

e f

rom

ba

seli

ne

A1

C:

L (3

33

):

-0.4

4

NA

Hy

po

gly

cem

ia:

L: 1

(0

.3 %

)

P:

1 (

0.6

%)

F

air

A

llo

cati

on

co

nce

alm

en

t

de

tail

s n

ot

dis

cuss

ed

30 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

6

Auth

or:

Kat

hy S

ente

na

Ph

ase

III

, P

C

RC

T,

DB

, P

G

Mu

lti-

cen

tre

11

Co

un

trie

s

FA

S a

na

lysi

s

wit

h L

OC

F

2.

Pla

ceb

o

* 6

we

ek

wa

sho

ut

for

pa

tie

nts

pre

vio

usl

y o

n

ora

l d

iab

eti

c

tre

atm

en

t

(in

clu

de

d 2

we

ek

pla

ceb

o

run

-in

)

* 2

we

ek

pla

ceb

o r

un

-

in f

or

all

pa

tie

nts

Incl

usi

on

:

Tre

atm

en

t n

aïv

e o

r o

n

on

e o

ral

dia

be

tic

ag

en

t,

18

-80

yr

old

s w

ith

ty

pe

2 D

M,

BM

I

40

kg

/m2

,

an

d b

ase

lin

e A

1C

6.5

%

to 9

% i

n p

retr

ea

ted

pa

tie

nts

an

d 7

% t

o 1

0%

in t

rea

tme

nt-

na

ïve

pa

tie

nts

.

Exc

lusi

on

:

Pa

tie

nts

wit

h a

his

tory

of

usi

ng

ro

sig

lita

zon

e,

pio

gli

tazo

ne

, a

GLP

-1

an

alo

gu

e,

insu

lin

or

an

tio

be

sity

dru

g w

ith

in

3 m

on

ths,

in

sta

bil

ity

in

thy

roid

do

se,

ste

roid

use

, h

ep

ati

c, c

ard

iac

or

cere

bra

l v

asc

ula

r

dis

ea

se.

2.

16

7

P (

16

3):

0.2

5

Ad

just

ed

me

an

tre

atm

en

t

eff

ect

: -0

.69

%

95

% C

I -0

.85

to

-0

.53

P<

0.0

00

1

RR

: 0

.50

95

% C

I 0

.30

to

7.8

Dis

con

tin

ua

tio

n d

ue

to A

E:

L: 4

(1

.2%

)

P:

4 (

2.5

%)

RR

: 0

.50

95

% C

I 0

.12

to

1.9

N

o s

ev

ere

hy

po

gly

cem

ia

ev

en

ts i

n e

ith

er

gro

up

N

o s

ign

ific

an

t ch

an

ge

s in

bo

dy

we

igh

t in

eit

he

r g

rou

p

U

ncl

ea

r if

ce

ntr

al

ad

jud

ica

tors

we

re b

lin

de

d

Stu

dy

17

6

Ta

skin

en

M,

et

al

Ph

ase

III

,

RC

T,

PC

82

Ce

nte

rs

10

Co

un

trie

s

FA

S

an

aly

sis

wit

h L

OC

F

1.

Me

tfo

rmin

>1

50

0m

g/d

ay

+ L

ina

gli

pti

n

5 m

g o

nce

da

ily

2.

Me

tfo

rmin

>1

50

0m

g/d

ay

+ P

lace

bo

* 4

we

ek

wa

sho

ut

for

pa

tie

nts

pre

vio

usl

y o

n

ora

l

an

tid

iab

eti

c

tre

atm

en

t

Me

an

Ag

e:

57

yrs

Ma

le:

57

% (

P)

an

d 5

3%

(L)

Me

an

ba

seli

ne

A1

C:

8.1

%

DM

fo

r >

5 y

rs:

55

%

Incl

usi

on

:

18

-80

yr

old

s w

ith

ty

pe

2 D

M,

BM

I

40

kg

/m2

,

sta

ble

me

tfo

rmin

do

se

of

>1

50

0 m

g/d

ay

or

ma

tole

rate

d d

ose

an

d n

ot

mo

re t

ha

n o

ne

oth

er

ora

l D

M m

ed

ica

tio

n a

nd

ba

seli

ne

A1

C 7

-10

%.

1.

52

4

2.

17

7

24

we

ek

s

Ad

just

ed

me

an

ch

an

ge

fro

m

ba

seli

ne

A1

C:

M +

L (

51

3):

-0

.49

%

M +

P (

17

5):

0.1

5%

Ad

just

ed

me

an

tre

atm

en

t

eff

ect

: -0

.64

%

95

% C

I -0

.78

to

-0

.50

P<

0.0

00

1

NA

Hy

po

gly

cem

ia:

M +

L:

3 (

0.6

%)

M +

P:

5 (

2.8

%)

RR

: 0

.20

95

% C

I 0

.05

to

0.8

4

Dis

con

tin

ua

tio

n d

ue

to A

E:

M +

L:

8 (

1.5

%)

M +

P:

3 (

1.7

%)

RR

: 0

.90

95

% C

I 0

.24

to

3.4

Fa

ir

A

llo

cati

on

co

nce

alm

en

t a

nd

ran

do

miz

ati

on

de

tail

s n

ot

dis

cuss

ed

E

ffe

ct w

as

gre

ate

r in

pa

tie

nts

pre

vio

usl

y t

rea

ted

wit

h o

ne

ora

l a

nti

dia

be

tic

dru

g

A

s e

xpe

cte

d,

A1

C c

ha

ng

es

we

re r

ed

uce

d t

o g

rea

test

ext

en

t in

pa

tie

nts

wit

h

hig

he

r b

ase

lin

e A

1C

va

lue

s

N

o s

ign

ific

an

t ch

an

ge

s in

me

an

bo

dy

we

igh

t in

eit

he

r

gro

up

R

esc

ue

me

dic

ati

on

wa

s

ind

ica

ted

fo

r p

ati

en

ts i

n t

he

31 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

7

Auth

or:

Kat

hy S

ente

na

* 2

we

ek

pla

ceb

o r

un

-

in f

or

bo

th

gro

up

s

Exc

lusi

on

Cri

teri

a:

Pa

tie

nts

wit

h a

his

tory

of

usi

ng

ro

sig

lita

zon

e,

pio

gli

tazo

ne

, a

GLP

-1

an

alo

gu

e,

insu

lin

or

an

tio

be

sity

dru

g w

ith

in

3 m

on

ths,

in

sta

bil

ity

in

thy

roid

do

se,

ste

roid

use

, re

na

l o

r ca

rdia

c

dis

ea

se,

ab

no

rma

l LF

Ts.

pla

ceb

o g

rou

p m

ore

oft

en

tha

n l

ina

gli

pti

n (

19

% v

s. 8

%)

N

o e

pis

od

es

of

sev

ere

hy

po

gly

cem

ia

U

ncl

ea

r if

ce

ntr

al

ad

jud

ica

tors

we

re b

lin

de

d

B

oth

gro

up

s re

ceiv

ed

die

tary

cou

nse

lin

g w

hic

h l

imit

s

ext

ern

al

va

lid

ity

.

Stu

dy

18

7

Ow

en

s, e

t a

l

Ph

ase

III

, D

B,

PG

, P

C,

RC

T

Mu

lti-

cen

tre

11

Co

un

trie

s

FA

S a

na

lysi

s

wit

h L

OC

F

1.

Me

tfo

rmin

!1

50

0m

g (

or

ma

x to

lera

ted

do

se)

+

sulf

on

ylu

rea

(ma

x to

lera

ted

do

se)

+

lin

ag

lip

tin

5m

g

on

ce d

ail

y

2.

Me

tfo

rmin

!1

50

0m

g (

or

ma

x

tole

rate

d

do

se)

+

sulf

on

ylu

rea

(ma

x

tole

rate

d

do

se)

+

pla

ceb

o

* 2

we

ek

pla

ceb

o r

un

-

in f

or

bo

th

gro

up

s

*

Re

gim

en

of

sulf

on

ylu

rea

an

d

me

tfo

rmin

Me

an

Ag

e:

58

yrs

.

Ma

le:

47

%

Me

an

ba

seli

ne

A1

C :

8%

DM

fo

r >

5 y

rs:

73

%

Incl

usi

on

:

Incl

usi

on

:

18

-80

yr

old

s w

ith

ty

pe

2 D

M,

BM

I

40

kg

/m2

,

me

tfo

rmin

do

se o

f

>1

50

0 m

g/d

ay

or

ma

x

tole

rate

d d

ose

an

d m

ax

tole

rate

d d

ose

of

sulf

on

ylu

rea

, a

nd

ba

seli

ne

A1

C 7

-10

%.

Exc

lusi

on

:

Pa

tie

nts

wit

h a

his

tory

of

usi

ng

ro

sig

lita

zon

e,

pio

gli

tazo

ne

, a

GLP

-1

an

alo

gu

e,

insu

lin

or

an

tio

be

sity

dru

g w

ith

in

3 m

on

ths,

re

na

l o

r

card

iac

dis

ea

se.

1.

79

3

2.

26

5

24

we

ek

s A

dju

ste

d m

ea

n c

ha

ng

e f

rom

ba

seli

ne

A1

C:

M +

S +

L (

77

8):

-0

.72

M +

S +

P (

26

2):

-0

.10

Ad

just

ed

me

an

tre

atm

en

t

eff

ect

: -0

.62

%

95

% C

I -0

.73

to

-0

.50

P<

0.0

00

1

NA

Hy

po

gly

cem

ia:

M +

S +

L:

18

0

(22

.7%

)

M +

S +

P:

39

(14

.8%

)

RR

: 1

.6

95

% C

I 1

.1 t

o 2

.1

Dis

con

tin

ua

tio

n d

ue

to A

E:

M +

S +

L:

23

(2

.9%

)

M +

S +

P:

5 (

1.9

%)

RR

: 1

.5

95

% C

I 0

.60

to

4.0

Fa

ir

A

llo

cati

on

co

nce

alm

en

t a

nd

ran

do

miz

ati

on

de

tail

s n

ot

dis

cuss

ed

A

s e

xpe

cte

d,

A1

C c

ha

ng

es

we

re r

ed

uce

d t

o g

rea

test

ext

en

t in

pt.

s w

ith

hig

he

r

ba

seli

ne

A1

C v

alu

es

N

o m

ea

nin

gfu

l ch

an

ge

s in

bo

dy

we

igh

t o

ccu

rre

d i

n

eit

he

r g

rou

p

S

ev

ere

hy

po

gly

cem

ia w

as

gre

ate

r in

pla

ceb

o g

rou

p

(4.8

%)

vs.

lin

ag

lip

tin

(2

.7%

)

U

ncl

ea

r if

ce

ntr

al

ad

jud

ica

tors

we

re b

lin

de

d

B

oth

gro

up

s re

ceiv

ed

die

tary

cou

nse

lin

g w

hic

h l

imit

s

ext

ern

al

va

lid

ity

.

D

eta

ils

on

su

lfo

ny

lure

as

use

d a

nd

do

ses

no

t

pro

vid

ed

.

R

esc

ue

tre

atm

en

t w

as

mo

re

com

mo

n i

n t

he

pla

ceb

o

gro

up

co

mp

are

d t

o

lin

ag

lip

tin

(1

3%

vs.

5.4

%)

32 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

8

Auth

or:

Kat

hy S

ente

na

we

re

un

cha

ng

ed

>1

0 w

ee

ks

pri

or

to

en

rolm

en

t

1S

tud

y d

esi

gn

ab

bre

via

tio

ns:

DB

= d

ou

ble

-bli

nd

, R

CT

= r

an

do

miz

ed

tri

al,

PC

= p

lace

bo

-co

ntr

oll

ed

, P

G =

pa

rall

el -g

rou

p,

XO

= c

ross

ov

er,

FA

S =

fu

ll a

na

lysi

s se

t d

ata

, LO

CF

= l

ast

ob

serv

ati

on

ca

rrie

d

forw

ard

.

2R

esu

lts

ab

bre

via

tio

ns:

RR

R =

re

lati

ve

ris

k r

ed

uct

ion

, R

R =

rela

tiv

e r

isk

, O

R=

Od

ds

Ra

tio

, H

R =

Ha

zard

Ra

tio

, A

RR

= a

bso

lute

ris

k r

ed

uct

ion

,

NN

T =

nu

mb

er

ne

ed

ed

to

tre

at,

NN

H =

nu

mb

er

ne

ed

ed

to

ha

rm,

CI

= c

on

fid

en

ce i

nte

rva

l 3N

NT

/NN

H a

re r

ep

ort

ed

on

ly f

or

sta

tist

ica

lly

sig

nif

ica

nt

resu

lts

4Q

ua

lity

Ra

tin

g:

(Go

od

- li

ke

ly v

ali

d,

Fa

ir-

lik

ely

va

lid

/po

ssib

ly v

ali

d,

Po

or-

fa

tal

fla

w-n

ot

va

lid

)

Cli

nic

al

Ab

bre

via

tio

ns:

A

1C

= h

em

og

lob

in A

1c,

Pio

= p

iog

lita

zon

e

33 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

9

Auth

or:

Kat

hy S

ente

na

CLI

NIC

AL

EFF

ICA

CY

-

FD

A e

ffic

acy

ap

pro

va

l o

f li

na

gli

pti

n w

as

ba

sed

on

se

ve

n s

tud

ies,

4 p

ub

lish

ed

an

d 3

un

pu

bli

she

d.

All p

ub

lish

ed

stu

die

s w

ere

ph

ase

III

, P

C,

DB

, P

G,

RC

Ts

in o

ve

r 2

,60

0 p

ati

en

ts w

ith

typ

e 2

dia

be

tes.

4,5

,6,7

T

he

stu

die

s w

ere

sim

ila

r in

re

spe

ct t

o m

ea

n a

ge

of

the

pa

tie

nt

po

pu

lati

on

s (5

6-5

8 y

ea

rs)

an

d

me

an

ba

selin

e H

bA

1cs

(8

.0%

-8.1

%)

in t

hre

e s

tud

ies,

wit

h t

he

stu

dy b

y G

om

is,

et

al,

ha

vin

g a

sli

gh

t h

igh

er

ba

seli

ne

va

lue

(8

.6%

).

Stu

die

s re

qu

ire

d a

2 w

ee

k p

lace

bo

ru

n-i

n f

or

all

gro

up

s. T

hre

e o

f th

e f

ou

r st

ud

ies

em

plo

ye

d a

4 w

ee

k w

ash

ou

t fo

r p

ati

en

ts o

n p

rio

r o

ral

an

tid

iab

eti

c tr

ea

tme

nts

, th

e

fort

h s

tud

y c

on

tin

ue

d p

ati

en

ts o

n t

he

ir p

revio

us

reg

ime

ns

of

me

tfo

rmin

an

d a

su

lfo

nylu

rea

; th

ere

fore

th

is d

id n

ot

ne

cess

ita

te a

wa

sho

ut

pe

rio

d.

Th

e p

rim

ary

ou

tco

me

wa

s a

n in

term

ed

iate

me

asu

re,

ad

just

ed

me

an

ch

an

ge

fro

m b

ase

lin

e H

bA

1c

for

all

stu

die

s.

Se

con

da

ry o

utc

om

es

incl

ud

ed

fast

ing

pla

sma

glu

cose

, p

ost

pra

nd

ial g

luco

se,

we

igh

t a

nd

be

ta-c

ell f

un

ctio

n.

He

alt

h o

utc

om

es

such

as

all-c

au

se m

ort

ali

ty a

nd

ma

cro

va

scu

lar

an

d

mic

rova

scu

lar

dis

ea

se w

ere

no

t st

ud

ied

. F

DA

re

qu

ire

me

nts

fo

r ca

rdio

va

scu

lar

ou

tco

me

an

aly

sis

is o

ng

oin

g.8

Lin

ag

lip

tin

5m

g o

nce

da

ily w

as

stu

die

d a

s m

on

oth

era

py in

a f

air

qu

ali

ty s

tud

y b

y D

el P

rato

, e

t a

l.5

Th

e s

tud

y p

op

ula

tio

n i

ncl

ud

ed

pa

tie

nts

tre

ate

d

pre

vio

usl

y w

ith

ora

l a

nti

dia

be

tic

ag

en

ts (

me

an

ba

seli

ne

A1

C 6

.5%

-9.0

%)

an

d t

rea

tme

nt

na

ïve

pa

tie

nts

(m

ea

n b

ase

lin

e A

1C

7.0

%-1

0.0

%).

T

he

re w

as

mo

de

rate

str

en

gth

of

evid

en

ce t

ha

t lin

ag

lip

tin

wa

s su

pe

rio

r to

pla

ceb

o in

lo

we

rin

g A

1C

(a

dju

ste

d m

ea

n t

rea

tme

nt

eff

ect

-0

.69

%,

95

% C

I -0

.85

to

-

0.5

3,

p<

0.0

00

1).

T

he

re w

as

mo

de

rate

-str

en

gth

of

evid

en

ce t

ha

t ra

tes

of

hyp

og

lyce

mia

we

re s

imila

r b

etw

ee

n l

ina

glip

tin

an

d p

lace

bo

an

d b

oth

gro

up

s w

ere

we

igh

t n

eu

tra

l.

Th

ere

wa

s m

od

era

te s

tre

ng

th o

f e

vid

en

ce t

o s

ug

ge

st t

ha

t d

isco

nti

nu

ati

on

ra

tes

du

e t

o a

dve

rse

eff

ect

s w

ere

lo

w a

nd

sim

ila

r fo

r lin

ag

lip

tin

an

d p

lace

bo

, 2

.4%

an

d 1

.2%

, re

spe

ctiv

ely

.

In a

fa

ir q

ua

lity

stu

dy b

y G

om

is,

et

al,

lin

ag

lip

tin

5m

g d

ail

y w

as

stu

die

d i

n c

om

bin

ati

on

wit

h p

iog

lita

zon

e 3

0m

g d

aily c

om

pa

red

to

pio

glita

zon

e 3

0m

g

da

ily a

nd

pla

ceb

o.4

Th

e m

ea

n b

ase

lin

e H

bA

1c

wa

s 8

.6%

, w

hic

h h

as

be

en

sh

ow

n in

oth

er

stu

die

s to

pro

du

ce g

rea

ter

glu

cose

lo

we

rin

g c

om

pa

red

to

low

er

me

an

ba

seli

ne

le

vels

. T

he

re w

as

mo

de

rate

str

en

gth

of

evid

en

ce t

ha

t th

e a

dd

itio

n o

f lin

ag

lip

tin

to

pio

gli

tazo

ne

wa

s su

pe

rio

r to

th

e a

dd

itio

n

of

pla

ceb

o t

o p

iog

lita

zon

e (

ad

just

ed

me

an

tre

atm

en

t e

ffe

ct -

0.5

1%

, 9

5%

CI

-0.7

1 t

o -

0.3

0,

p<

0.0

00

1).

T

he

re w

as

mo

de

rate

str

en

gth

of

evid

en

ce

tha

t th

ere

wa

s st

ati

stic

ally s

ign

ific

an

t w

eig

ht

ga

in in

th

e p

iog

lita

zon

e +

lin

ag

lip

tin

gro

up

co

mp

are

d t

o p

iog

lita

zon

e +

pla

ceb

o g

rou

p (

1.1

kg

, 9

5%

CI

0.2

to

2.0

, p

=0

.01

4).

T

he

re w

as

mo

de

rate

str

en

gth

of

evid

en

ce t

ha

t ra

tes

of

hyp

og

lyce

mia

we

re s

imil

ar

be

twe

en

gro

up

s.

Lin

ag

lip

tin

5m

g d

ail

y w

as

stu

die

d w

ith

me

tfo

rmin

(>

15

00

mg

/da

y o

r m

ax

tole

rate

d d

ose

) co

mp

are

d t

o p

lace

bo

an

d m

etf

orm

in i

n a

fa

ir q

ua

lity

stu

dy

by T

ask

ine

n,

et

al.

6

Incl

usi

on

cri

teri

a r

eq

uir

ed

th

at

pa

rtic

ipa

nts

no

t b

e o

n m

ore

th

an

on

e o

the

r o

ral

an

tid

iab

eti

c m

ed

ica

tio

n b

esi

de

s m

etf

orm

in.

Th

ere

wa

s m

od

era

te s

tre

ng

th o

f e

vid

en

ce t

ha

t lin

ag

lip

tin

an

d m

etf

orm

in w

ere

su

pe

rio

r to

pla

ceb

o a

nd

me

tfo

rmin

wit

h a

me

an

tre

atm

en

t e

ffe

ct o

f

-.6

4%

, 9

5%

CI

-0.7

8 t

o -

0.5

0,

p<

0.0

00

1.

Th

ere

wa

s m

od

era

te s

tre

ng

th o

f e

vid

en

ce t

ha

t h

yp

og

lyce

mia

eve

nts

we

re h

igh

er

for

the

pla

ceb

o a

nd

me

tfo

rmin

gro

up

(2

.8%

) co

mp

are

d t

o l

ina

gli

pti

n a

nd

me

tfo

rmin

(0

.6%

), w

ith

no

ep

iso

de

s o

f se

ve

re h

yp

og

lyce

mia

in

eit

he

r g

rou

p.

A f

air

qu

ali

ty s

tud

y w

as

con

du

cte

d b

y O

we

ns,

et

al,

wh

ich

in

clu

de

d l

ina

gli

pti

n 5

mg

da

ily w

ith

a s

ulf

on

ylu

rea

(sp

eci

fic

dru

g a

nd

do

se n

ot

pro

vid

ed

)

an

d m

etf

orm

in (

15

00

mg

/da

y o

r m

ax

tole

rate

d d

ose

) co

mp

are

d t

o p

lace

bo

an

d a

su

lfo

nylu

rea

(sp

eci

fic

dru

g a

nd

do

se n

ot

pro

vid

ed

) a

nd

me

tfo

rmin

(15

00

mg

/da

y o

r m

ax

tole

rate

d d

ose

).7 T

his

stu

dy e

nro

lle

d 7

3%

of

pa

tie

nts

wh

om

ha

d h

ad

typ

e 2

dia

be

tes

for

gre

ate

r th

an

5 y

ea

rs.

Th

ere

wa

s

34 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

10

Auth

or:

Kat

hy S

ente

na

mo

de

rate

str

en

gth

of

evid

en

ce t

ha

t lin

ag

lip

tin

+ s

ulf

on

ylu

rea

+ m

etf

orm

in w

as

sup

eri

or

to p

lace

bo

+ s

ulf

on

ylu

rea

+ m

etf

orm

in (

ad

just

ed

me

an

tre

atm

en

t e

ffe

ct -

0.6

2%

, 9

5%

CI

-0.7

3 t

o -

0.5

0,

p<

0.0

00

1).

T

he

re w

as

mo

de

rate

str

en

gth

of

evid

en

ce t

ha

t h

yp

og

lyce

mia

ra

tes

we

re h

igh

er

in t

he

gro

up

co

nta

inin

g l

ina

gli

pti

n (

22

.7%

) co

mp

are

d t

o t

he

pla

ceb

o c

on

tain

ing

gro

up

(1

4.8

%).

B

oth

gro

up

s h

ad

an

in

cre

ase

d i

nci

de

nce

co

mp

are

d t

o

oth

er

stu

die

s th

at

did

no

t co

nta

in a

su

lfo

nylu

rea

. S

eve

re h

yp

og

lyce

mia

eve

nts

we

re h

igh

er

in t

he

pla

ceb

o +

su

lfo

nylu

rea

+ m

etf

orm

in g

rou

p

com

pa

red

to

th

e l

ina

glip

tin

+ s

ulf

on

ylu

rea

+ m

etf

orm

in g

rou

p,

4.8

% v

s. 2

.7%

, re

spe

ctiv

ely

. D

isco

nti

nu

ati

on

ra

tes

du

e t

o a

dve

rse

eff

ect

s re

ma

ine

d

low

wit

h m

od

era

te s

tre

ng

th o

f e

vid

en

ce t

o s

ug

ge

st t

ha

t ra

tes

we

re s

imil

ar

be

twe

en

th

e g

rou

ps

(2.9

% f

or

lin

ag

lip

tin

+ s

ulf

on

ylu

rea

+ m

etf

orm

in v

s.

1.9

% f

or

pla

ceb

o +

su

lfo

nylu

rea

+ m

etf

orm

in).

All

of

the

ab

ove

stu

die

s a

re l

imit

ed

by t

he

ab

bre

via

ted

de

scri

pti

on

s o

f a

llo

cati

on

co

nce

alm

en

t a

nd

bli

nd

ing

me

tho

do

log

y g

ive

n t

o t

he

ir d

ou

ble

-bli

nd

de

sig

n d

esi

gn

ati

on

. S

tud

ies

by T

ask

ine

n a

nd

Ow

en

s a

lso

fa

ile

d t

o d

esc

rib

e r

an

do

miz

ati

on

de

tail

s. T

his

ca

n p

rod

uce

ass

ess

me

nt,

pe

rfo

rma

nce

an

d

sele

ctio

n b

ias

favo

rin

g l

ina

gli

pti

n.

All

of

the

stu

die

s w

ere

24

we

eks

in l

en

gth

pro

vid

ing

on

ly s

ho

rt t

erm

re

sult

s, h

ow

eve

r, g

luco

se l

ow

eri

ng

by

lin

ag

lip

tin

wa

s m

axi

miz

ed

by w

ee

ks

6-8

an

d s

ust

ain

ed

th

rou

gh

ou

t th

e d

ura

tio

n o

f th

e s

tud

y.

Th

ese

re

sult

s su

gg

est

th

at

lin

ag

lip

tin

wo

uld

pro

vid

e

con

tin

ue

d e

ffic

acy

be

yo

nd

24

we

eks

bu

t lo

ng

te

rm s

tud

ies

are

ne

ed

ed

. T

he

eff

ect

of

lin

ag

lip

tin

on

dir

ect

he

alt

h o

utc

om

es

such

as

mo

rta

lity

an

d

ma

cro

va

scu

lar

an

d m

icro

va

scu

lar

dis

ea

se a

re u

nkn

ow

n.

Pu

bli

she

d s

tud

ies

are

lim

ite

d t

o p

lace

bo

co

ntr

oll

ed

co

mp

ari

son

s. T

he

re i

s in

suff

icie

nt

com

pa

rati

ve

eff

ica

cy a

nd

sa

fety

evid

en

ce c

om

pa

rin

g l

ina

glip

tin

to

oth

er

an

tid

iab

eti

c a

ge

nts

.

Sim

ila

r re

sult

s w

ere

fo

un

d i

n t

he

un

pu

bli

she

d s

tud

ies

use

d f

or

FD

A a

pp

rova

l, a

s in

th

e p

revio

usl

y d

iscu

sse

d s

tud

ies.

8 A

co

mp

ari

son

of

lin

ag

lip

tin

5m

g d

ail

y to

pla

ceb

o d

em

on

stra

ted

lin

ag

lip

tin

be

ing

su

pe

rio

r to

pla

ceb

o (

-0.5

7,

95

% C

I -0

.89

to

-0

.26

).

Lin

ag

lip

tin

wa

s st

ud

ied

as

ad

d-o

n t

he

rap

y t

o

a s

ulf

on

ylu

rea

co

mp

are

d t

o p

lace

bo

ad

d-o

n i

n p

ati

en

ts w

ith

in

ad

eq

ua

te g

lyce

mic

co

ntr

ol.

Li

na

gli

pti

n 5

mg

da

ily w

as

fou

nd

to

be

su

pe

rio

r to

pla

ceb

o

(-0

.47

, 9

5%

CI

-0.7

1 t

o -

0.2

2).

A

no

n-i

nfe

rio

rity

, h

ea

d-t

o-h

ea

d c

om

pa

riso

n s

tud

y o

f li

na

glip

tin

5m

g w

as

com

pa

red

to

gli

me

pir

ide

(in

itia

ted

at

1m

g

an

d t

itra

ted

up

to

a m

ax

of

4m

g)

in p

ati

en

ts p

revio

usl

y o

n o

the

r a

nti

dia

be

tic

tre

atm

en

t(s)

an

d m

ain

tain

ed

on

me

tfo

rmin

. L

ina

gli

pti

n w

as

fou

nd

to

be

no

n-i

nfe

rio

r to

gli

me

pir

ide

at

an

in

teri

m a

na

lysi

s o

f 5

2 w

ee

ks

(0.2

0%

, 9

7.5

% C

I 0

.11

to

0.3

0).

DR

UG

SA

FE

TY

1

Se

rio

us

(RE

MS,

Bla

ck B

ox

Wa

rnin

gs,

Co

ntr

ain

dic

ati

on

s):

Do

no

t u

se l

ina

glip

tin

in

pa

tie

nts

wit

h h

isto

ry o

f h

yp

ers

en

siti

vit

y t

o l

ina

gli

pti

n.

Ca

uti

on

s:

If l

ina

glip

tin

is

use

d w

ith

an

in

suli

n s

ecr

eta

go

gu

e (

e.g

., s

ulf

on

ylu

rea

s) i

t is

re

com

me

nd

ed

th

at

the

do

se o

f th

e i

nsu

lin

se

cre

tag

og

ue

be

low

ere

d t

o a

vo

id h

ypo

gly

cem

ia.

Lin

ag

lip

tin

sh

ou

ld n

ot

be

use

d i

n p

ati

en

ts w

ith

typ

e 1

dia

be

tes

or

for

tre

ati

ng

dia

be

tic

ke

toa

cid

osi

s.

Lin

ag

lip

tin

ha

s

no

t b

ee

n s

tud

ied

wit

h i

nsu

lin

.

Hyp

og

lyce

mia

: L

ina

gli

pti

n w

as

ass

oci

ate

d w

ith

sim

ila

r ra

tes

of

hyp

og

lyce

mia

as

pla

ceb

o w

he

n n

ot

com

bin

ed

wit

h a

su

lfo

nylu

rea

. H

igh

est

ra

tes

of

hyp

og

lyce

mia

we

re s

ee

n w

he

n lin

ag

lip

tin

wa

s u

sed

wit

h a

su

lfo

nylu

rea

ba

ckg

rou

nd

tre

atm

en

t, r

an

gin

g f

rom

4.8

% t

o 2

3.7

%.8

35 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

11

Auth

or:

Kat

hy S

ente

na

Pa

ncr

ea

titi

s: L

ina

gli

pti

n w

as

ass

oci

ate

d w

ith

hig

he

r ra

tes

of

pa

ncr

ea

titi

s th

an

pla

ceb

o,

8 v

s. 0

, re

spe

ctiv

ely

. W

he

n c

orr

ect

ing

fo

r im

ba

lan

ces

in

gro

up

all

oca

tio

n,

ove

rall r

isk s

ug

ge

sts

an

in

cid

en

ce o

f 1

pe

r 5

38

pa

tie

nt-

ye

ars

.8

Ad

ve

rse

Eff

ect

s:

Th

e m

ost

co

mm

on

ad

ve

rse

re

act

ion

re

po

rte

d i

n s

tud

ies

wit

h l

ina

gli

pti

n w

as

na

sop

ha

ryn

git

is,

5.8

% v

s. 5

.5%

fo

r p

lace

bo

. A

dve

rse

eff

ect

s re

po

rte

d

in

2%

o

f p

ati

en

ts

in

stu

die

s w

ith

lin

ag

lip

tin

in

co

mb

ina

tio

n

wit

h

me

tfo

rmin

, p

iog

lita

zon

e

or

a

sulf

on

ylu

rea

in

clu

de

na

sop

ha

ryn

git

is,

hyp

erl

ipid

em

ia,

cou

gh

, h

yp

ert

rig

lyce

rid

em

ia a

nd

in

cre

ase

d w

eig

ht.

In

a 5

2 w

ee

k s

tud

y c

om

pa

rin

g l

ina

glip

tin

to

gli

me

pir

ide

, w

ith

pa

tie

nts

als

o o

n m

etf

orm

in t

he

rap

y,

ad

ve

rse

eff

ect

s th

at

occ

urr

ed

in

!5

% o

f p

ati

en

ts i

n t

he

lin

ag

lip

tin

gro

up

we

re a

rth

ralg

ia,

ba

ck p

ain

an

d

he

ad

ach

e.

To

lera

bil

ity (

Dro

p-o

ut

rate

s, m

an

ag

em

en

t st

rate

gie

s):

Lin

ag

lip

tin

wa

s w

ell

to

lera

ted

in

stu

die

s.

Dro

p-o

ut

rate

s fr

om

ad

ve

rse

eff

ect

s w

ere

lo

w,

ran

gin

g f

rom

1.5

% t

o 2

.9%

, n

ot

sig

nif

ica

ntl

y d

iffe

ren

t fr

om

pla

ceb

o.

Pre

gn

an

cy/L

act

ati

on

ra

tin

g:

Lin

ag

lip

tin

is

rate

d a

s P

reg

na

ncy

Ca

teg

ory

B.

Th

ere

are

no

we

ll-c

on

tro

lle

d s

tud

ies

on

usi

ng

lin

ag

lip

tin

in

pre

gn

an

t

ind

ivid

ua

ls.

Use

in

pre

gn

an

t w

om

en

on

ly if

cle

arl

y n

ee

de

d. C

au

tio

n i

s a

dvis

ed

if

use

d d

uri

ng

nu

rsin

g.

Un

an

swe

red

sa

fety

qu

est

ion

s:

Eff

ica

cy i

n u

sin

g l

ina

gli

pti

n in

pa

tie

nts

un

de

r 1

8 y

ea

rs o

f a

ge

ha

s n

ot

be

en

stu

die

d. C

ard

iova

scu

lar

(CV

) o

utc

om

e

an

aly

sis

by F

DA

wa

s n

ot

ab

le t

o c

on

clu

de

a p

rote

ctiv

e o

r d

etr

ime

nta

l e

ffe

ct o

f li

na

glip

tin

du

e t

o f

ew

eve

nts

an

d t

he

refo

re a

po

stm

ark

eti

ng

CV

ou

tco

me

s tr

ial

wil

l b

e r

eq

uir

ed

. T

he

sa

fety

an

d e

ffic

acy

of

usi

ng

lin

ag

lip

tin

wit

h i

nsu

lin

ha

s n

ot

be

en

fu

lly s

tud

ied

, h

ow

eve

r, o

ng

oin

g s

tud

ies

usi

ng

this

co

mb

ina

tio

n a

re u

nd

erw

ay.

Lab

Te

sts:

Lin

ag

lip

tin

re

sult

ed

in

in

cre

ase

s in

uri

c a

cid

le

ve

ls (

1.3

% in

th

e p

lace

bo

gro

up

ve

rsu

s 2

.7%

in

th

e l

ina

glip

tin

).

Do

se I

nd

ex

(eff

ica

cy/t

oxi

c):

No

do

se a

dju

stm

en

ts a

re n

ee

de

d i

n p

ati

en

ts w

ith

re

na

l o

r h

ep

ati

c im

pa

irm

en

t. D

ose

s u

p t

o 1

00

-fo

ld in

exc

ess

of

lin

ag

lip

tin

5m

g h

ave

be

en

we

ll t

ole

rate

d.7

Loo

k-a

like

/ S

ou

nd

-ali

ke

(LA

/SA

) E

rro

r R

isk P

ote

nti

al:

LA

/SA

na

me

s a

re a

sse

sse

d d

uri

ng

th

e P

DL

sele

ctio

n o

f d

rug

s.

Ba

sed

on

cli

nic

al

jud

gm

en

t a

nd

an

eva

lua

tio

n o

f LA

/SA

in

form

ati

on

fro

m f

ou

r d

ata

so

urc

es

(Le

xi-C

om

p,

US

P O

nli

ne

LA

SA

Fin

de

r, F

irst

Da

tab

an

k,

an

d I

SM

P C

on

fuse

d D

rug

Na

me

Lis

t),

the

foll

ow

ing

dru

g n

am

es

ma

y c

au

se L

AS

A c

on

fusi

on

:

NM

E D

rug

Na

me

(V

a m

on

og

rap

h)

Lex

i-C

om

p

US

P O

nli

ne

F

irst

Da

taB

an

k

ISM

P

Cli

nic

al

Jud

gm

en

t

LA/S

A f

or

lin

ag

lip

tin

(g

en

eri

c)

No

ne

N

on

e

No

ne

N

on

e

Sit

ag

lip

tin

lira

glu

tid

e

LA/S

A f

or

Tra

dje

nta

(b

ran

d)

No

ne

N

on

e

No

ne

N

on

e

Tre

an

da

Tru

va

da

36 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

12

Auth

or:

Kat

hy S

ente

na

DO

SE

& A

VA

ILA

BIL

ITY

1

ST

RE

NG

TH

F

OR

M

RO

UT

E

FR

EQ

UE

NC

Y

RE

NA

L A

DJ

HE

PA

TIC

AD

J P

ed

iatr

ic

Do

se

Eld

erl

y

Do

se

OT

HE

R D

OS

ING

CO

NS

IDE

RA

TIO

NS

Lin

ag

lip

tin

5

mg

Ta

ble

ts

Ora

l

On

ce D

ail

y

No

ad

just

me

nt

ne

ed

ed

No

ad

just

me

nt

ne

ed

ed

NA

N

A

Ma

y b

e t

ak

en

wit

h o

r w

ith

ou

t

foo

d.

A

LLE

RG

IES

/IN

TE

RA

CT

ION

S1

Dru

g-D

rug

:

Lin

ag

lip

tin

eff

ica

cy m

ay b

e r

ed

uce

d b

y c

on

com

ita

nt

ad

min

istr

ati

on

of

P-g

lyco

pro

tein

(P

-gp

) a

nd

CY

P3

A4

in

du

cers

(e

.g.

rifa

mp

in).

R

eco

mm

en

d u

sin

g

a d

iffe

ren

t a

ge

nt.

Li

na

glip

tin

is

a w

ea

k t

o m

od

era

te i

nh

ibit

or

of

CY

P3

A4

. L

ina

gli

pti

n i

s a

P-g

p s

ub

stra

te a

nd

blo

cks

P-g

p m

ed

iate

d t

ran

spo

rt o

f

dig

oxi

n a

t h

igh

co

nce

ntr

ati

on

s.

Wh

en

lin

ag

lip

tin

wa

s a

dm

inis

tere

d w

ith

me

tfo

rmin

, g

lyb

uri

de

, p

iog

lita

zon

e,

dig

oxi

n,

wa

rfa

rin

an

d s

imva

sta

tin

no

me

an

ing

ful ch

an

ge

in

co

nce

ntr

ati

on

s w

ere

ob

serv

ed

.8

In v

ivo

stu

die

s su

gg

est

th

at

lin

ag

lip

tin

ha

s a

lo

w p

rop

en

sity

to

ca

use

dru

g in

tera

ctio

ns.

Fo

od

-Dru

g:

No

fo

od

-dru

g in

tera

ctio

ns

ha

ve

be

en

re

po

rte

d.

All

erg

y/C

ross

Re

act

ive

Su

bst

an

ces:

Hyp

ers

en

siti

vit

y r

ea

ctio

ns

ha

ve

be

en

re

po

rte

d w

ith

lin

ag

lip

tin

. H

igh

er

rate

s w

ere

de

mo

nst

rate

d w

ith

lin

ag

lip

tin

(0

.7%

) ve

rsu

s co

mp

ara

tors

(0

.5%

).

37 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

13

Auth

or:

Kat

hy S

ente

na

AP

PE

ND

IX:

Inc

reti

n E

nh

an

ce

rs(D

PP

-4 I

nh

ibit

ors

)

Init

iati

ve:

Op

tim

ize c

orr

ec

t u

se t

hat

co

rresp

on

ds

to

Nati

on

al G

uid

elin

es o

f in

cre

tin

en

han

cers

.

Len

gth

of

Au

tho

rizati

on

: U

p t

o 1

ye

ar

Pre

ferr

ed

Alt

ern

ati

ves:

Lis

ted a

t: h

ttp

://w

ww

.ore

gon.g

ov/D

HS

/he

althp

lan/t

oo

ls_

pro

v/p

dl.shtm

l

Req

uir

es P

A:

sit

ag

lip

tin

(Jan

uv

ia®

), s

itag

lip

tin

/me

tfo

rmin

(Jan

um

et®

), s

ax

ag

lip

tin

(O

ng

lyza®

), s

axag

lip

tin

/metf

orm

in (

Ko

mb

igly

ze

XR

®),

lin

ag

lip

tin

(T

rad

jen

ta®

), lin

ag

lip

tin

/metf

orm

in (

Jen

tad

ueto

®).

Ap

pro

val

Cri

teri

a

1. D

oes the p

atien

t ha

ve

a d

iagnosis

of

type

2dia

bete

s?

Yes: G

o t

o #

2N

o:

Pass to R

PH

; D

en

y (

medic

al a

ppro

pri

ate

ness)

2. W

illth

e p

rescrib

er

consid

er

a c

ha

ng

e to a

pre

ferr

ed p

roduct?

Message:

P

refe

rred p

rod

ucts

do n

ot re

qu

ire P

A.

P

refe

rred p

rod

ucts

are

evid

ence-b

ase

d

revie

we

d f

or

com

para

tive e

ffectiven

ess &

safe

ty b

y th

e H

ealth R

eso

urc

es

Com

mis

sio

n (

HR

C).

Report

s a

re a

vaila

ble

at:

http://w

ww

.ore

go

n.g

ov/O

HP

PR

/HR

C/E

vid

ence_

Based

_R

eport

s.s

htm

l.

Yes:

Info

rm p

rovid

er

of

covere

d

altern

atives in c

lass.

http://www.dhs.state.or.us/policy/healt

hplan/guides/pharmacy/main.html

No

: G

o to #

3.

3.H

as t

he p

atient

trie

d a

nd

faile

d m

etf

orm

in

an

dsulfon

ylu

rea th

era

py o

r ha

ve

contr

ain

dic

atio

ns to t

hese tre

atm

ents

?

Contr

ain

dic

ations t

o m

etf

orm

in:

-K

no

wn h

yp

ers

ensitiv

ity

-R

ena

l d

isease o

r re

na

l d

ysfu

nctio

n-

Acute

or

chro

nic

meta

bolic

acid

osis

-In

cre

ased r

isk o

f la

ctic a

cid

osis

(C

HF

,

Yes:

Appro

ve f

or

up t

o 1

ye

ar.

No

: P

ass to R

PH

; D

en

y (

medic

al a

ppro

pri

ate

ness).

Recom

mend

tria

l of

metform

in o

r sulfon

ylu

rea.

See b

elo

w f

or

metf

orm

in titra

tion

schedule

.

38 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

14

Auth

or:

Kat

hy S

ente

na

advanced

ag

e, im

paire

d h

epatic

function)

Contr

ain

dic

ations t

o s

ulfon

ylu

reas:

-K

no

wn h

yp

ers

ensitiv

ity

Initia

ting

Metf

orm

in

1.

Beg

in w

ith lo

w-d

ose m

etf

orm

in (

500 m

g)

taken o

nce o

r tw

ice p

er

da

y w

ith m

eals

(bre

akfa

st and/o

r din

ner)

or

850 m

g o

nce p

er

da

y.

2.

Aft

er

5-7

da

ys,

if g

astr

oin

testina

l sid

e e

ffects

have n

ot

occurr

ed, ad

va

nce d

ose to 8

50 m

g, or

two 5

00

mg table

ts, tw

ice

per

da

y (

medic

ation to

be t

aken

befo

re b

reakfa

st and/o

r d

inner)

.

3.

If g

astr

oin

testina

l sid

e e

ffects

appe

ar

as d

oses a

dvanced, d

ecre

ase t

o p

revio

us lo

wer

dose a

nd

try

to a

dvance the

dose a

t a

la

ter

tim

e.

4.

The m

axim

um

eff

ective d

ose c

an b

e u

p t

o 1

,00

0 m

g tw

ice p

er

da

y b

ut

is o

ften 8

50 m

g tw

ice p

er

da

y.

Modestly g

reate

r eff

ectiven

ess h

as b

een o

bserv

ed

with d

oses u

p to a

bo

ut 2

,50

0 m

g/d

ay. G

astr

oin

testin

al sid

e e

ffects

ma

y lim

it the

dose tha

t can b

e u

se

d.

Nath

an,

et al. M

edic

al M

anagem

ent

of H

yperg

lycem

ia in T

ype 2

Dia

bete

s; A

Consensus A

lgorith

m f

or

the I

nitia

tion a

nd A

dju

stm

ent

of

Thera

py. D

iabete

s C

are

31;1

-11, 2008.

RE

FE

RE

NC

ES

1.

Tra

dje

nta

® P

resc

rib

ing

In

form

ati

on

. B

oe

hri

ng

er

Ing

elh

eim

Ph

arm

ace

uti

cals

, In

c. R

idg

efi

eld

, C

T.

July

20

11

.

2.

Tu

rne

r R

, C

ull

C,

Fri

gh

i V

, e

t a

l.

Gly

cem

ic c

on

tro

l w

ith

die

t, s

ulf

on

ylu

rea

, m

etf

orm

in o

r in

suli

n i

n p

ati

en

ts w

ith

ty

pe

2 d

iab

ete

s m

ell

itu

s: p

rog

ress

ive

re

qu

ire

me

nt

for

mu

ltip

le t

he

rap

ies

(UK

PD

S 4

9).

JA

MA

19

99

; 2

81

:20

05

-20

12

. €3.Nat

han D,

Buse J,

Davidso

n M, et

al. Me

dical Ma

nageme

nt of Hy

perglyc

emia in

Type 2

Diabet

es: A C

onsens

us Algo

rithm f

or the I

nitiatio

n and A

djustm

ent of

Therap

y: A

Consen

sus Sta

tement

of the

Americ

an Diabe

tes Ass

ociation

and the

Europe

an Asso

ciation

for the

Study o

fDiabe

tes. Di

abetes

Care 20

08;31:

1-11.

4.

Go

mis

R,

Esp

ad

ero

R.-

M,

Jon

es

R,

et

al.

E

ffic

acy

an

d s

afe

ty o

f in

itia

l co

mb

ina

tio

n t

he

rap

y w

ith

lin

ag

lip

tin

an

d p

iog

lita

zon

e i

n p

ati

en

ts w

ith

in

ad

eq

ua

tely

co

ntr

oll

ed

ty

pe

2 d

iab

ete

s: a

ra

nd

om

ize

d,

do

ub

le-b

lin

d,

pla

ceb

o-c

on

tro

lle

d s

tud

y.

Dia

b,

Ob

esi

ty a

nd

Me

tab

20

11

; 1

3;6

53

-66

1.

5.

De

l P

rato

S,

Ba

rne

tt A

, H

uis

ma

n H

, e

t a

l.

Eff

ect

of

lin

ag

lip

tin

mo

no

the

rap

y o

n g

lyca

em

ic c

on

tro

l a

nd

ma

rke

rs o

f b

eta

-ce

ll f

un

ctio

n i

n p

ati

en

ts w

ith

in

ad

eq

ua

tely

con

tro

lle

d t

yp

e 2

dia

be

tes:

a r

an

do

miz

ed

co

ntr

oll

ed

tri

al.

D

iab

, O

be

sity

an

d M

eta

b 2

01

1;

13

:25

8-2

67

.

6.

Ta

skin

en

M.-

R,

Ro

sen

sto

ck J

, T

am

min

en

I,

et

al.

S

afe

ty a

nd

eff

ica

cy o

f li

na

gli

pti

n a

s a

dd

-on

th

era

py

to

me

tfo

rmin

in

pa

tie

nts

wit

h t

yp

e 2

dia

be

tes:

a r

an

do

miz

ed

,

do

ub

le-b

lin

d,

pla

ceb

o-c

on

tro

lle

d s

tud

y.

Dia

b,

Ob

esi

ty a

nd

Me

tab

20

11

:13

; 6

5-7

4.

7.

Ow

en

s D

, S

wa

llo

w R

, D

ug

it K

, e

t a

l.

Eff

ica

cy a

nd

sa

fety

of

lin

ag

lip

tin

in

pe

rso

ns

wit

h T

yp

e 2

dia

be

tes

ina

de

qu

ate

ly c

on

tro

lle

d b

y a

co

mb

ina

tio

n o

f m

etf

orm

in a

nd

sulf

ph

on

ylu

rea

: a

24

-we

ek

ra

nd

om

ize

d s

tud

y.

De

iab

et

Me

d 2

01

1:

28

:13

52

-13

61

.

8.

Lin

ag

lip

tin

, F

DA

Ce

nte

r fo

r D

rug

Eva

lua

tio

n a

nd

Re

sea

rch

.

Su

mm

ary

Re

vie

w D

ocu

me

nt.

M

ay

2,

20

11

.

Acc

ess

ed

1/2

4/1

2.

ww

w.a

cce

ssd

ata

.fd

a.g

ov

/dru

gsa

tfd

a_

do

cs/n

da

/20

11

/20

12

80

Ori

g1

s00

0S

um

R.p

df

9.

Sch

ern

tha

ne

r G

, B

arn

ett

A,

Em

ser

A.

Sa

fety

an

d t

ole

rab

ilit

y o

f li

na

gli

pti

n:

a p

oo

led

an

aly

sis

of

da

ta f

rom

ra

nd

om

ize

d c

on

tro

lle

d t

ria

ls i

n 3

57

2 p

ati

en

ts w

ith

ty

pe

2

dia

be

tes

me

llit

us.

D

iab

, O

be

sity

an

d M

eta

b 2

01

2.

DO

I: 1

0.1

11

1/j

.14

63

-13

26

.20

12

.01

56

5.x

l.

10.AAC

E Diabe

tes Mel

litus C

linical P

ractice

Guideli

ne Task

Force.

AACE

diabetes

mellitu

s guidel

ines. G

lycemic

manag

ement.

Endocr

in Prac

2007 M

ay-Jun

;13(Sup

pl 1):40

-82.

39 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

15

Auth

or:

Kat

hy S

ente

na

11

.Q

ase

em

A,

Hu

mp

hre

y L

, S

we

et

D,

et

al.

O

ral

ph

arm

aco

log

ic t

rea

tme

nt

of

typ

e 2

dia

be

tes

me

llit

us:

a c

lin

ica

l p

ract

ice

gu

ide

lin

e f

rom

th

e A

me

rica

n C

oll

eg

e o

f P

hy

sici

an

s.

An

n I

nte

rn M

ed

20

12

;15

6:2

18

-23

1.

12

.R

ich

ter

B,

Ba

nd

eir

a-E

chtl

er

E,

Be

rge

rho

ff K

, e

t a

l.

Dip

ep

tid

yl

pe

pti

da

se-4

(D

PP

-4)

inh

ibit

ors

fo

r ty

pe

2 d

iab

ete

s m

ell

itu

s (R

evi

ew

).

Co

chra

ne

Co

lla

bo

rati

on

of

Sy

ste

ma

tic

Re

vie

ws

20

08

, Is

sue

2.

Art

. N

o.

CD

00

67

39

. D

OI:

10

.10

02

/14

65

18

58

.CD

00

67

39

.pu

b2

.

13

.

14

.C

on

no

lly

SJ,

Eze

ko

wit

z M

D,

Yu

suf

S,

et

al.

Da

big

atr

an

ve

rsu

s w

arf

ari

n i

n p

ati

en

ts w

ith

atr

ial

fib

rill

ati

on

(R

E-L

Y).

N E

ng

l J

Me

d.

20

09

;36

1:1

13

9-5

1.

15

.D

ab

iga

tra

n,

FD

A C

en

ter

for

Dru

g E

valu

ati

on

an

d R

ese

arc

h.

S

um

ma

ry R

evi

ew

Do

cum

en

t.

Oct

ob

er

19

, 2

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0.

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cce

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ww

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da

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25

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Ori

g1

s00

0S

um

R.p

df

16

.W

all

en

tin

L,

Yu

suf

S,

Eze

ko

wit

z M

D,

et

al.

Eff

ica

cy a

nd

sa

fety

of

da

big

atr

an

co

mp

are

d w

ith

wa

rfa

rin

at

dif

fere

nt

leve

ls o

f in

tern

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on

al

no

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lize

d r

ati

o c

on

tro

l fo

r st

rok

e

pre

ven

tio

n i

n a

tria

l fi

bri

lla

tio

n:

an

an

aly

sis

of

the

RE

-LY

tri

al.

La

nce

t. 2

01

0;3

76

:97

5-8

3.

17

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on

no

lly

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ko

wit

z M

, Y

usu

f S

, e

t a

l.

Ne

wly

Id

en

tifi

ed

Ev

en

ts i

n t

he

RE

-LY

Tri

al.

N

En

gl

J M

ed

20

10

;36

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18

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E-M

OB

ILIZ

E W

riti

ng

Co

mm

itte

e,

Gin

sbe

rg J

S,

Da

vid

son

BL,

Co

mp

PC

et

al.

Ora

l th

rom

bin

in

hib

ito

r d

ab

iga

tra

n e

texi

late

vs.

No

rth

Am

eri

can

en

oxa

pa

rin

re

gim

en

fo

r

pre

ven

tio

n o

f ve

no

us

thro

mb

oe

mb

oli

sm a

fte

r k

ne

e a

rth

rop

last

y s

urg

ery

. J

Art

hro

pla

sty

. 2

00

9;2

4(1

):1

-9.

19

.E

rik

sso

n B

I, D

ah

l O

E,

Ro

sen

che

r N

, e

t a

l. O

ral

da

big

atr

an

ete

xila

te v

s. s

ub

cuta

ne

ou

s e

no

xap

ari

n f

or

the

pre

ven

tio

n o

f v

en

ou

s th

rom

bo

em

bo

lism

aft

er

tota

l k

ne

e

rep

lace

me

nt:

th

e R

E-M

OD

EL

ran

do

miz

ed

tri

al.

J T

hro

mb

Ha

em

ost

. 2

00

7;5

:21

78

-85

.

20

.E

rik

sso

n B

I, D

ah

l O

E,

Ro

sen

che

r N

, e

t a

l. D

ab

iga

tra

n e

texi

late

ve

rsu

s e

no

xap

ari

n f

or

the

pre

ve

nti

on

of

ven

ou

s th

rom

bo

em

bo

lism

aft

er

tota

l h

ip r

ep

lace

me

nt:

a

ran

do

miz

ed

, d

ou

ble

-bli

nd

, n

on

-in

feri

ori

ty t

ria

l. L

an

cet.

20

07

;37

0:9

49

-95

6.

(RE

-NO

VA

TE

)

21

.N

de

gw

a S

, M

ou

lto

n K

, A

rgá

ez

C.

Da

big

atr

an

an

d R

iva

roxa

ba

n v

ers

us

Oth

er

An

tico

ag

ula

nts

fo

r T

hro

mb

op

rop

hy

laxi

s A

fte

r M

ajo

r O

rth

op

ed

ic S

urg

ery

: S

yst

em

ati

c R

evi

ew

of

Co

mp

ara

tive

Cli

nic

al-

Eff

ect

ive

ne

ss a

nd

Sa

fety

. O

tta

wa

: C

an

ad

ian

Ag

en

cy f

or

Dru

gs

an

d T

ech

no

log

ies

in H

ea

lth

; 2

00

9.

22

.S

ala

zar,

Ca

rlo

s A

, M

ala

ga

, G

erm

an

, M

ala

squ

ez.

Giu

lia

na

. D

ire

ct t

hro

mb

in i

nh

ibit

ors

ve

rsu

s vi

tam

in K

an

tag

on

ists

or

low

mo

lecu

lar

we

igh

t h

ep

ari

ns

for

pre

ven

tio

n o

f

ven

ou

s th

rom

bo

em

bo

lism

fo

llo

win

g t

ota

l h

ip o

r k

ne

e r

ep

lace

me

nt.

Th

e C

och

ran

e D

ata

ba

se o

f S

yst

Re

v. 2

01

1(3

): C

D0

05

98

1.

23

.S

chu

lma

n S

, K

ea

ron

C,

Ka

kk

ar

AK

, e

t a

l. D

ab

iga

tra

n v

ers

us

wa

rfa

rin

in

th

e t

rea

tme

nt

of

acu

te v

en

ou

s th

rom

bo

em

bo

lism

. N

En

gl

J M

ed

. 2

00

9;3

61

(24

):2

34

2-5

2.

24

.H

art

R,

Pe

arc

e L

, A

gu

ila

r M

. M

eta

-an

aly

sis:

An

tith

rom

bo

tic

Th

era

py

to

Pre

ve

nt

Str

ok

e i

n P

ati

en

ts W

ho

Ha

ve N

on

valv

ula

r A

tria

l F

ibri

lla

tio

n.

An

n I

nte

rn M

ed

.

20

07

;14

6:8

57

-86

7.

25

.A

gu

ila

r, M

, H

art

R.

Ora

l a

nti

coa

gu

lan

ts f

or

pre

ve

nti

ng

str

ok

e i

n p

ati

en

ts w

ith

no

n-v

alv

ula

r a

tria

l fi

bri

lla

tio

n a

nd

no

pre

vio

us

his

tory

of

stro

ke

or

tra

nsi

en

t is

che

mic

att

ack

s.

Th

e C

och

ran

e D

ata

ba

se o

f S

yst

Re

v.

20

09

(1

): C

D0

01

92

7.

26

.C

ou

ma

din

® P

resc

rib

ing

In

form

ati

on

. B

rist

ol-

My

ers

Sq

uib

b,

Inc.

Pri

nce

ton

, N

J. J

an

ua

ry 2

01

0.

27

.B

irm

an

-De

ych

E,

Ra

dfo

rd M

, N

ila

sen

a D

, e

t a

l.

Use

an

d E

ffe

ctiv

en

ess

of

Wa

rfa

rin

in

Me

dic

are

Be

ne

fici

ari

es

wit

h A

tria

l F

ibri

lla

tio

n.

Str

ok

e.

20

06

;37

:10

70

-10

74

.

28

.S

ing

er

DE

, A

lbe

rs G

W,

Da

len

JE

, e

t a

l.

An

tith

rom

bo

tic

the

rap

y i

n a

tria

l fi

bri

lla

tio

n.

CH

ES

T.

20

08

;13

3(6

): 5

46

S-5

92

S.

29

.G

ag

e B

F,

Wa

term

an

AD

, S

ha

nn

on

W,

et

al.

Va

lid

ati

on

of

clin

ica

l cl

ass

ific

ati

on

sch

em

es

for

pre

dic

tin

g s

tro

ke

. R

esu

lts

fro

m t

he

Na

tio

na

l R

eg

istr

y o

f A

tria

l F

ibri

lla

tio

n.

JAM

A.

20

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30

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irsh

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ya

tt G

, A

lbe

rs G

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t a

l.

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cuti

ve S

um

ma

ry:

Am

eri

can

Co

lle

ge

of

Ch

est

Ph

ysi

cia

ns

Evi

de

nce

-Ba

sed

Cli

nic

al

Pra

ctic

e G

uid

eli

ne

s (8

th E

dit

ion

).

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est

20

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.

31

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me

rica

n A

cad

em

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f O

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ae

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Su

rge

on

s.

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ve

nti

ng

Ve

no

us

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rom

bo

em

bo

lic

Dis

ea

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n P

ati

en

ts U

nd

erg

oin

g E

lect

ive

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an

d K

ne

e A

rth

rop

last

y E

vid

en

ce-B

ase

d

Gu

ide

lin

e a

nd

Evi

de

nce

Re

po

rt,

20

11

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ess

ed

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ob

er

27

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01

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40 of 108

Gen

eric

Nam

e:

Lin

agli

pti

nR

evie

w D

ate:

Ap

ril

2011

16

Auth

or:

Kat

hy S

ente

na

32

.V

ard

i M

, Z

itta

n E

, B

itte

rma

n H

, e

t a

l.

Su

bcu

tan

eo

us

un

fra

ctio

na

ted

he

pa

rin

fo

r th

e i

nit

ial

tre

atm

en

t o

f ve

no

us

thro

mb

oe

mb

oli

sm.

Co

chra

ne

Da

tab

ase

of

Sy

ste

ma

tic

Re

vie

ws.

2

00

9,

Issu

e 4

.

33

.F

oo

d a

nd

Dru

g A

dm

inis

tra

tio

n.

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up

ple

me

nta

l N

ew

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g A

pp

lica

tio

n f

or

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da

xa.

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41 of 108

©C

op

yri

gh

t 20

12

Ore

gon

Sta

te U

niv

ersi

ty.

All

Rig

hts

Res

erved

Dru

g U

se R

ese

arch

& M

an

ag

em

en

t P

rogra

m

Ore

gon

Sta

te U

niv

ersi

ty,

500

Su

mm

er S

tree

t N

E,

E3

5,

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em,

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gon

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on

e503

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ax 5

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-11

19

1

Ne

w D

osa

ge

Fo

rmu

lati

on

Mo

nth

/Ye

ar

of

Re

vie

w:

Ap

ril 2

01

2

E

nd

da

te o

f li

tera

ture

se

arc

h:

Fe

bru

ary

20

12

Ge

ne

ric

Na

me

: E

xen

ati

de

ext

en

de

d–

rele

ase

in

ject

ion

(E

QW

)

Bra

nd

Na

me

(M

an

ufa

ctu

rer)

: B

yd

ure

on

(A

myli

n P

ha

rma

ceu

tica

ls)

PD

L C

lass

: In

cre

tin

Mim

eti

cs

Do

ssie

r R

ece

ive

d:

Pe

nd

ing

Pre

ferr

ed

Ag

en

ts:

Me

tfo

rmin

, g

lim

ep

irid

e,

glip

izid

e,

gly

bu

rid

e,

Co

mp

ara

tor

Th

era

pie

s: M

etf

orm

in,

sulf

on

ylu

rea

s, p

iog

lita

zon

e

pio

gli

tazo

ne

si

tag

lip

tin

, sa

xag

lip

tin

, e

xen

ati

de

, li

rag

luti

de

, p

ram

lin

tid

e

No

n-p

refe

rre

d A

ge

nts

: S

ita

gli

pti

n,

saxa

gli

pti

n,

exe

na

tid

e,

lira

glu

tid

e,

pra

mlin

tid

e

FD

A A

pp

rove

d I

nd

ica

tio

ns:

E

xen

ati

de

ext

en

de

d–

rele

ase

, o

nce

we

ekly

in

ject

ion

(E

QW

) is

a g

luca

go

n-l

ike

pe

pti

de

-1 (

GLP

-1)

ag

on

ist

ap

pro

ve

d a

s a

n

ad

jun

ct t

o d

iet

an

d e

xerc

ise

to

im

pro

ve

gly

cem

ic c

on

tro

l in

ad

ult

s w

ith

typ

e 2

dia

be

tes.

E

QW

is

an

ext

en

de

d r

ele

ase

fo

rmu

lati

on

of

the

tw

ice

da

ily

inje

cta

ble

pro

du

ct e

xen

ati

de

(B

ye

tta

) w

hic

h w

as

FD

A a

pp

rove

d in

20

05

. T

he

do

se o

f E

QW

is

a 2

mg

su

bcu

tan

eo

us

(SQ

) in

ject

ion

on

ce w

ee

kly

at

an

y

tim

e o

f d

ay w

ith

ou

t re

ga

rd t

o m

ea

ls.1

Ba

ckg

rou

nd

: T

he

GLP

-1 a

na

log

ue

s, w

hic

h in

clu

de

EQ

W,

twic

e d

ail

y e

xen

ati

de

an

d l

ira

glu

tid

e,

stim

ula

te G

LP-1

re

cep

tors

to

in

cre

ase

in

sulin

pro

du

ctio

n in

re

spo

nse

to

glu

cose

, w

hic

h d

ecr

ea

ses

po

stp

ran

dia

l g

luca

go

n r

ele

ase

an

d s

low

s g

ast

ric

em

pty

ing

. E

xen

ati

de

im

me

dia

te r

ele

ase

wa

s

eva

lua

ted

in

th

e 2

01

1 s

yste

ma

tic

revie

w o

n n

ew

er

dru

gs

for

the

tre

atm

en

t o

f d

iab

ete

s m

ell

itu

s fr

om

th

e O

reg

on

Dru

g E

ffe

ctiv

en

ess

Re

vie

w P

roje

ct

(DE

RP

).2

Th

ere

we

re n

o s

tud

ies

tha

t e

xam

ine

d t

he

im

pa

ct o

f e

xen

ati

de

th

era

py o

n l

on

g t

erm

he

alt

h o

utc

om

es

an

d f

ou

r tr

ials

fo

un

d m

od

era

te

stre

ng

th e

vid

en

ce t

ha

t th

ere

is

no

sig

nif

ica

nt

dif

fere

nce

be

twe

en

exe

na

tid

e a

nd

in

sulin

in

re

du

ctio

n in

Hb

A1

c (r

an

ge

fo

r e

xen

ati

de

-1

.0%

to

-1

.4%

;

ran

ge

fo

r in

sulin

-0

.9%

to

-1

.4%

). A

s la

be

lin

g s

ug

ge

sts,

th

e G

LP-1

an

alo

gu

es

are

no

t re

com

me

nd

ed

as

firs

t li

ne

ag

en

ts b

ut

in t

he

ap

pro

pri

ate

pa

tie

nts

th

ey c

an

be

a u

sefu

l o

pti

on

fo

r o

pti

miz

ing

gly

cem

ic c

on

tro

l w

hil

e p

rom

oti

ng

we

igh

t lo

ss.

Th

e A

me

rica

n D

iab

ete

s A

sso

cia

tio

n (

AD

A)

con

sid

ers

th

e G

LP-1

an

alo

gu

es

tie

r-2

ag

en

ts;

he

lpfu

l fo

r th

ose

pa

tie

nts

exp

eri

en

cin

g h

yp

og

lyce

mia

or

in w

hic

h w

eig

ht

loss

is

imp

ort

an

t.

Ad

dit

ion

all

y,

the

y s

ug

ge

st t

ha

t G

LP-1

an

alo

gu

es

be

use

d in

co

nju

nct

ion

wit

h l

ife

style

mo

dif

ica

tio

ns

an

d m

etf

orm

in.3

T

he

Am

eri

can

Ass

oci

ati

on

of

Cli

nic

al

En

do

crin

olo

gis

ts/A

me

rica

n C

olle

ge

of

En

do

crin

olo

gy (

AA

CE

/AC

E)

reco

mm

en

ds

GLP

-1 a

na

log

ue

s a

s o

ne

of

the

ir p

refe

rre

d a

ge

nts

, a

fte

r

me

tfo

rmin

, b

eca

use

of

eff

ect

ive

ne

ss a

nd

lo

w r

isk o

f h

yp

og

lyce

mia

, u

sed

alo

ne

or

in a

mu

lti-

dru

g t

rea

tme

nt

reg

ime

n.

Th

e A

AC

E/A

CE

pre

fere

nce

th

e

GLP

-1 a

na

log

ue

s o

ve

r th

e d

ipe

pti

dyl p

ep

tid

ase

-4 (

DP

P-4

) in

hib

ito

rs d

ue

to

be

tte

r p

ost

pra

nd

ial

glu

cose

re

du

ctio

ns

an

d w

eig

ht

loss

.4 T

he

Am

eri

can

42 of 108

Gen

eric

Nam

e: E

xen

atid

e E

xte

nded

-Rel

ease

Rev

iew

Dat

e: A

pri

l 2012

2

Auth

or:

Kat

hy S

ente

na

Co

lle

ge

of

Ph

ysi

cia

ns

(AC

P)

gu

ide

lin

es

fou

nd

lo

w o

r in

suff

icie

nt

evid

en

ce f

or

eff

ica

cy o

f G

LP-1

ag

on

ists

wit

ho

ut

spe

cifi

c re

com

me

nd

ati

on

s fo

r u

se.5

An

ima

l st

ud

ies

sug

ge

st b

eta

ce

ll p

rese

rva

tio

n a

nd

sti

mu

lati

on

of

be

ta c

ell

pro

life

rati

on

, h

ow

eve

r, i

t is

un

kn

ow

n if

this

ca

n b

e e

xpe

cte

d i

n h

um

an

s.6

Cli

nic

al

Eff

ica

cy:

EQ

W w

as

stu

die

d a

s m

on

oth

era

py a

nd

in

co

mb

ina

tio

n t

he

rap

y in

tw

o d

ou

ble

-blin

d (

DU

RA

TIO

N-2

an

d D

UR

AT

ION

-4)

an

d

thre

e

op

en

-la

be

l st

ud

ies

(DU

RA

TIO

N-1

, D

UR

AT

ION

-3,

DU

RA

TIO

N-5

).7

,8,9

,10

,11

Stu

die

s in

clu

de

d p

ati

en

ts w

ith

typ

e 2

dia

be

tes

an

d m

ea

n b

ase

lin

e H

bA

1c

va

lue

s o

f 8

.3-

8.5

%.

Pa

tie

nts

na

ïve

to

dru

g t

he

rap

y a

nd

th

ose

on

on

e o

r m

ore

an

itd

iab

eti

c a

ge

nts

we

re i

ncl

ud

ed

. T

he

stu

dy d

ura

tio

ns

ran

ge

d f

rom

24

to

30

we

eks.

E

QW

wa

s co

mp

are

d t

o t

wic

e d

aily e

xen

ati

de

, m

etf

orm

in,

pio

glita

zon

e a

nd

sit

ag

lip

tin

. T

he

pri

ma

ry o

utc

om

e w

as

cha

ng

e i

n H

bA

1c

fro

m b

ase

lin

e.

No

lo

ng

-te

rm d

ata

is

ava

ila

ble

. N

o a

ll-c

au

se m

ort

ality

, m

icro

va

scu

lar

or

ma

cro

va

sula

r o

utc

om

es

ha

ve

be

en

eva

lua

ted

.

Th

e t

wo

do

ub

le-b

lin

d,

do

ub

le-d

um

my,

pla

ceb

o c

on

tro

lle

d,

RC

Ts

wit

h E

QW

fo

un

d s

imil

ar

resu

lts,

wit

h e

xce

pti

on

of

the

pio

gli

tazo

ne

co

mp

ari

son

arm

. I

n D

UR

AT

ION

-4 P

ati

en

ts w

ere

ra

nd

om

ize

d t

o s

ub

cuta

ne

ou

s (S

Q)

EQ

W o

nce

we

ekly

+ o

ral p

lace

bo

da

ily,

me

tfo

rmin

20

00

mg

/da

y +

SQ

pla

ceb

o

on

ce w

ee

kly

, p

iog

lita

zon

e 4

5m

g/d

ay +

SQ

pla

ceb

o o

nce

we

ekly

or

sita

gli

pti

n 1

00

mg

/da

y +

SQ

pla

ceb

o o

nce

we

ekly

.9 E

QW

wa

s fo

un

d t

o b

e

no

nin

feri

or

to m

etf

orm

in,

infe

rio

r to

pio

glita

zon

e a

nd

su

pe

rio

r to

sit

ag

lip

tin

(T

ab

le1

). E

QW

sig

nif

ica

ntl

y d

ecr

ea

sed

we

igh

t m

ore

th

an

pio

gli

tazo

ne

(-2

.0kg

fo

r E

QW

vs.

+1

.5kg

wit

h p

iog

lita

zon

e,

p<

0.0

01

) a

nd

sit

ag

lip

tin

(-2

.0kg

fo

r E

QW

vs.

-0

.8kg

fo

r si

tag

lip

tin

, p

<0

.00

1).

In

DU

RA

TIO

N-2

EQ

W 2

mg

SQ

+ o

ral p

lace

bo

on

ce d

ail

y (

n=

16

0)

wa

s co

mp

are

d t

o 1

00

mg

ora

l si

tag

lip

tin

+ p

lace

bo

in

ject

ion

we

ekly

(n

=1

66

) a

nd

45

mg

pio

gli

tazo

ne

+ p

lace

bo

inje

ctio

n w

ee

kly

(n

=1

65

), w

ith

all g

rou

ps

on

ba

ckg

rou

nd

me

tfo

rmin

th

era

py.7

Tre

atm

en

t w

ith

EQ

W r

esu

lte

d in

gre

ate

r H

bA

1c

red

uct

ion

s co

mp

are

d

to e

ith

er

sita

gli

pti

n o

r p

iog

lita

zon

e g

rou

ps.

T

rea

tme

nt

dif

fere

nce

s fo

r E

QW

co

mp

are

d t

o s

ita

gli

pti

n w

ere

-0

.6%

(9

5%

CI

-0.9

to

-0

.4,

p<

0.0

00

1)

an

d -

0.3

% (

95

% C

I -0

.6 t

o -

0.1

, p

=0

.01

65

) fo

r E

QW

co

mp

are

d t

o p

iog

lita

zon

e (

Ta

ble

2).

W

eig

ht

loss

wa

s g

rea

ter

wit

h E

QW

th

an

wit

h s

ita

gli

pti

n o

r

pio

gli

tazo

ne

.

Ta

ble

1.

Pri

ma

ry O

utc

om

e R

esu

lts

for

DU

RA

TIO

N-4

9

Co

mp

ara

tor

Tre

atm

en

t M

ea

n r

ed

uct

ion

s in

Hb

A1

c

Act

ua

l T

rea

tme

nt

Dif

fere

nce

EQ

W v

s. C

om

pa

rato

r

98

.3%

Co

nfi

de

nce

Inte

rva

ls

P-v

alu

e

EQ

W

-1.5

3%

--

--

----

- --

--

Me

tfo

rmin

-1

.48

%

-0.0

5%

-0

.26

to

0.1

7

0.6

2

Pio

gli

tazo

ne

-1

.63

%

0.1

0%

-0

.15

to

0.3

5

0.3

3

Sit

ag

lip

tin

-1

.15

%

-0.3

8%

-0

.62

to

-0

.13

<

0.0

01

Ta

ble

2.

Pri

ma

ry O

utc

om

e R

esu

lts

for

DU

RA

TIO

N-2

7

Co

mp

ara

tor

Tre

atm

en

t M

ea

n r

ed

uct

ion

s in

Hb

A1

c

Act

ua

l T

rea

tme

nt

Dif

fere

nce

EQ

W v

s. C

om

pa

rato

r

95

%C

on

fid

en

ce

Inte

rva

ls

P-v

alu

e

EQ

W

-1.5

%

----

--

--

----

Pio

gli

tazo

ne

-1

.2%

-0

.3%

-0

.6 t

o -

0.1

0

.01

65

Sit

ag

lip

tin

-0

.9%

-0

.6%

-0

.9 t

o -

0.4

<

0.0

00

1

43 of 108

Gen

eric

Nam

e: E

xen

atid

e E

xte

nded

-Rel

ease

Rev

iew

Dat

e: A

pri

l 2012

3

Auth

or:

Kat

hy S

ente

na

Sa

fety

: S

tud

ies

fou

nd

th

e m

ost

co

mm

on

ad

ve

rse

re

act

ion

s (

5%

) to

be

na

use

a,

dia

rrh

ea

, h

ea

da

che

, vo

mit

ing

, co

nst

ipa

tio

n,

inje

ctio

n s

ite

pru

ritu

s,

inje

ctio

n s

ite

no

du

les

an

d d

ysp

ep

sia

. E

QW

use

wa

s a

sso

cia

ted

wit

h a

4.9

% (

n=

45

) in

cid

en

ce o

f w

ith

dra

wa

ls d

ue

to

ad

ve

rse

eve

nts

co

mp

are

d t

o

4.9

% (

n=

13

) w

ith

exe

na

tid

e t

wic

e d

ail

y a

nd

2.0

% (

n=

23

) fo

r co

mp

ara

tor

the

rap

ies.

1 O

ve

rall

in

cid

en

ce o

f m

ino

r h

ypo

gly

cem

ia a

sso

cia

ted

wit

h E

QW

(mo

no

the

rap

y a

nd

co

mb

ina

tio

n t

he

rap

y)

ran

ge

d f

rom

1.3

% t

o 3

.7%

, e

xclu

din

g s

tud

ies

wit

h s

ulf

on

ylu

rea

s.

In t

ria

ls w

ith

co

nco

mit

an

t su

lfo

nylu

rea

the

rap

y m

ino

r h

yp

og

lyce

mia

ra

tes

ran

ge

d f

rom

12

.5-2

0%

. N

o m

ajo

r h

yp

og

lyce

mia

wa

s re

po

rte

d in

an

y s

tud

y.1

EQ

W i

s n

ot

reco

mm

en

de

d f

or

use

wit

h in

suli

n.

EQ

W m

ay i

ncr

ea

se i

nte

rna

tio

na

l n

orm

alize

d r

ati

os

(IN

R)

in p

ati

en

ts t

akin

g w

arf

ari

n.

It

is

reco

mm

en

de

d t

o m

on

ito

r IN

R f

req

ue

ntl

y if

wa

rfa

rin

an

d E

QW

are

to

be

ad

min

iste

red

co

nco

mit

an

tly.

EQ

W h

as

a b

lack

bo

x w

arn

ing

du

e t

o t

he

po

ten

tia

l fo

r ca

usi

ng

th

yro

id C

-ce

ll t

um

ors

in

ra

ts a

nd

fo

r b

ein

g c

on

tra

ind

ica

ted

in

pa

tie

nts

wit

h a

pe

rso

na

l o

r fa

mil

y h

isto

ry o

f m

ed

ulla

ry t

hyro

id

carc

ino

ma

(M

TC

) o

r in

pa

tie

nts

wit

h M

ult

iple

En

do

crin

e N

eo

pla

sia

syn

dro

me

typ

e 2

(M

EN

2).

P

ost

ma

rke

tin

g r

ep

ort

s h

ave

sh

ow

n f

ata

l a

nd

no

n-

fata

l h

em

orr

ha

gic

or

ne

cro

tizi

ng

pa

ncr

ea

titi

s a

nd

re

na

l im

pa

irm

en

t so

me

tim

es

req

uir

ing

he

mo

dia

lysi

s a

nd

kid

ne

y t

ran

spla

nt.

E

QW

is

no

t

reco

mm

en

de

d t

o b

e u

sed

in

pa

tie

nts

wit

h a

his

tory

of

pa

ncr

ea

titi

s, r

en

al

imp

air

me

nt

(CrC

l <

30

mL/

min

), s

eve

re g

ast

roin

test

ina

l d

ise

ase

or

hyp

ers

en

siti

vit

y re

act

ion

s.

Ca

uti

on

is

ad

vis

ed

wh

en

usi

ng

in

mo

de

rate

re

na

l im

pa

irm

en

t (C

rCl

30

-50

mL/

min

).

Hyp

og

lyce

mia

ris

k i

ncr

ea

ses

wh

en

EQ

W i

s u

sed

in

co

mb

ina

tio

n w

ith

su

lfo

nylu

rea

s a

nd

do

sag

e r

ed

uct

ion

is

reco

mm

en

de

d.1

Co

ncl

usi

on

: E

QW

ha

s d

em

on

stra

ted

eff

ica

cy o

f a

s a

on

ce w

ee

kly

fo

rmu

lati

on

of

exe

na

tid

e.

Oth

er

tha

n t

he

ob

vio

us

con

ve

nie

nce

of

a o

nce

we

ekly

pre

pa

rati

on

, E

QW

dif

fers

fro

m t

wic

e d

ail

y e

xen

ati

de

by h

avin

g a

bla

ck b

ox

wa

rnin

g,

du

e t

o t

hyro

id C

-ce

ll t

um

or

risk

, a

nd

th

e a

bil

ity t

o a

dm

inis

ter

the

we

ekly

do

se w

ith

ou

t re

ga

rd t

o m

ea

ls.

Sim

ila

r si

de

eff

ect

s a

re e

xpe

rie

nce

d b

y b

oth

fo

rmu

lati

on

s w

ith

th

e e

xce

pti

on

of

inje

ctio

n s

ite

pru

ritu

s

an

d in

ject

ion

sit

e n

od

ule

s a

sso

cia

ted

wit

h E

QW

an

d a

hig

he

r in

cid

en

ce o

f n

au

sea

ass

oci

ate

d w

ith

tw

ice

da

ily e

xen

ati

de

(3

0%

vs.

14

%).

Evid

en

ce

sug

ge

sts

tha

t E

QW

is

sim

ila

r in

eff

ica

cy a

nd

sa

fety

to

oth

er

curr

en

tly a

va

ila

ble

GLP

-1 a

go

nis

ts,

wh

ich

are

re

com

me

nd

ed

as

tie

r 2

ag

en

ts.

EQ

W i

s a

tre

atm

en

t o

pti

on

fo

r th

ose

pa

tie

nts

wh

om

hyp

og

lyce

mia

an

d w

eig

ht

ga

in a

re o

f co

nce

rn a

nd

are

un

ab

le t

o t

ole

rate

or

exp

eri

en

ce t

rea

tme

nt

failu

re

wit

h t

ier

1 a

ge

nts

.

Re

com

me

nd

ati

on

: I

t is

re

com

me

nd

ed

to

use

cli

nic

al

pri

or

au

tho

riza

tio

n c

rite

ria

to

lim

it t

he

use

of

EQ

W t

o p

ati

en

ts t

ha

t h

ave

tri

ed

an

d f

aile

d

an

tid

iab

eti

c tr

ea

tme

nts

th

at

ha

ve

a p

rove

n h

isto

ry o

f sa

fety

an

d e

ffic

acy

as

ou

tlin

ed

in

th

e P

A c

rite

ria

fo

r In

cre

tin

Mim

eti

cs (

ap

pe

nd

ix).

44 of 108

Gen

eric

Nam

e: E

xen

atid

e E

xte

nded

-Rel

ease

Rev

iew

Dat

e: A

pri

l 2012

4

Auth

or:

Kat

hy S

ente

na

AP

PE

ND

IX:

Incre

tin

Mim

eti

cs

Init

iati

ve:

To

op

tim

ize t

he c

orr

ect

use o

f in

su

lin

mim

eti

cs.

Len

gth

of

Au

tho

rizati

on

: U

p t

o 1

ye

ar

Pre

ferr

ed

Alt

ern

ati

ves:

Lis

ted a

t: h

ttp

://w

ww

.ore

gon.g

ov/D

HS

/he

althp

lan/t

oo

ls_

pro

v/p

dl.shtm

l

Req

uir

es P

A:

Exen

ati

de

(B

yett

a®

) an

d L

irag

luti

de (

Vic

toza®

), E

xen

ati

de E

xte

nd

ed

-Rele

ase (

Byd

ure

on

®)

Ap

pro

val

Cri

teri

a

1.D

oes the p

atien

t ha

ve

a d

iagnosis

of

Type 2

dia

bete

s?

Yes: G

o t

o #

2N

o: D

en

y b

ase

d o

n

appro

priate

ness o

f th

era

py.

2. W

illth

e p

rescrib

er

consid

er

a c

ha

ng

e to a

pre

ferr

ed p

roduct?

Message:

P

refe

rred p

rod

ucts

do n

ot re

qu

ire P

A.

P

refe

rred p

rod

ucts

are

evid

ence-b

ase

d

revie

we

d f

or

com

para

tive e

ffectiven

ess &

safe

ty b

y th

e H

ealth R

eso

urc

es

Com

mis

sio

n (

HR

C).

Report

s a

re a

vaila

ble

at:

http://w

ww

.ore

go

n.g

ov/O

HP

PR

/HR

C/E

vid

ence_

Based

_R

eport

s.s

htm

l.

Yes:

Info

rm p

rovid

er

of

covere

d

altern

atives in c

lass.

http://www.dhs.state.or.us/policy/healt

hplan/guides/pharmacy/main.html

No

: G

o to #

3.

3.H

as t

he p

atient

trie

d a

nd

faile

d m

etf

orm

in

an

dsulfon

ylu

rea th

era

py o

r ha

ve

contr

ain

dic

atio

ns to t

hese tre

atm

ents

?C

ontr

ain

dic

ations t

o m

etf

orm

in:

-K

no

wn h

yp

ers

ensitiv

ity

-R

ena

l d

isease o

r re

na

l d

ysfu

nctio

n-

Acute

or

chro

nic

meta

bolic

acid

osis

-In

cre

ased r

isk o

f la

ctic a

cid

osis

(C

HF

,

Yes:

Go to #

4.

No

: D

en

y.

Reco

mm

en

d t

rial o

f m

etf

orm

in o

r su

lfo

nylu

rea. S

ee

belo

w f

or

metf

orm

in

titr

ati

on

sch

ed

ule

.

45 of 108

Gen

eric

Nam

e: E

xen

atid

e E

xte

nded

-Rel

ease

Rev

iew

Dat

e: A

pri

l 2012

5

Auth

or:

Kat

hy S

ente

na

advanced

ag

e, im

paire

d h

epatic

function)

Contr

ain

dic

ations t

o s

ulfon

ylu

reas:

-K

no

wn h

yp

ers

ensitiv

ity

4.

Is th

e p

atient curr

en

tly t

akin

g insu

lin?

Yes:

Go to #

5N

o:

Appro

ve

for

up to 1

ye

ar.

5. Is th

e p

atient re

questing

exenta

tid

e (

Byett

a)

and is takin

g insulin

gla

rgin

e?

Yes:

Ap

pro

ve f

or

up t

o 1

year.

No

: D

en

y. T

he s

afe

ty

and e

ffic

acy o

f oth

er

insulin

form

ations a

nd

GLP

-1 A

go

nis

ts h

ave

not b

een

stu

die

d.

Init

iati

ng

Metf

orm

in

1.

Beg

in w

ith lo

w-d

ose m

etf

orm

in (

500 m

g)

taken o

nce o

r tw

ice p

er

da

y w

ith m

eals

(bre

akfa

st and/o

r din

ner)

or

850 m

g o

nce p

er

da

y.

2.

Aft

er

5-7

da

ys,

if g

astr

oin

testina

l sid

e e

ffects

have n

ot

occurr

ed, ad

va

nce d

ose to 8

50 m

g, or

two 5

00

mg

table

ts, tw

ice p

er

da

y (

medic

ation

to b

e t

aken b

efo

re b

reakfa

st and/o

r din

ner)

.

3.

If g

astr

oin

testina

l sid

e e

ffects

appe

ar

as d

oses a

dvanced, d

ecre

ase t

o p

revio

us lo

wer

dose a

nd

try

to a

dvance

the d

ose a

t a late

r tim

e.

4.

The m

axim

um

eff

ective d

ose c

an b

e u

p t

o 1

,00

0 m

g tw

ice p

er

da

y b

ut

is o

ften 8

50 m

g tw

ice p

er

da

y.

Modestly

gre

ate

r eff

ectiveness h

as b

een o

bserv

ed w

ith

doses u

p to a

bo

ut 2,5

00

mg/d

ay. G

astr

oin

testin

al sid

e e

ffects

m

ay lim

it the d

ose th

at can b

e u

se

d.

Na

tha

n,

et a

l.

Me

dic

al M

an

ag

em

en

t o

f H

yp

erg

lyce

mia

in

Typ

e 2

Dia

be

tes;

A C

on

sen

sus A

lgo

rith

m f

or

the

Initia

tion

and

Ad

justm

en

t o

f T

he

rap

y. D

iabe

tes C

are

31

;1-1

1,

20

08.

DU

R B

oard

Action:

3/1

7/1

1 (

KS

), 4

/26

/12 (

KS

)R

evis

ion(s

):

1/3

1/1

2 (

KS

)In

itia

ted:

46 of 108

Gen

eric

Nam

e: E

xen

atid

e E

xte

nded

-Rel

ease

Rev

iew

Dat

e: A

pri

l 2012

6

Auth

or:

Kat

hy S

ente

na

RE

FE

RE

NC

ES

:

1.

By

du

reo

n®

Pre

scri

bin

g I

nfo

rma

tio

n.

Am

yli

n P

ha

rma

ceu

tica

ls,

Inc.

Sa

n D

ieg

o,

CA

. Ja

nu

ary

20

12

.

2.

Jon

as

D,

Va

n S

coy

oc

E,

Ge

rra

ld K

, e

t a

l.

Dru

g C

lass

Re

vie

w:

Ne

we

r D

iab

ete

s M

ed

ica

tio

ns,

TZ

Ds,

an

d C

om

bin

ati

on

s.

htt

p:/

/de

rp.o

hsu

.ed

u/a

bo

ut/

fin

al-

do

cum

en

t-

dis

pla

y.c

fm.

3.

Na

tha

n D

, B

use

J,

Da

vid

son

M,

et

al.

M

ed

ica

l M

an

ag

em

en

t o

f H

yp

erg

lyce

mia

in

Ty

pe

2 D

iab

ete

s:

A C

on

sen

sus

Alg

ori

thm

fo

r th

e I

nit

iati

on

an

d A

dju

stm

en

t o

f T

he

rap

y:

A

Co

nse

nsu

s S

tate

me

nt

of

the

Am

eri

can

Dia

be

tes

Ass

oci

ati

on

an

d t

he

Eu

rop

ea

n A

sso

cia

tio

n f

or

the

Stu

dy

of

Dia

be

tes.

D

iab

ete

s C

are

20

08

. 3

1:1

-11

.

4.

Ro

db

ard

HW

, Je

llin

ge

r P

S,

Da

vid

son

JA

, e

t a

l.

Sta

tem

en

t b

y a

n A

me

rica

n A

sso

cia

tio

n o

f C

lin

ica

l E

nd

ocr

ino

log

ists

/Am

eri

can

Co

lle

ge

of

En

do

crin

olo

gy

co

nse

nsu

s p

an

el

on

typ

e 2

dia

be

tes

me

llit

us:

an

alg

ori

thm

fo

r g

lyce

mic

co

ntr

ol.

E

nd

oc

Pra

ct 2

00

9;

15

:54

0-5

9.

5.

Qa

see

m A

, H

um

ph

rey

L,

Sw

ee

t D

, e

t a

l.

Ora

l P

ha

rma

colo

gic

Tre

atm

en

t o

f T

yp

e 2

Dia

be

tes

Me

llit

us:

A C

lin

ica

l P

ract

ice

Gu

ide

lin

e f

rom

th

e A

me

rica

n C

oll

eg

e o

f

Ph

ysi

cia

ns.

A

nn

In

tern

Me

d 2

01

2;1

56

:21

8-2

31

.

6.

Wa

jch

en

be

rg B

L.

Be

ta-c

ell

fa

ilu

re i

n d

iab

ete

s a

nd

pre

serv

ati

on

by

cli

nic

al

tre

atm

en

t.

En

do

cr R

ev

20

07

; 2

8:1

87

-21

8.

7.

Be

rge

nst

al

R,

Wy

sha

m C

, M

acC

on

ne

ll,

et

al.

E

ffic

acy

an

d s

afe

ty o

f e

xen

ati

de

on

ce w

ee

kly

ve

rsu

s si

tag

lip

tin

or

pio

gli

tazo

ne

as

an

ad

jun

ct t

o m

etf

orm

in f

or

tre

atm

en

t o

f

typ

e 2

dia

be

tes

(DU

RA

TIO

N-2

): a

ra

nd

om

ize

d t

ria

l.

Lan

cet

20

10

; 3

76

:43

1-4

39

.

8.

Dia

ma

nt

M,

Va

n G

aa

l L,

Str

an

ks

S,

et

al.

O

nce

we

ek

ly e

xen

ati

de

co

mp

are

d w

ith

in

suli

n g

larg

ine

tit

rate

d t

o t

arg

et

in p

ati

en

ts w

ith

ty

pe

2 d

iab

ete

s (D

UR

AT

ION

-3):

an

op

en

-la

be

l ra

nd

om

ize

d t

ria

l.

Lan

cet

20

10

; 3

75

(9

73

3):

22

34

-43

.

9.

Ru

sse

ll-J

on

es

D,

Cu

dd

ihy

R,

Ha

ne

feld

M,

et

al.

E

ffic

acy

an

d s

afe

ty o

f e

xen

ati

de

on

ce w

ee

kly

ve

rsu

s m

etf

orm

in,

pio

gli

tazo

ne

an

d s

ita

gli

pti

n u

sed

as

mo

no

the

rap

y i

n d

rug

-

na

ïve

pa

tie

nts

wit

h t

yp

e 2

dia

be

tes

(DU

RA

TIO

N-4

).

Dia

be

tes

Ca

re 2

01

2;

35

:25

2-2

58

.

10

.D

ruck

er

D,

Bu

se J

, T

ay

lor

K,

et

al.

E

xen

ati

de

on

ce w

ee

kly

ve

rsu

s tw

ice

da

ily

fo

r th

e t

rea

tme

nt

of

typ

e 2

dia

be

tes:

a r

an

do

mis

ed

, o

pe

n-l

ab

el,

no

n-i

nfe

rio

rity

stu

dy

.

Lan

cet

20

08

; 3

72

(96

45

):1

24

0-5

0.

11

.B

levi

ns

T,

Pu

llm

an

J,

Ma

llo

y J

, e

t a

l.

DU

RA

TIO

N-5

: E

xen

ati

de

on

ce w

ee

kly

re

sult

ed

in

gre

ate

r im

pro

ve

me

nts

in

gly

cem

ic c

on

tro

l co

mp

are

d w

ith

exe

na

tid

e t

wic

e d

ail

y i

n

pa

tie

nts

wit

h t

yp

e 2

dia

be

tes.

J

Cli

n E

nd

ocr

ino

l M

eta

b 2

01

1;9

6:1

30

1-1

31

0.

47 of 108

©

Cop

yrig

ht 2

012

Ore

gon

Sta

te U

nive

rsity

. A

ll R

igh

ts

Res

erve

d

Dru

g U

se R

esea

rch

& M

anag

emen

t P

rogr

am

Ore

gon

Sta

te U

niv

ersi

ty,

500

Su

mm

er S

tree

t N

E,

E3

5, S

ale

m,

Ore

gon

97

301

-107

9

Pho

ne 5

03-9

47

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0 | F

ax 5

03-9

47-1

119

1 M

on

th/Y

ea

r o

f R

ev

iew

: A

pri

l 2

01

2

E

nd

da

te o

f li

tera

ture

se

arc

h:

Fe

bru

ary

20

12

Ge

ne

ric

Na

me

: F

ida

xom

icin

B

ran

d N

am

e (

Ma

nu

fact

ure

r):

Dif

icid

® (

Op

tim

er

Ph

arm

ace

uti

cals

)

Do

ssie

r re

ceiv

ed

: Y

es

Co

mp

ara

tor

Th

era

pie

s: V

an

com

yci

n,

Me

tro

nid

azo

le

Ex

ecu

tiv

e S

um

ma

ry:

FD

A A

pp

rove

d I

nd

ica

tio

ns:

F

ida

xom

icin

is

a m

acr

oli

de

an

tib

act

eri

al d

rug

in

dic

ate

d f

or

tre

atm

en

t o

f C

lost

rid

ium

dif

fici

le a

sso

cia

ted

dia

rrh

ea

(C

DA

D)

in a

du

lts

> 1

8 y

ea

rs o

f a

ge

.1

Su

mm

ary

: C

lost

rid

ium

dif

fici

le in

fect

ion

(C

DI)

is

a g

row

ing

he

alt

h c

are

pro

ble

m a

nd

a s

eri

ou

s h

ea

lth

care

-ass

oci

ate

d in

fect

ion

th

at

ha

s co

nti

nu

ed

to

em

erg

e o

ve

r th

e p

ast

th

ree

de

cad

es.

C

urr

en

t e

pid

em

ic r

ate

s o

f C

DI

in t

he

Un

ite

d S

tate

s, C

an

ad

a,

an

d E

uro

pe

ha

ve

be

en

ass

oci

ate

d w

ith

a h

yp

er-

vir

ule

nt

stra

in (

BI/

NA

P1

/02

7).

T

his

str

ain

is

ass

oci

ate

d w

ith

in

cre

ase

d t

oxi

n p

rod

uct

ion

an

d in

cre

ase

d m

ort

ality

an

d m

orb

idit

y.2

Pre

vio

usl

y t

ho

ug

ht

to b

e a

dis

ea

se o

f h

osp

ita

lize

d p

ati

en

ts,

com

mu

nit

y-a

sso

cia

ted

CD

I is

in

cre

asi

ng

ly b

ein

g r

eco

gn

ize

d in

ch

ild

ren

an

d a

du

lts

wit

h s

imila

r ri

sk f

act

ors

.

Th

e e

vid

en

ce u

sed

fo

r m

an

y o

f th

e c

urr

en

t g

uid

elin

es

is w

ea

k d

ue

to

sm

all s

tud

ies

oft

en

wit

h a

hig

h r

isk o

f b

ias

an

d f

req

ue

ntl

y e

xclu

din

g p

ati

en

ts

wit

h s

eve

re d

ise

ase

. T

he

re

lati

ve

bu

rde

n o

f C

DI

in n

on

ho

spit

al h

ea

lth

-ca

re s

ett

ing

s re

ma

ins

un

kn

ow

n.

In

Ma

y,

20

11

, th

e F

DA

ap

pro

ve

d f

ida

xom

icin

for

the

tre

atm

en

t o

f C

DA

D.

In

De

cem

be

r 2

01

1,

the

Ag

en

cy f

or

He

alt

hca

re R

ese

arc

h a

nd

Qu

ali

ty (

AH

RQ

) p

ub

lish

ed

a c

om

pa

rati

ve

eff

ect

ive

ne

ss

revie

w (

CE

R)

on

th

e e

ffe

ctiv

en

ess

of

ea

rly d

iag

no

sis,

pre

ve

nti

on

, a

nd

tre

atm

en

t o

f C

DI

tha

t w

as

up

da

ted

to

in

clu

de

on

e o

f th

e a

pp

rova

l st

ud

ies

of

fid

axo

mic

in t

ha

t w

as

pu

bli

she

d a

t th

e t

ime

as

we

ll a

s th

e in

cre

asi

ng

am

ou

nt

of

pu

bli

she

d t

rea

tme

nt

stu

die

s co

inci

din

g w

ith

th

e in

cre

ase

d i

nci

de

nce

an

d s

eve

rity

of

CD

I.3

Fid

axo

mic

in i

s a

ne

w a

nti

ba

cte

ria

l d

rug

in

dic

ate

d p

rim

ary

fo

r tr

ea

tme

nt

of

Clo

stri

diu

m d

iffi

cile

. T

he

au

tho

rs o

f th

e A

HR

Q C

ER

co

ncl

ud

ed

th

at

no

an

tim

icro

bia

l is

cle

arl

y s

up

eri

or

for

the

in

itia

l cu

re o

f C

DI.

T

he

re w

as

mo

de

rate

-str

en

gth

evid

en

ce

tha

t fi

da

xom

icin

an

d v

an

com

yci

n d

id n

ot

dif

fer

for

the

ou

tco

me

of

init

ial cu

re b

ut

tha

t re

curr

en

ce w

as

less

fre

qu

en

t w

ith

fid

axo

mic

in b

ase

d o

n o

ne

hig

h-q

ua

lity

stu

dy.3

Th

ere

wa

s a

lso

mo

de

rate

-str

en

gth

evid

en

ce t

ha

t o

utc

om

es

did

no

t d

iffe

r b

etw

ee

n m

etr

on

ida

zole

an

d v

an

com

yci

n i

n n

on

seve

re

dis

ea

se a

nd

in

suff

icie

nt

evid

en

ce t

o e

va

lua

te a

dif

fere

nce

in

se

ve

re C

DI.

T

he

re w

as

insu

ffic

ien

t e

vid

en

ce t

o c

om

pa

re t

he

ris

ks

of

an

y p

art

icu

lar

an

tim

icro

bia

l w

ith

an

oth

er

on

e.

Alt

ho

ug

h g

uid

elin

es

reco

mm

en

d v

an

com

yci

n a

s fi

rst

lin

e in

se

ve

re d

ise

ase

, th

ere

is

insu

ffic

ien

t e

vid

en

ce t

o

sup

po

rt t

ha

t it

is

ge

ne

rally s

up

eri

or

to m

etr

on

ida

zole

. H

ow

eve

r, t

he

re a

lso

ap

pe

ars

to

be

cli

nic

al co

nse

nsu

s to

tre

at

mil

d t

o m

od

era

te C

DI

wit

h

me

tro

nid

azo

le,

in p

art

be

cau

se o

f th

e c

on

cern

th

at

ove

ruse

of

va

nco

myci

n m

ay c

on

trib

ute

to

in

cre

asi

ng

pa

tho

ge

n r

esi

sta

nce

an

d c

ost

con

sid

era

tio

ns.

3

48 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

2 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

Eff

ica

cy:

Tw

o p

ha

se I

II r

an

do

miz

ed

, co

ntr

olle

d,

do

ub

le-b

lin

d,

ide

nti

call

y d

esi

gn

ed

clin

ica

l tr

ials

co

mp

are

d t

he

eff

ica

cy o

f fi

da

xom

icin

20

0 m

g t

wic

e

da

ily v

ers

us

ora

l va

nco

myci

n 1

25

mg

fo

ur

tim

es

da

ily f

or

10

da

ys

in a

du

lt p

ati

en

ts w

ith

a d

iag

no

sis

of

CD

AD

an

d h

isto

ry o

f ≤

1 r

ecu

rre

nce

.4,

5 T

he

pri

ma

ry e

nd

po

int

in b

oth

tri

als

wa

s th

e c

lin

ica

l re

spo

nse

ra

te a

t th

e e

nd

of

the

rap

y.

On

e t

ria

l w

as

con

du

cte

d i

n N

ort

h A

me

rica

4 a

nd

th

e s

eco

nd

tri

al

in

No

rth

Am

eri

ca a

nd

Eu

rop

e.5

B

oth

tri

als

de

mo

nst

rate

d t

ha

t fi

da

xom

icin

wa

s n

on

infe

rio

r to

va

nco

myci

n i

n c

lin

ica

l cu

re r

ate

wit

h 8

8.2

% o

f p

ati

en

ts o

n

fid

axo

mic

in a

chie

vin

g c

lin

ica

l cu

re c

om

pa

red

to

85

.8%

on

va

nco

myci

n in

on

e t

ria

l (

RR

0.9

7 9

5%

CI

0.9

1 t

o 1

.04

)4 a

nd

88

% o

f fi

da

xom

icin

ve

rsu

s 8

7%

va

nco

myci

n p

ati

en

ts in

th

e s

eco

nd

tri

al (p

=0

.07

4).

5

Bo

th t

ria

ls a

lso

de

mo

nst

rate

d a

sta

tist

ica

lly s

ign

ific

an

t d

iffe

ren

ce i

n r

ecu

rre

nce

ra

tes

be

twe

en

th

e

two

gro

up

s.

Re

curr

en

ce r

ate

s w

ere

15

.4%

fo

r fi

da

xom

icin

ve

rsu

s 2

5.3

% f

or

va

nco

myci

n (

p=

0.0

05

) in

on

e t

ria

l a

nd

12

.7%

fo

r fi

da

xom

icin

ve

rsu

s 2

7%

for

va

nco

myci

n (

p<

0.0

01

) in

th

e s

eco

nd

tri

al.

H

ow

eve

r, i

n p

ati

en

ts w

ith

th

e h

yp

er-

vir

ule

nt

stra

in,

(ap

pro

xim

ate

ly 4

0%

of

all i

sola

tes)

th

ere

wa

s n

o

sig

nif

ica

nt

dif

fere

nce

in

re

curr

en

ce r

ate

be

twe

en

th

e t

wo

gro

up

s in

eit

he

r st

ud

y.4

, 5

In

a s

ub

gro

up

an

aly

sis,

re

curr

en

ce r

ate

s w

ere

sig

nif

ica

ntl

y lo

we

r

in f

ida

xom

icin

-tre

ate

d p

ati

en

ts w

ho

we

re >

65

ye

ars

old

, h

ad

no

pri

or

ep

iso

de

s o

f C

DA

D,

we

re n

ot

rece

ivin

g c

on

com

ita

nt

an

tib

ioti

cs,

an

d h

ad

a n

on

-

BI/

NA

P1

/02

7 s

tra

in.

Sa

fety

: R

ate

s o

f a

dve

rse

an

d s

eri

ou

s a

dve

rse

eve

nts

we

re s

imil

ar

in t

he

fid

axo

mic

in a

nd

va

nco

myci

n g

rou

ps

an

d b

oth

als

o h

ad

sim

ila

r ra

tes

of

dis

con

tin

ua

tio

ns

du

e t

o a

dve

rse

eve

nts

(5

.9%

in

fid

axo

mic

in c

om

pa

red

to

6.9

% f

or

va

nco

myci

n g

rou

p).

4,5

Th

e m

ost

co

mm

on

ad

ve

rse

re

act

ion

s

ass

oci

ate

d w

ith

fid

axo

mic

in t

rea

tme

nt

in c

lin

ica

l tr

ials

are

na

use

a (

11

%),

vo

mit

ing

(7

%),

ab

do

min

al p

ain

(6

%),

ga

stro

inte

stin

al

he

mo

rrh

ag

e (

4%

),

an

em

ia (

2%

), a

nd

ne

utr

op

en

ia (

2%

).1 B

oth

th

e A

HR

Q r

evie

w a

nd

a r

ece

nt

syst

em

ati

c re

vie

w f

rom

th

e C

och

ran

e C

oll

ab

ora

tio

n f

ou

nd

th

at

alt

ho

ug

h

ha

rms

we

re o

fte

n n

ot

rep

ort

ed

wit

h s

uff

icie

nt

de

tail

to

co

mp

are

ris

ks

ass

oci

ate

d w

ith

th

e a

nti

bio

tics

, a

dve

rse

eve

nts

we

re in

fre

qu

en

t a

nd

tra

nsi

en

t

an

d w

ere

ge

ne

rall

y n

ot

seri

ou

s.3

,6 T

he

sa

fety

an

d e

ffe

ctiv

en

ess

of

fid

axo

mic

in h

as

no

t b

ee

n s

tud

ied

in

pa

tie

nts

yo

un

ge

r th

an

18

ye

ars

.1

Co

ncl

usi

on

s:

Th

ere

is

mo

de

rate

str

en

gth

evid

en

ce t

ha

t th

ere

is

no

dif

fere

nce

in

cli

nic

al

cure

ra

te b

etw

ee

n f

ida

xom

icin

, va

nco

myci

n,

an

d m

etr

on

ida

zole

. T

he

re i

s

mo

de

rate

str

en

gth

evid

en

ce t

ha

t re

curr

en

ce o

ccu

rs l

ess

fre

qu

en

tly w

ith

fid

axo

mic

in v

ers

us

va

nco

myci

n.

Cu

rre

nt

gu

ide

lin

es

reco

mm

en

d

me

tro

nid

azo

le a

nd

va

nco

myci

n a

s th

e s

tan

da

rd t

rea

tme

nt

op

tio

ns

for

Clo

stri

diu

m d

iffi

cile

in

fect

ion

.7 H

ow

eve

r, a

re

cen

t C

och

ran

e r

evie

w o

f cl

inic

al

tria

ls s

ho

we

d t

ha

t th

ere

is

no

str

on

g e

vid

en

ce t

o s

up

po

rt c

urr

en

t re

com

me

nd

ati

on

s m

ad

e b

y t

he

gu

ide

lin

es.

6 F

urt

he

r h

ea

d-t

o-h

ea

d s

tud

ies

are

ne

ed

ed

in

se

ve

re d

ise

ase

an

d t

o c

om

pa

re d

ire

ctly

fid

axo

mic

in t

o m

etr

on

ida

zole

. T

he

rap

y w

ith

fid

axo

mic

in m

ay p

rovid

e v

alu

e t

o p

ati

en

ts a

t h

igh

risk

of

reh

osp

ita

liza

tio

n d

ue

to

re

curr

en

ce o

r o

the

r se

rio

us

com

pli

cati

on

s.

It is

stil

l u

nkn

ow

n h

ow

to

be

st id

en

tify

th

is p

ati

en

t p

op

ula

tio

n.

Re

com

me

nd

ati

on

s:

• R

eco

mm

en

d m

akin

g f

ida

xom

icin

a n

on

-pre

ferr

ed

an

tim

icro

bia

l fo

r C

DI

an

d r

eq

uir

ing

a d

ocu

me

nte

d t

ria

l o

f a

pp

rop

ria

te t

he

rap

y o

f

va

nco

myci

n (

12

5m

g o

ral f

ou

r ti

me

s d

ail

y)

or

me

tro

nid

azo

le (

50

0m

g o

rall

y th

ree

tim

es

da

ily)

for

firs

t re

curr

en

ce o

r co

ntr

ain

dic

ati

on

to

the

rap

y a

nd

exc

lud

ing

use

of

fid

axo

mic

in i

n p

ati

en

ts w

ith

se

ve

re,

com

pli

cate

d C

DA

D (

life

-th

rea

ten

ing

or

fulm

ina

nt

infe

ctio

n o

r to

xic

me

ga

colo

n).

• R

eco

mm

en

d a

dd

ing

ora

l m

etr

on

ida

zole

an

d o

ral

van

com

yci

n a

s p

refe

rre

d a

ge

nts

on

th

e P

DL

for

the

tre

atm

en

t o

f C

DI.

• F

urt

he

r e

va

lua

te c

om

pa

rati

ve

co

sts

of

the

rap

y.

49 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

3 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

BA

CK

GR

OU

ND

/CU

RR

EN

T L

AN

DS

CA

PE

/SU

MM

AR

Y

Th

e in

cid

en

ce,

mo

rta

lity

, a

nd

me

dic

al

care

co

sts

of

CD

Is h

ave

re

ach

ed

his

tori

c h

igh

s. F

rom

20

00

to

20

09

, th

e n

um

be

r o

f h

osp

ita

lize

d p

ati

en

ts w

ith

an

y C

DI

dis

cha

rge

dia

gn

ose

s m

ore

th

an

do

ub

led

, fr

om

ap

pro

xim

ate

ly 1

39

,00

0 t

o 3

36

,00

0.2

Str

ate

gie

s fo

r p

reve

nti

on

sh

ou

ld b

e in

itia

ted

to

re

du

ce

the

in

cid

en

ce o

f C

DI

as

ma

ny o

f th

ese

in

fect

ion

s ca

n b

e p

reve

nte

d.2

C.

dif

fici

le g

en

era

lly o

ccu

rs a

fte

r e

xpo

sure

to

bro

ad

-sp

ect

rum

an

tib

ioti

cs,

bu

t

an

y a

nti

bio

tic

tha

t d

isru

pts

th

e n

orm

al fl

ora

of

the

gu

t ca

n in

cre

ase

su

sce

pti

bil

ity.7

A

re

cen

t d

rug

sa

fety

co

mm

un

ica

tio

n w

as

rele

ase

d b

y t

he

FD

A,

no

tify

ing

th

e p

ub

lic

tha

t th

e u

se o

f st

om

ach

aci

d d

rug

s su

ch a

s p

roto

n p

um

p i

nh

ibit

ors

ma

y a

lso

be

ass

oci

ate

d w

ith

an

in

cre

ase

d r

isk o

f C

. d

iffi

cile

ass

oci

ate

d d

iarr

he

a (

CD

AD

).8

Th

ey a

re a

lso

re

vie

win

g t

he

ris

k o

f C

DA

D a

sso

cia

ted

wit

h h

ista

min

e H

2 r

ece

pto

r b

lock

ers

.8 R

ecu

rre

nce

of

CD

I o

ccu

rs

in a

pp

roxi

ma

tely

20

% o

f p

ati

en

ts.

Aft

er

two

re

curr

en

ces,

th

e r

isk t

ha

t a

dd

itio

na

l e

pis

od

es

wil

l o

ccu

r in

cre

ase

s to

65

%.7

T

he

tre

atm

en

t g

oa

ls f

or

CD

I

incl

ud

e r

eso

luti

on

of

dia

rrh

ea

an

d o

the

r si

gn

s a

nd

sym

pto

ms,

la

ck o

f d

ise

ase

re

curr

en

ce,

avo

ida

nce

of

cole

cto

my,

an

d n

o o

the

r se

rio

us

seq

ue

lae

of

dis

ea

se.

Ora

l m

etr

on

ida

zole

an

d v

an

com

yci

n a

re t

he

an

tib

ioti

cs m

ost

oft

en

use

d t

o t

rea

t C

DI.

G

uid

elin

es

fro

m t

he

So

cie

ty f

or

He

alt

hca

re E

pid

em

iolo

gy o

f

Am

eri

ca (

SH

EA

) a

nd

Th

e I

nfe

ctio

us

Dis

ea

ses

So

cie

ty o

f A

me

rica

(ID

SA

) w

ere

up

da

ted

in

20

10

(p

rio

r to

fid

oxa

mic

in’s

FD

A a

pp

rova

l fo

r C

DA

D)

an

d

reco

mm

en

d m

etr

on

ida

zole

fo

r in

itia

l e

pis

od

es

of

mil

d t

o m

od

era

te d

ise

ase

s a

nd

ora

l va

nco

myci

n a

s th

e d

rug

of

cho

ice

fo

r se

ve

re d

ise

ase

, u

sin

g

cha

ng

ing

cre

ati

nin

e v

alu

es

an

d a

n a

bn

orm

all

y h

igh

wh

ite

blo

od

ce

ll c

ou

nt

to d

efi

ne

se

ve

rity

.7 T

he

usu

al d

ura

tio

n o

f th

era

py i

s 1

0 t

o 1

4 d

ays,

alt

ho

ug

h n

o w

ell

-pe

rfo

rme

d s

tud

ies

ha

ve

est

ab

lish

ed

th

e p

ote

nti

al

ad

va

nta

ge

of

sho

rte

nin

g o

r le

ng

the

nin

g t

he

co

urs

e.

Co

mp

ara

tive

cli

nic

al tr

ials

de

mo

nst

rate

d e

qu

iva

len

t ra

tes

of

clin

ica

l cu

re f

or

the

tw

o a

ge

nts

, b

ut

me

tro

nid

azo

le i

s p

refe

rre

d f

or

init

ial d

ise

ase

du

e t

o c

on

cern

s re

ga

rdin

g t

he

em

erg

en

ce o

f va

nco

myci

n r

esi

sta

nce

an

d c

ost

s.3 O

ve

rall

, p

revio

us

syst

em

ati

c re

vie

ws

ha

ve

co

ncl

ud

ed

th

ere

is

insu

ffic

ien

t o

r lo

w-s

tre

ng

th e

vid

en

ce

for

an

y o

utc

om

es

eva

lua

tin

g e

ffic

acy

in

se

ve

re C

DI

as

ma

ny s

tud

ies

exc

lud

ed

th

ese

pa

tie

nts

, a

lth

ou

gh

co

nse

nsu

s g

uid

eli

ne

s re

com

me

nd

va

nco

myci

n a

s fi

rst

lin

e in

se

ve

re d

ise

ase

. T

he

on

ly c

om

pa

rati

ve

evid

en

ce f

or

va

nco

myci

n v

ers

us

me

tro

nid

azo

le i

n s

eve

re d

ise

ase

co

me

s fr

om

a

pe

r-p

roto

col

sub

gro

up

an

aly

sis

of

69

pa

tie

nts

in

a s

ing

le t

ria

l. A

lth

ou

gh

th

ere

wa

s a

sta

tist

ica

lly s

ign

ific

an

t d

iffe

ren

ce f

avo

rin

g v

an

com

yci

n i

n t

he

pe

r-p

roto

col

an

d m

od

ifie

d i

nte

nti

on

-to

-tre

at

an

aly

sis,

th

ere

wa

s n

o s

ign

ific

an

t d

iffe

ren

ce u

sin

g a

str

ict

inte

nti

on

-to

-tre

at

an

aly

sis.

3

A r

ece

nt

Co

chra

ne

syst

em

ic r

evie

w f

rom

th

e C

och

ran

e C

oll

ab

ora

tio

n a

ime

d t

o e

va

lua

te t

he

eff

ica

cy o

f a

nti

bio

tic

the

rap

y f

or

CD

AD

.7 O

ut

of

the

15

stu

die

s in

clu

de

d,

12

we

re r

ate

d a

s h

avin

g a

hig

h r

isk o

f b

ias.

In

3 s

tud

ies

(n=

33

5),

no

sta

tist

ica

lly s

ign

ific

an

t d

iffe

ren

ce w

as

fou

nd

be

twe

en

va

nco

myci

n a

nd

me

tro

nid

azo

le f

or

sym

pto

ma

tic

cure

of

CD

AD

. S

ym

pto

ma

tic

cure

wa

s a

chie

ve

d in

79

% o

f p

ati

en

ts i

n v

an

com

yci

n g

rou

p c

om

pa

red

to 7

1%

in

me

tro

nid

azo

le g

rou

p (

RR

0.9

1;

95

% C

I: 0

.81

-1.0

3).

7

Th

e a

uth

ors

co

ncl

ud

ed

th

at

du

e t

o s

ma

ll n

um

be

r o

f p

ati

en

ts,

po

or

me

tho

do

log

ica

l

qu

ality

stu

die

s, a

nd

exc

lusi

on

of

seve

re d

ise

ase

, a

re

com

me

nd

ati

on

to

ach

ieve

ove

rall

go

als

co

uld

no

t b

e m

ad

e.

Als

o,

the

re w

as

no

sta

tist

ica

l

dif

fere

nce

in

ba

cte

rio

log

ic c

ure

be

twe

en

me

tro

nid

azo

le a

nd

va

nco

myci

n in

on

e s

tud

y w

ith

62

pa

tie

nts

.

50 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

4 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

Cli

nic

al

ph

arm

aco

log

y

Fid

axo

mic

in i

s a

ba

cte

rici

da

l m

acr

olid

e a

nti

bio

tic,

pri

ma

rily

act

ive

ag

ain

st C

lost

rid

ium

dif

fici

le.

Th

e d

rug

wo

rks

by in

hib

itin

g b

act

eri

al

RN

A

po

lym

era

se w

hic

h s

top

s R

NA

syn

the

sis

du

rin

g t

ran

scri

pti

on

ph

ase

of

pro

tein

syn

the

sis.

1

Ph

arm

aco

kin

eti

cs:

Fid

axo

mic

in h

as

po

or

pe

rme

ab

ilit

y a

nd

so

lub

ilit

y;

the

refo

re it

is m

inim

all

y a

bso

rbe

d f

rom

th

e g

ast

roin

test

ina

l tr

act

. T

he

dru

g i

s m

eta

bo

lize

d v

ia

hyd

roly

sis

to a

n a

ctiv

e m

eta

bo

lite

OP

-11

18

. N

o C

YP

en

zym

es

we

re f

ou

nd

to

pla

y s

ign

ific

an

t ro

le in

th

e m

eta

bo

lism

of

fid

axo

mic

in o

r fo

rma

tio

n o

f

OP

-11

18

. T

he

dru

g i

s p

rim

ari

ly e

xcre

ted

in

fe

ces.

F

ida

xom

icin

fe

cal co

nce

ntr

ati

on

s a

re d

ete

cte

d u

p t

o 5

da

ys

aft

er

tre

atm

en

t.1

2 T

he

dru

g d

osi

ng

do

es

no

t n

ee

d t

o b

e a

dju

ste

d f

or

de

cre

ase

d r

en

al fu

nct

ion

, a

s th

ere

is

<1

% r

en

al e

lim

ina

tio

n.

Th

e i

mp

act

of

he

pa

tic

imp

air

me

nt

on

ph

arm

aco

kin

eti

cs o

f fi

da

xom

icin

ha

s n

ot

be

en

eva

lua

ted

be

cau

se h

ep

ati

c m

eta

bo

lism

is

no

t si

gn

ific

an

t.1

T

ab

le 1

in

Ap

pe

nd

ix 1

co

mp

are

s

ph

arm

aco

kin

eti

c p

ara

me

ters

of

fid

axo

mic

in w

ith

oth

er

tre

atm

en

ts f

or

CD

I in

clu

din

g m

etr

on

ida

zole

an

d o

ral va

nco

myci

n.

51 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

5 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

CO

MP

ER

AT

IVE

CLI

NIC

AL

EF

FIC

AC

Y

Re

lev

an

t E

nd

po

ints

S

tud

y E

nd

po

ints

:

Init

ial

Cu

re

P

rim

ary

: C

lin

ica

l C

ure

(re

solu

tio

n o

f sy

mp

tom

s a

nd

no

ne

ed

fo

r fu

rth

er

tre

atm

en

t)

Re

curr

en

ce

S

eco

nd

ary

: R

ecu

rre

nce

(d

iarr

he

a a

nd

a p

osi

tive

re

sult

on

a s

too

l to

xin

te

st w

ith

in 4

we

eks

aft

er

Mo

rta

lity

tr

ea

tme

nt)

Glo

ba

l C

ure

(cu

re w

ith

no

re

curr

en

ce)

Ev

ide

nce

ta

ble

R

ef.

/

Stu

dy

De

sig

n

Dru

g

Re

gim

en

s

Pa

tie

nt

Po

pu

lati

on

N

5

Du

rati

on

E

ffic

acy

Re

sult

s2

(CI,

p-v

alu

es)

AR

R /

NN

T3

S

afe

ty R

esu

lts2

(CI,

p-v

alu

es)

AR

R

/ NN

H

Qu

ali

ty R

ati

ng

4;

Co

mm

en

ts

Lo

uie

et

al.

,

Ph

ase

III

,

DB

, R

CT

4

Stu

dy

00

3

F:F

ida

xom

yci

n

20

0m

g P

O B

ID

V:V

an

com

icin

12

5m

g P

O Q

ID

Ad

ult

s w

ith

acu

te s

ym

pto

ms

of

CD

I a

nd

a

po

siti

ve

re

sult

on

a s

too

l to

xin

te

st in

Ca

na

da

an

d t

he

USA

.

Me

an

ag

e:

61

.6

Fe

ma

le 5

5.9

%,

In

pa

tie

nt

59

.4%

,

Me

an

nu

mb

er

of

un

form

ed

sto

ols

/da

y:

8.2

Incl

usi

on

: cr

ite

ria

:

• >

16

y.o

, C

.dif

fici

le

dia

gn

osi

s (>

3 u

nfo

rme

d

sto

ols

i

n 2

4 h

pri

or

ran

do

miz

ati

on

, p

rese

nce

of

toxi

n A

, o

r b

oth

in

sto

ol w

ith

in 4

8 h

o

f

ran

do

miz

ati

on

).

Excl

usi

on

cri

teri

a:

• L

ife

-th

rea

ten

ing

C.d

ific

ile

in

fect

ion

, T

oxi

c

me

ga

colo

n,

His

tory

of

U

C,

Cro

hn

’s d

ise

ase

, >

1

C.d

iffi

cile

in

fect

ion

w

ith

in 3

mo

nth

s, U

se o

f

dru

gs

to c

on

tro

l d

iarr

he

a o

r th

ose

th

at

aff

ect

pa

rist

als

is.

F:

30

2

V:

32

7

Tre

atm

en

t:

10

da

ys

Fo

llo

w u

p:

30

da

ys

Init

ial

Cli

nic

al

Cu

re

Clin

ica

l cu

re:

F:

25

3 (

88

%)

V:

26

5 (

85

%)

RR

0.9

7

95

% C

I (0

.91

to

1.0

4)

Cli

nic

al

Re

curr

en

ce:

F:

39

(1

5%

)

V:

67

(2

5%

)

RR

0.6

95

% C

I (0

.41

to

0.8

7 )

P=

0.0

05

Glo

ba

l C

ure

:

F:

21

4 (

74

.6%

)

V:

19

8 (

64

.1%

)

RR

1.1

6

95

% C

I (1

.15

to

2.3

4 )

P=

0.0

06

NS

AR

R

9.9

%

NN

T 1

0

AR

R

10

.5%

NN

T 9

.5

All-C

au

se M

ort

ality

:

F:

16

(5

.3%

)

V:

21

(6

.5%

)

P=

0.6

12

2

An

y s

eri

ou

s

ad

ve

rse

ev

en

t:

F:

25

%

V:2

4.1

%

P=

0.8

52

No

su

bje

cts

dis

con

tin

ue

d t

he

stu

dy

as

a r

esu

lt o

f

into

lera

nce

or

alle

rgy

to

me

dic

ati

on

s

NS

NS

Go

od

;

Ad

eq

ua

te a

llo

cati

on

co

nce

alm

en

t;

do

ub

le b

lin

din

g,

pa

rtia

lly

IT

T a

na

lysi

s

To

tal w

ith

dra

wa

ls a

nd

dro

po

uts

:

33

(5

%)

Fu

nd

ed

by

Op

tim

er

Ph

arm

ace

uti

cals

.

Inte

nti

on

-to

-tre

at

an

aly

sis:

mo

dif

ied

(su

bje

cts

wit

hd

raw

ing

be

fore

tre

atm

en

t, h

ad

≤3

bo

we

l m

oti

on

s in

24

ho

urs

,

or

test

ed

ne

ga

tiv

e f

or

C.

dif

fici

le t

oxi

n w

ere

exc

lud

ed

)

Oth

er

me

dic

ati

on

use

th

at

can

ca

use

dia

rrh

ea

no

t re

po

rte

d a

t b

ase

lin

e.

Pa

tie

nts

we

re a

llo

we

d t

o u

se o

pio

ids

du

rin

g h

osp

ita

l st

ay

. O

pio

id d

ose

s u

sed

by

bo

th g

rou

ps

no

t re

po

rte

d.

52 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

6 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

Co

rne

ly,

et

al.

Ph

ase

III

, D

B,

RC

T,

PG

5

Stu

dy

: 0

04

F:

Fid

axo

mic

in

20

0m

g P

O B

ID

V:

Va

nco

myc

in

12

5m

g P

O Q

ID

Ad

ult

s w

ith

acu

te s

ym

pto

ms

of

CD

I a

nd

a

po

siti

ve

re

sult

on

a s

too

l to

xin

te

st in

Eu

rop

e,

as

we

ll a

s in

Ca

na

da

an

d t

he

USA

.

Me

an

ag

e:

63

, F

em

ale

: 6

0.9

%

Incl

usi

on

: cr

ite

ria

:

• >

16

y.o

, C

.dif

fici

le

dia

gn

osi

s (>

3 u

nfo

rme

d

sto

ols

in

24

h p

rio

r ra

nd

om

iza

tio

n,

pre

sen

ce o

f

toxi

n A

, o

r b

oth

in

sto

ol w

ith

in 4

8 h

o

f

ran

do

miz

ati

on

).

Excl

usi

on

cri

teri

a:

• L

ife

-th

rea

ten

ing

C.d

ific

ile

in

fect

ion

, T

oxi

c

me

ga

colo

n,

His

tory

of

U

C,

Cro

hn

’s d

ise

ase

,

>1

C.d

iffi

cile

in

fect

ion

w

ith

in 3

mo

nth

s, U

se

of

dru

gs

to c

on

tro

l d

iarr

he

a o

r th

ose

th

at

aff

ect

pa

rist

als

is.

F:

27

0

V:

26

5

Tre

atm

en

t:

10

da

ys

Fo

llo

w u

p:

28

da

ys

aft

er

tre

atm

en

t

Cli

nic

al

Cu

re:

F:

22

1 (

87

.7%

)

V:

22

3 (

86

.8%

)

P=

0.7

54

Re

curr

en

ce:

F:

28

(1

2.6

%)

V:

60

(2

7%

)

RR

0.5

P=

0.0

00

2

Glo

ba

l cu

re:

F:

19

3 (

76

.6%

)

V:

16

3 (

63

.4%

)

RR

1.2

P=

0.0

01

NS

AR

R

14

.4%

NN

T 7

AR

R

13

.2%

NN

T 7

Se

rio

us

ad

ve

rse

ev

en

t:

F:

70

(2

6.5

%)

V:

58

(2

2.3

%)

Ad

ve

rse

ev

en

ts

lea

din

g t

o

dis

con

tin

ua

tio

n:

F:

16

(6

.1%

)

V:

16

(6

.2%

)

NS

NS

Fa

ir;

Ad

eq

ua

te a

llo

cati

on

co

nce

alm

en

t;

do

ub

le b

lin

din

g,

pa

rtia

lly

IT

T a

na

lysi

s

To

tal w

ith

dra

wa

ls a

nd

dro

po

uts

:

79

(1

5%

)

Fu

nd

ed

by

Op

tim

er

Ph

arm

ace

uti

cals

.

Inte

nti

on

-to

-tre

at

an

aly

sis:

mo

dif

ied

(su

bje

cts

wit

hd

raw

ing

be

fore

tre

atm

en

t, h

ad

≤3

bo

we

l m

oti

on

s in

24

ho

urs

,

or

test

ed

ne

ga

tiv

e f

or

C.

dif

fici

le t

oxi

n w

ere

exc

lud

ed

)

So

me

re

gio

na

l d

iffe

ren

ces

in t

he

cha

ract

eri

stic

s a

nd

re

spo

nse

s o

f p

ati

en

ts.

1S

tud

y d

esi

gn

ab

bre

via

tio

ns:

DB

= d

ou

ble

-blin

d,

RC

T =

ra

nd

om

ize

d t

ria

l, P

C =

pla

ceb

o-c

on

tro

lled

, P

G =

pa

rall

el -g

rou

p,

XO

= c

ross

ove

r. O

P=

op

en

la

be

l. 2

Re

sult

s a

bb

rev

iati

on

s: A

RR

= a

bso

lute

ris

k r

ed

uct

ion

, N

NT

= n

um

be

r n

ee

de

d t

o

tre

at,

NN

H =

nu

mb

er

ne

ed

ed

to

ha

rm,

CI

= c

on

fid

en

ce in

terv

al.

3N

NT

/NN

H a

re r

ep

ort

ed

on

ly f

or

sta

tist

ica

lly s

ign

ific

an

t re

sult

s 4Q

ua

lity

Ra

tin

g:

(Go

od

- lik

ely

va

lid,

Fa

ir-

like

ly v

alid

/po

ssib

ly v

alid

, P

oo

r- f

ata

l fla

w-n

ot

va

lid

)

CA

= c

on

com

ita

nt

an

tib

ioti

c, U

C=

ulc

era

tive

co

litis

, N

5=

nu

mb

er

ran

do

miz

ed

, 6

=d

ata

fro

m m

od

ifie

d in

ten

tio

n-t

o-t

rea

t p

op

ula

tio

n.

Cli

nic

al

Eff

ica

cy:

In o

ne

go

od

qu

ality

stu

dy a

nd

on

e f

air

qu

ality

stu

dy,

fid

axo

mic

in w

as

sho

wn

to

be

no

n-i

nfe

rio

r to

va

nco

myci

n t

ho

ug

h it

wa

s a

lso

sh

ow

n t

o h

ave

sig

nif

ica

ntl

y l

ow

er

rate

s o

f re

curr

en

ce a

nd

hig

he

r ra

tes

of

glo

ba

l cu

re.

Stu

dy 0

03

en

roll

ed

su

bje

cts

in t

he

US a

nd

Ca

na

da

, w

hil

e s

tud

y 0

04

en

roll

ed

sub

ject

s in

Ca

na

da

, th

e U

S,

an

d E

uro

pe

. P

ati

en

ts w

ith

se

ve

re,

com

pli

cate

d C

DA

D w

ere

exc

lud

ed

fro

m t

he

cli

nic

al tr

ials

. C

lin

ica

l cu

re w

as

the

pri

nci

pa

l co

mp

ari

son

ou

tco

me

be

twe

en

tw

o t

rea

tme

nts

.9 C

lin

ica

l cu

re w

as

de

fin

ed

as

thre

e o

r le

ss u

nfo

rme

d s

too

ls f

or

2 c

on

secu

tive

da

ys,

wit

h

ma

inte

na

nce

of

reso

luti

on

fo

r th

e d

ura

tio

n o

f th

era

py a

nd

no

fu

rth

er

req

uir

em

en

t fo

r th

era

py a

s o

f th

e s

eco

nd

da

y a

fte

r th

e e

nd

tre

atm

en

t

(10

da

ys)

.9 R

esu

lts

for

tria

l (0

03

) p

ub

lish

ed

by

Lou

ie e

t a

l.,

sho

we

d c

lin

ica

l cu

re r

ate

in

mo

dif

ied

in

ten

t-to

-tre

at

(mIT

T)

po

pu

lati

on

at

88

.2%

(2

53

/28

7)

in f

ida

xom

icin

gro

up

co

mp

are

d t

o 8

5.8

% (

26

5/3

09

) in

va

nco

myci

n g

rou

p (

RR

0.9

7;

95

% C

I 0

.91

to

1.0

4).

4 T

he

lo

we

r b

ou

nd

ary

of

the

97

.5%

co

nfi

de

nce

inte

rva

l fo

r th

e d

iffe

ren

ce o

f cu

re r

ate

s w

as

at

-3.1

% p

oin

ts;

the

refo

re f

ida

xom

icin

me

t th

e n

on

-in

feri

ori

ty c

rite

ria

. 9 T

he

re

sult

s fr

om

tri

al (0

04

)

sho

we

d t

ha

t cu

re r

ate

fo

r fi

da

xom

icin

gro

up

wa

s a

t 8

6%

(2

17

/25

3)

com

pa

red

to

85

% (

21

9/2

56

) in

va

nco

myci

n g

rou

p,

resp

ect

ive

ly.5

,9

In S

tud

y 0

03

, S

ub

gro

up

an

aly

ses

of

the

ra

tes

of

clin

ica

l cu

re a

cco

rdin

g t

o t

he

pa

tie

nts

’ a

ge

, in

pa

tie

nt

vs.

ou

tpa

tie

nt

sta

tus,

pri

or

occ

urr

en

ce,

tre

atm

en

t fo

r C

dif

fici

le in

fect

ion

vs.

no

tre

atm

en

t w

ith

in 2

4 h

ou

rs b

efo

re t

he

sta

rt o

f th

e t

ria

l, n

o r

esp

on

se v

s. r

esp

on

se t

o p

revio

us

me

tro

nid

azo

le

the

rap

y a

nd

use

vs.

no

nu

se o

f co

nco

mit

an

t sy

ste

mic

an

tim

icro

bia

l th

era

py s

ho

we

d n

o s

ign

ific

an

t d

iffe

ren

ces

be

twe

en

tre

atm

en

ts.

In t

ria

l 0

04

,

mo

re p

ati

en

ts w

ho

re

ceiv

ed

co

nco

mit

an

t a

nti

bio

tics

fo

r o

the

r in

fect

ion

s d

uri

ng

th

e s

tud

y t

rea

tme

nt

pe

rio

d a

chie

ved

clin

ica

l cu

re w

ith

fid

axo

mic

in

tha

n w

ith

va

nco

myci

n (

90

.2%

in

fid

axo

mic

in v

s. 7

3.3

% i

n v

an

com

yci

n;

p=

0.0

31

).

Fo

r th

e s

eco

nd

ary

en

dp

oin

ts o

f re

curr

en

ce a

nd

su

sta

ine

d

53 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

7 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

resp

on

se,

fid

axo

mic

in w

as

sta

tist

ica

lly s

up

eri

or

to v

an

com

yin

on

ly f

or

pa

tie

nts

re

ceiv

ing

no

co

nco

mit

an

t a

nti

bio

tics

du

rin

g t

he

stu

dy.

A f

oll

ow

-up

stu

dy c

om

bin

ed

th

e r

esu

lts

of

the

se t

ria

ls t

o i

nve

stig

ate

th

e a

sso

cia

tio

n b

etw

ee

n c

on

com

ita

nt

use

of

an

tib

ioti

cs (

CA

) a

nd

re

curr

en

ce r

ate

s.1

0

An

aly

sis

of

the

po

ole

d p

ha

se I

II d

ata

, d

em

on

stra

ted

th

at

recu

rre

nce

ra

tes

we

re l

ow

er

wh

en

pa

tie

nts

wh

o r

eq

uir

ed

CA

we

re g

ive

n f

ida

xom

icin

; a

hig

he

r ra

te w

as

see

n in

pa

tie

nts

on

an

tib

ioti

cs h

isto

rica

lly a

sso

cia

ted

wit

h a

hig

h r

isk o

f C

DI

recu

rre

nce

. U

se o

f co

nco

mit

an

t a

nti

bio

tics

an

d C

DI

tre

atm

en

t w

as

ass

oci

ate

d w

ith

a lo

we

r cu

re r

ate

, 8

0%

in

co

nco

mit

an

t a

nti

bio

tic

use

rs v

ers

us

93

% o

f n

on

use

rs (

P<

0.0

01

). C

lin

ica

l cu

re r

ate

s in

th

e

PP

an

aly

sis

we

re 8

7%

in

co

nco

mit

an

t a

nti

bio

tic

use

rs a

nd

93

% i

n n

on

use

rs i

n t

he

fid

axo

mic

in g

rou

p,

an

d 7

7%

in

co

nco

mit

an

t a

nti

bio

tic

use

rs a

nd

94

% i

n n

on

use

rs i

n t

he

va

nco

myci

n g

rou

p.1

0

In

stu

dy 0

03

, th

ere

wa

s n

o s

ign

ific

an

t d

iffe

ren

ce in

me

an

da

ys

to r

eso

luti

on

of

dia

rrh

ea

(V

an

com

ycin

me

dia

n 3

.3 d

ays

vs.

Fid

axo

mic

in 2

.4 d

ays;

p=

NS

).

An

d t

he

re w

as

no

sig

nif

ica

nt

dif

fere

nce

in

all

-ca

use

mo

rta

lity

(7

% i

n v

an

com

yci

n g

rou

p v

s. 5

% i

n f

ida

xom

icin

gro

up

).

Th

e m

ajo

rity

of

pa

tie

nts

en

roll

ed

in

th

e c

lin

ica

l tr

ials

we

re in

pa

tie

nts

an

d t

he

BI/

NA

P1

/02

7 s

tra

in c

om

pri

sed

ap

pro

xim

ate

ly 4

0%

of

all

iso

late

s.

Aro

un

d 4

0%

of

pa

tie

nts

in

th

e 0

03

tri

al a

nd

30

% i

n t

he

00

4 t

ria

l w

ere

ou

tpa

tie

nt.

In

pa

tie

nts

wit

h t

he

hyp

er-

vir

ule

nt

stra

in,

the

re w

as

no

sig

nif

ica

nt

dif

fere

nce

in

recu

rre

nce

ra

te in

eit

he

r st

ud

y (

fid

axo

mic

in 2

7.1

% v

s. v

an

com

yci

n 2

0.9

%,

p=

0.4

2 in

stu

dy

00

3,

an

d 2

2.2

% v

s. 3

8%

, p

=0

.07

9 i

n s

tud

y 0

04

).

Sa

fety

:

Ad

ve

rse

eve

nts

we

re n

ot

sig

nif

ica

ntl

y d

iffe

ren

t b

etw

ee

n f

ida

xom

icin

an

d v

an

com

yci

n g

rou

ps.

Th

e o

ccu

rre

nce

of

an

y s

eri

ou

s a

dve

rse

eve

nt

wa

s a

t

25

% i

n f

ida

xom

icin

gro

up

co

mp

are

d t

o 2

4.1

% i

n v

an

com

yci

n g

rou

p in

stu

dy 0

03

.1,4

Ho

we

ve

r, t

he

fid

axo

mic

in g

rou

p h

ad

sig

nif

ica

ntl

y m

ore

ad

ve

rse

eve

nts

re

late

d t

o l

ab

ora

tory

te

sts

at

4.7

% c

om

pa

red

to

va

nco

myci

n g

rou

p a

t 1

.2%

(P

=0

.01

). A

cco

rdin

g t

o a

FD

A m

ed

ica

l re

vie

w,

wh

ich

lo

oke

d a

t

da

ta f

rom

bo

th p

ha

se I

II t

ria

ls,

seri

ou

s a

dve

rse

eve

nts

occ

urr

ed

at

rate

of

25

.7%

in

fid

axo

mic

in t

rea

ted

in

div

idu

als

co

mp

are

d t

o 2

3.2

% i

n

va

nco

myci

n p

ati

en

ts.9

Th

e t

hre

e s

eve

re a

dve

rse

eff

ect

s th

at

occ

urr

ed

mo

re f

req

ue

ntl

y i

n f

ida

xom

icin

gro

up

we

re g

ast

roin

test

ina

l h

em

orr

ha

ge

,

me

ga

colo

n a

nd

de

cre

ase

in

WB

C c

ou

nts

. A

rou

nd

3 p

ati

en

ts d

eve

lop

ed

me

ga

colo

n in

fid

axo

mic

in g

rou

p c

om

pa

red

to

no

ne

in

va

nco

myci

n.

Th

e m

ost

com

mo

n a

dve

rse

eve

nts

re

po

rte

d i

n b

oth

gro

up

s d

uri

ng

ph

ase

III

tri

als

we

re n

au

sea

, vo

mit

ing

, h

yp

oka

lem

ia,

he

ad

ach

e,

ab

do

min

al p

ain

, d

iarr

he

a,

con

stip

ati

on

an

d p

yre

xia

. T

he

in

cid

en

ce o

f a

bd

om

ina

l p

ain

, co

nst

ipa

tio

n a

nd

hyp

oka

lem

ia w

as

hig

he

r in

fid

axo

mic

in g

rou

p.

In a

dd

itio

n,

the

ra

te o

f

de

ath

s in

bo

th p

ha

se I

II t

ria

ls w

as

sim

ila

r fo

r b

oth

gro

up

s. A

rou

nd

36

pe

op

le d

ied

in

fid

axo

mic

in g

rou

p (

6.4

%)

com

pa

red

to

38

in

va

nco

myci

n g

rou

p

(6.5

%).

9

54 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

8 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

Ta

ble

3.

Ad

ve

rse

ev

en

t co

mp

ari

son

be

twe

en

fid

ax

om

icin

an

d v

an

com

yci

n1

,9

F

ida

xo

mic

in

(N=

56

4)

Va

nco

my

cin

(N=

58

3)

An

em

ia

14

(2

.5%

) 1

2 (

2.1

%)

Ne

utr

op

en

ia

14

(2

.5%

) 6

(1

.0%

)

Lym

ph

op

en

ia

11

(1

.9%

) 5

(0

.9%

)

Ga

stro

inte

stin

al h

em

orr

ha

ge

2

0 (

3.5

%)

12

(2

.1%

)

Na

use

a

62

(1

1%

) 6

6 (

11

.3%

)

Vo

mit

ing

4

1 (

7.3

%)

37

(6

.3%

)

Co

nst

ipa

tio

n

25

(4

.4%

) 1

2 (

2.1

%)

Dia

rrh

ea

2

8 (

5%

) 3

9 (

6.7

%)

Ab

do

min

al p

ain

3

3 (

5.9

%)

23

(3

.9%

)

Hyp

oka

lem

ia

47

(8

.3%

) 3

8 (

6.5

%)

He

ad

ach

e

37

(6

.6%

) 2

7 (

4.6

%)

Pyre

xia

2

4 (

4.3

%)

31

(5

.3%

)

Pre

cau

tio

ns/

Co

ntr

ain

dic

ati

on

s:

Cu

rre

ntl

y t

he

re a

re n

o c

on

tra

ind

ica

tio

ns

list

ed

fo

r fi

da

xom

icin

. T

he

dru

g s

ho

uld

no

t b

e u

sed

fo

r sy

ste

mic

in

fect

ion

s. A

lso

, fi

da

xom

icin

sh

ou

ld b

e

on

ly u

sed

fo

r tr

ea

tme

nt

of

C.d

iffi

cile

ass

oci

ate

d in

fect

ion

in

ord

er

to a

vo

id b

act

eri

a r

esi

sta

nce

. 1

To

lera

bil

ity

:

Acc

ord

ing

to

th

e F

DA

re

vie

w,

a t

ota

l o

f 5

7 p

ati

en

ts (

10

.1%

) in

fid

axo

mic

in g

rou

p a

nd

58

pa

tie

nts

(9

.9%

) in

va

nco

myci

n g

rou

p w

ere

wit

hd

raw

n f

rom

ph

ase

III

tri

als

du

e t

o t

rea

tme

nt

fail

ure

or

ad

ve

rse

eve

nts

.9 D

uri

ng

tre

atm

en

t p

ha

se in

bo

th p

ha

se I

II t

ria

ls t

he

re w

ere

22

pa

tie

nts

(3

.9%

) in

fid

axo

mic

in g

rou

p a

nd

36

pa

tie

nts

(6

.2%

) in

va

nco

my

cin

gro

up

wh

o s

top

pe

d t

he

dru

g d

ue

to

ad

ve

rse

eve

nt.

Aro

un

d 2

2 p

ati

en

ts (

3.9

%)

takin

g

fid

axo

mic

in a

nd

17

pa

tie

nts

(2

.9%

) ta

kin

g v

an

com

yci

n h

ad

dis

con

tin

ue

d t

he

rap

y d

uri

ng

fo

llo

w-u

p in

bo

th p

ha

se I

II t

ria

ls.

9

Pre

gn

an

cy/L

act

ati

on

ra

tin

g:

Pre

gn

an

cy c

ate

go

ry B

ba

sed

fro

m a

nim

al st

ud

ies.

Ho

we

ve

r, n

o s

tud

ies

in p

reg

na

nt

wo

me

n w

ere

do

ne

. T

he

refo

re,

the

ma

nu

fact

ure

r re

com

me

nd

s

usi

ng

th

e d

rug

du

rin

g p

reg

na

ncy

on

ly i

f cl

ea

rly n

ee

de

d.

It i

s u

nkn

ow

n if

fid

axo

mic

in i

s e

xcre

ted

in

mil

k.

Nu

rsin

g w

om

en

sh

ou

ld u

se t

he

dru

g w

ith

cau

tio

n.

1

55 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

9 A

utho

r: D

mitr

iy S

imet

s, P

harm

.D. C

andi

date

, Me

gan

Her

ink,

Pha

rm.D

.

Do

se I

nd

ex

(e

ffic

acy

/to

xic

):

Th

e g

rea

test

eff

ica

cy i

n C

DI

tre

atm

en

t w

as

est

ab

lish

ed

wit

h f

ida

xom

icin

20

0m

g t

wic

e d

ail

y i

n p

ha

se I

I tr

ial.

No

dru

g-r

ela

ted

ad

ve

rse

eff

ect

s w

ere

see

n in

do

gs

do

sed

wit

h f

ida

xom

icin

ta

ble

ts a

t 9

60

0 m

g/d

ay.

9

Loo

k-a

lik

e /

So

un

d-a

lik

e (

LA/S

A)

Err

or

Ris

k P

ote

nti

al:

LA/S

A n

am

es

are

ass

ess

ed

du

rin

g t

he

PD

L se

lect

ion

of

dru

gs.

B

ase

d o

n c

lin

ica

l ju

dg

me

nt

an

d a

n e

va

lua

tio

n o

f LA

/SA

in

form

ati

on

fro

m f

ou

r d

ata

sou

rce

s (L

exi

-Co

mp

, U

SP

On

lin

e L

AS

A F

ind

er,

Fir

st D

ata

ba

nk,

an

d I

SM

P C

on

fuse

d D

rug

Na

me

Lis

t),

the

fo

llo

win

g d

rug

na

me

s m

ay c

au

se L

AS

A

con

fusi

on

:

NM

E D

rug

Na

me

Le

xi-

Co

mp

U

SP

On

lin

e

Fir

st D

ata

Ba

nk

IS

MP

C

lin

ica

l Ju

dg

me

nt

LA/S

A f

or

[F

ida

xom

icin

] N

on

e I

de

nti

fie

d

No

ne

Id

en

tifi

ed

N

on

e i

de

nti

fie

d

No

ne

Id

en

tifi

ed

F

ilg

rast

im

LA/S

A f

or

[D

ific

id]

No

ne

Id

en

tifi

ed

N

on

e I

de

nti

fie

d

No

ne

id

en

tifi

ed

N

on

e I

de

nti

fie

d

Dif

ira

m,

Dif

il-G

, D

ila

ud

id,

Dil

aco

r

XR

, D

en

avir

, D

yna

cin

, D

iflo

sid

,

Dig

ifa

b,

All

erg

ies/

Inte

ract

ion

s:

Dru

g-D

rug

: F

ida

xom

icin

is

po

orl

y a

bso

rbe

d a

nd

me

tab

oli

zed

pri

ma

rily

by e

ste

rase

to

an

act

ive

me

tab

oli

te.

Th

ere

are

no

kn

ow

n d

rug

s in

th

e m

ark

et

tha

t ca

use

clin

ica

lly r

ele

va

nt

dru

g i

nte

ract

ion

s b

y i

nh

ibit

ing

est

era

ses;

th

ere

fore

th

e i

nh

ibit

ion

of

me

tab

oli

sm o

f fi

da

xom

icin

is

no

t a

nti

cip

ate

d.

Fid

axo

mic

in a

nd

its

ma

in m

eta

bo

lite

are

su

bst

rate

s o

f p

-gly

cop

rote

in.

Ba

sed

on

in

viv

o s

tud

ies

it w

as

con

clu

de

d t

ha

t n

o d

ose

ad

just

me

nt

is

wa

rra

nte

d w

he

n f

ida

xom

icin

is

co-a

dm

inis

tere

d w

ith

su

bst

rate

s o

f p

-gly

cop

rote

in o

r C

YP

en

zym

es.

Als

o,

fid

axo

mic

in m

ay b

e c

o-a

dm

inis

tere

d w

ith

p-g

lyco

pro

tein

in

hib

ito

rs w

ith

ou

t d

ose

ad

just

me

nt.

1

Fo

od

-Dru

g:

Fid

axo

mic

in m

ay b

e t

ake

n w

ith

or

wit

ho

ut

foo

d.

1

Do

se a

nd

Av

ail

ab

ilit

y: 1

ST

RE

NG

TH

F

OR

M

RO

UT

E

FR

EQ

UE

NC

Y

RE

NA

L

AD

J

HE

PA

TIC

AD

J

Pe

dia

tric

Do

se

Eld

erl

y

Do

se

OT

HE

R D

OS

ING

CO

NS

IDE

RA

TIO

NS

20

0m

g

Ta

ble

t O

ral

Tw

ice

da

ily

No

ne

N

on

e

No

t re

com

me

nd

ed

A

dju

stm

en

t n

ot

reco

mm

en

de

d

No

ne

56 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

10

Aut

hor:

Dm

itriy

Sim

ets,

Pha

rm.D

. Can

dida

te, M

ega

n H

erin

k, P

harm

.D.

Ap

pe

nd

ix 1

:

Ta

ble

1.

Ph

arm

aco

kin

eti

c co

mp

ari

son

of

fid

ax

om

icin

, m

etr

on

ida

zole

an

d v

an

com

yci

n.

Pa

ram

ete

rs

Fid

ax

om

icin

1

Me

tro

nid

azo

le1

1

Va

nco

cin

*1

2,1

3

Ro

ute

of

ad

min

istr

ati

on

O

ral

(PO

) O

ral

(PO

) O

ral

(PO

)

Ora

l b

ioa

va

ila

bil

ity

M

inim

al a

bso

rpti

on

fro

m G

I tr

act

8

0%

P

oo

rly a

bso

rbe

d

Cm

ax

(n

g/m

L)

5.2

0 +

2.8

1

Pro

tein

Bin

din

g

N/A

<

20

%

~ 5

0%

-55

%

Ha

lf-l

ife

(h

) 1

1.7

fo

r d

rug

,

11

.2 f

or

act

ive

me

tab

oli

te

~ 8

(r

an

ge

6-1

2)

Lon

ge

r in

ne

on

ate

s, h

ep

ati

c a

nd

ren

al

imp

air

me

nt.

4-6

Me

tab

oli

sm

Hyd

roly

sis

in in

test

ine

,

ha

s a

ctiv

e m

eta

bo

lite

He

pa

tic

(30

%-6

0%

) N

o a

pp

are

nt

me

tab

oli

sm

Eli

min

ati

on

F

ece

s (>

92

% u

nch

an

ge

d d

rug

, a

nd

me

tab

oli

tes)

.

Re

na

l (6

0%

-80

% a

s u

nch

an

ge

d

dru

g),

fe

ces

(6%

-15

%).

PO

(fe

ces)

Re

na

l Im

pa

irm

en

t D

ose

Ad

just

me

nt

No

t re

com

me

nd

ed

G

FR

<1

0m

L/m

in,

red

uce

no

rma

l

do

se b

y 5

0%

at

usu

al in

terv

al.

Re

com

me

nd

ed

He

pa

tic

Imp

air

me

nt

Do

se

Ad

just

me

nt

No

t e

va

lua

ted

R

eco

mm

en

de

d f

or

seve

re

imp

air

me

nt

N/A

Fo

od

eff

ect

on

ph

arm

aco

kin

eti

cs

No

t cl

inic

all

y s

ign

ific

an

t. M

ay t

ake

dru

g r

eg

ard

less

to

me

als

.

Low

ers

an

d d

ela

ys

pe

ak

con

cen

tra

tio

n.

No

eff

ect

on

to

tal

dru

g a

bso

rbe

d.

*T

he

pa

ren

tera

l fo

rm o

f S

teri

le V

an

com

yci

n H

yd

roch

lori

de

ma

y b

e a

dm

inis

tere

d o

rall

y fo

r tr

ea

tme

nt

of

an

tib

ioti

c-a

sso

cia

ted

psu

ed

om

em

bra

ne

ou

s

coli

tis

pro

du

ced

by C

. d

iffi

cile

. T

he

ap

pro

pri

ate

do

se m

ay b

e d

ilu

ted

in

1 o

z o

f w

ate

r a

nd

giv

en

to

th

e p

ati

en

t to

dri

nk.

Co

mm

on

fla

vo

rin

g s

yru

ps

ma

y b

e a

dd

ed

to

th

e s

olu

tio

n t

o i

mp

rove

th

e t

ast

e f

or

ora

l a

dm

inis

tra

tio

n.

Th

e d

ilu

ted

so

luti

on

ma

y b

e a

dm

inis

tere

d v

ia a

na

sog

ast

ric

tub

e.

57 of 108

Gen

eric

Nam

e: F

idax

omic

in

R

evie

w D

ate:

Ap

ril 2

012

11

Aut

hor:

Dm

itriy

Sim

ets,

Pha

rm.D

. Can

dida

te, M

ega

n H

erin

k, P

harm

.D.

Re

fere

nce

s:

1.

Dif

icid

® P

resc

rib

ing

In

form

ati

on

. O

pti

me

r P

ha

rma

ceu

tica

ls,

Inc.

Sa

n D

ieg

o,

CA

.

2.

McD

on

ald

L,

et

al.

Vit

al S

ign

s :

Pre

ve

nti

ng

Clo

stri

diu

m d

iffi

cile

In

fect

ion

s. C

en

ters

fo

r D

ise

ase

Co

ntr

ol

MM

WR

20

12

;61

:1-6

.

3.

Bu

tle

r M

, B

liss

D,

Dre

kon

ja D

, F

ilic

e G

, R

ect

or

T,

Ma

cDo

na

ld R

, W

ilt

T.

Eff

ect

ive

ne

ss o

f E

arl

y D

iag

no

sis,

Pre

ve

nti

on

, a

nd

Tre

atm

en

t o

f C

lost

rid

ium

dif

fici

le

Infe

ctio

n.

Co

mp

ara

tiv

e E

ffe

ctiv

en

ess

Re

vie

w N

o.

31

(P

rep

are

d b

y th

e M

inn

eso

ta E

vid

en

ce-b

ase

d P

ract

ice

Ce

nte

r u

nd

er

Co

ntr

act

No

. 2

90

-02

-00

09

.)

AH

RQ

Pu

bli

cati

on

No

. 1

1(1

2)-

EH

C0

51

-EF

. R

ock

vil

le,

MD

. A

ge

ncy

fo

r H

ea

lth

care

Re

sea

rch

an

d Q

ua

lity

. D

ece

mb

er

20

11

4.

Lou

ie T

.J.,

Mil

ler

M.A

., M

ulla

ne

K.M

., W

eis

s K

., L

en

tne

k A

., G

ola

n Y

., G

orb

ach

S.,

Se

ars

P.,

Sh

ue

Y.K

., F

ida

xom

icin

ve

rsu

s v

an

com

ycin

fo

r C

lost

rid

ium

dif

fici

le.

NE

JM,

20

11

; 3

64

: 4

22

-31

5.

Co

rne

ly O

l, C

roo

k D

r.,

Esp

osi

to R

., P

oir

ier

A.,

So

me

ro M

., S

ea

rs P

., e

t a

l.

Fid

axo

mic

in v

ers

us

va

nco

myc

in f

or

infe

ctio

n w

ith

Clo

stri

diu

m d

iffi

cile

in

Eu

rop

e,

Ca

na

da

, a

nd

th

e U

SA

: a

do

ub

le-b

lin

d,

no

n-i

nfe

rio

rity

, ra

nd

om

ize

d c

on

tro

lle

d t

ria

l.

Lan

cet

Infe

ct D

is.

Av

ail

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fif

th u

pd

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at

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reg

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alt

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an

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ir c

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clu

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are

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in

Ap

pe

nd

ix 1

.1 T

his

an

d o

the

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revio

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com

pa

rati

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eff

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ss r

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ha

ve

fo

un

d

tha

t se

con

d g

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ific

an

tly in

eff

ica

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f m

ajo

r d

ep

ress

ive

dis

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er

(MD

D).

Sin

ce t

he

la

st O

R r

evie

w,

ho

we

ve

r, a

ne

w a

nti

de

pre

ssa

nt,

vil

azo

do

ne

(V

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ha

s b

ee

n F

DA

ap

pro

ve

d a

nd

an

up

da

te t

o t

he

co

mp

ara

tive

eff

ect

ive

ne

ss r

evie

w o

n s

eco

nd

-

ge

ne

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on

an

tid

ep

ress

an

ts in

th

e t

rea

tme

nt

of

ad

ult

de

pre

ssio

n w

as

com

ple

ted

by t

he

Ag

en

cy f

or

He

alt

hca

re R

ese

arc

h a

nd

Qu

ali

ty (

AH

RQ

).3

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e

evid

en

ce-b

ase

d p

ract

ice

gu

ide

lin

es

en

do

rse

d b

y t

he

Am

eri

can

Psy

chia

tric

Ass

oci

ati

on

ha

ve

no

t b

ee

n u

pd

ate

d s

ince

20

10

fo

r th

e t

rea

tme

nt

of

ma

jor

59 of 108

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pre

ssiv

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iso

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his

up

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ill

exa

min

e t

he

pla

ce i

n t

he

rap

y f

or

vila

zod

on

e,

an

d id

en

tify

an

y o

the

r n

ew

re

leva

nt

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pa

rati

ve e

ffe

ctiv

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ess

evid

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ce,

hig

h-q

ua

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syst

em

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c re

vie

ws,

or

evid

en

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ase

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uid

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s.

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11

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rt r

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Do

se l

imit

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ave

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en

ad

vis

ed

.5,6

Issu

es:

Is

th

ere

an

y n

ew

evid

en

ce o

f e

ffe

ctiv

en

ess

or

ha

rms

tha

t w

ill

sup

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eco

nd

ge

ne

rati

on

an

tid

ep

ress

an

t m

an

ag

em

en

t st

rate

gie

s o

r ch

an

ge

s?

Is

th

ere

an

y e

vid

en

ce t

ha

t vil

azo

do

ne

is

mo

re e

ffe

ctiv

e o

r sa

fer

tha

n c

urr

en

tly a

va

ila

ble

me

dic

ati

on

s in

th

e P

DL

dru

g c

lass

in

clu

din

g s

ub

gro

up

s

of

pa

tie

nts

?

W

ha

t re

com

me

nd

ati

on

s fo

r m

an

ag

em

en

t o

f th

e a

nti

de

pre

ssa

nt

cla

ss c

an

be

ma

de

?

Sh

ou

ld a

do

se lim

it b

e in

clu

de

d f

or

cita

lop

ram

?

Co

ncl

usi

on

s

C

om

pa

rati

ve

eff

ica

cy a

nd

eff

ect

ive

ne

ss o

f se

con

d-g

en

era

tio

n a

nti

de

pre

ssa

nts

do

es

no

t d

iffe

r su

bst

an

tia

lly f

or

tre

ati

ng

pa

tie

nts

wit

h m

ajo

r

de

pre

ssiv

e d

iso

rde

r (M

DD

).

Th

ese

fin

din

gs

pe

rta

in t

o p

ati

en

ts i

n t

he

acu

te,

con

tin

ua

tio

n,

an

d m

ain

ten

an

ce p

ha

ses;

th

ose

wit

h a

cco

mp

an

yin

g

sym

pto

m c

lust

ers

; a

nd

su

bg

rou

ps

de

fin

ed

by a

ge

, se

x, e

thn

icit

y,

or

com

orb

id c

on

dit

ion

s, a

lth

ou

gh

on

ly s

pa

rse

evid

en

ce f

or

the

se f

ind

ing

s e

xist

s

for

sub

gro

up

s.

T

he

re i

s fa

ir q

ua

lity

evid

en

ce t

ha

t vil

azo

do

ne

is

safe

an

d e

ffe

ctiv

e f

or

the

tre

atm

en

t o

f M

DD

ba

sed

on

sh

ort

-te

rm p

lace

bo

co

ntr

oll

ed

tri

als

.

Th

ere

is

insu

ffic

ien

t e

vid

en

ce t

o d

ete

rmin

e c

om

pa

rati

ve

eff

ect

ive

ne

ss o

f vi

lazo

do

ne

co

mp

are

d t

o o

the

r a

nti

de

pre

ssa

nt

me

dic

ati

on

s.

T

he

re i

s in

suff

icie

nt

evid

en

ce t

o d

ete

rmin

e t

he

eff

ect

ive

ne

ss o

f vil

azo

do

ne

in

th

e m

ain

ten

an

ce t

rea

tme

nt

of

MD

D,

for

the

tre

atm

en

t o

f

ge

ne

ralize

d a

nxi

ety

dis

ord

er

or

oth

er

ind

ica

tio

ns,

as

we

ll a

s in

pe

dia

tric

pa

tie

nts

or

pa

tie

nts

wit

h s

eve

re h

ep

ati

c im

pa

irm

en

t.

C

ita

lop

ram

ca

use

s d

ose

-de

pe

nd

en

t Q

T in

terv

al

pro

lon

ga

tio

n.

Th

e F

DA

re

com

me

nd

s th

at

cita

lop

ram

sh

ou

ld n

o l

on

ge

r b

e p

resc

rib

ed

at

do

ses

gre

ate

r th

an

40

mg

pe

r d

ay.

Re

com

me

nd

ati

on

s:

1.

Ba

sed

up

on

cu

rre

nt

com

pa

rati

ve

eff

ect

ive

ne

ss r

ese

arc

h,

no

ch

an

ge

s a

re r

eco

mm

en

de

d f

or

the

se

con

d g

en

era

tio

n a

nti

de

pre

ssa

nt

pre

ferr

ed

dru

g c

lass

lis

t b

ase

d o

n s

afe

ty a

nd

eff

ica

cy.

Co

sts

sho

uld

be

re

vie

we

d in

exe

cuti

ve

se

ssio

n.

2.

Evid

en

ce d

oe

s n

ot

sup

po

rt s

up

eri

ori

ty o

f vil

azo

do

ne

ove

r o

the

r a

ge

nts

in

th

is d

rug

cla

ss.

Re

com

me

nd

th

at

is b

e l

iste

d a

s a

no

n-p

refe

rre

d

ag

en

t.

3.

Incl

ud

e a

do

se l

imit

of

40

mg

/da

y f

or

cita

lop

ram

.

4.

Du

e t

o t

he

ne

ed

fo

r vo

lun

tary

co

mp

lia

nce

wit

h t

he

PD

L fo

r th

is d

rug

cla

ss,

it i

s re

com

me

nd

ed

th

at

ed

uca

tio

na

l o

utr

ea

ch i

nte

rve

nti

on

s b

e

con

sid

ere

d in

th

e m

an

ag

em

en

t st

rate

gy.

1.

As

an

exa

mp

le,

aca

de

mic

de

tail

ing

ca

n b

e u

se t

o p

rom

ote

ap

pro

pri

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60 of 108

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ack

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Be

fore

th

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ph

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an

xie

ty d

iso

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dju

stm

en

t

dis

ord

er,

a

nd

p

rem

en

stru

al

dis

ord

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) w

as

lim

ite

d

to

tric

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ic

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ts

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a

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da

se

inh

ibit

ors

(M

AO

Is)

(wit

h

the

exc

ep

tio

n o

f p

rem

en

stru

al

dis

ord

er,

wh

ich

his

tori

call

y w

as

un

tre

ate

d).

TC

As

an

d M

AO

Is s

om

eti

me

s a

re r

efe

rre

d t

o a

s tr

ad

itio

na

l o

r fi

rst-

ge

ne

rati

on

an

tid

ep

ress

an

ts.

Th

ese

d

rug

s a

re o

fte

n a

cco

mp

an

ied

b

y m

ult

iple

si

de

e

ffe

cts

tha

t m

an

y p

ati

en

ts fi

nd

in

tole

rab

le;

e.g

., T

CA

s te

nd

to

ca

use

an

tich

oli

ne

rgic

eff

ect

s in

clu

din

g d

ry m

ou

th a

nd

eye

s, u

rin

ary

he

sita

ncy

, a

nd

so

me

tim

es

rete

nti

on

an

d c

on

stip

ati

on

an

d M

AO

Is h

ave

th

e p

ote

nti

al to

pro

du

ce h

ype

rte

nsi

ve

cri

sis

if t

ake

n a

lon

g w

ith

ce

rta

in f

oo

ds

or

die

tary

su

pp

lem

en

ts c

on

tain

ing

exc

ess

ive

am

ou

nts

of

tyra

min

e.

Th

us,

fir

st-

ge

ne

rati

on

an

tid

ep

ress

an

ts a

re n

o lo

ng

er

ag

en

ts o

f ch

oic

e i

n m

an

y c

ircu

mst

an

ces.

Ne

we

r tr

ea

tme

nts

in

clu

de

se

lect

ive

se

roto

nin

re

up

take

in

hib

ito

rs (

SS

RIs

), s

ero

ton

in a

nd

no

rep

ine

ph

rin

e r

eu

pta

ke

in

hib

ito

rs (

SN

RIs

), a

nd

oth

er

seco

nd

-ge

ne

rati

on

dru

gs

tha

t se

lect

ive

ly t

arg

et

ne

uro

tra

nsm

itte

rs.

In

19

87

, th

e U

S F

oo

d a

nd

Dru

g A

dm

inis

tra

tio

n (

FD

A)

ap

pro

ve

d t

he

fir

st S

SR

I,

flu

oxe

tin

e.

Sin

ce t

he

n,

five

oth

er

SS

RIs

ha

ve

be

en

in

tro

du

ced

: se

rtra

lin

e,

pa

roxe

tin

e,

cita

lop

ram

, fl

uvo

xam

ine

, a

nd

esc

ita

lop

ram

. T

he

SN

RIs

we

re

firs

t in

tro

du

ced

to

th

e m

ark

et

in 1

99

3 a

nd

in

clu

de

ve

nla

faxi

ne

, d

ulo

xeti

ne

, a

nd

mo

st r

ece

ntl

y d

esv

en

lafa

xin

e.

Oth

er

ag

en

ts u

sed

fo

r tr

ea

tme

nt

of

MD

D i

ncl

ud

e,

ne

fazo

do

ne

,mir

taza

pin

e,

an

d b

up

rop

ion

.

In g

en

era

l, t

he

se d

rug

s w

ork

th

rou

gh

th

eir

eff

ect

on

pro

min

en

t n

eu

rotr

an

smit

ters

in

th

e c

en

tra

l n

erv

ou

s sy

ste

m.

Th

e S

SR

Is a

ct b

y s

ele

ctiv

ely

inh

ibit

ing

th

e r

eu

pta

ke

of

sero

ton

in (

5-h

yd

roxy

-try

pta

min

e,

5-H

T)

at

the

pre

syn

ap

tic

ne

uro

na

l m

em

bra

ne

. T

he

SN

RIs

are

po

ten

t in

hib

ito

rs o

f

sero

ton

in a

nd

no

rep

ine

ph

rin

e r

eu

pta

ke

an

d w

ea

k i

nh

ibit

ors

of

do

pa

min

e r

eu

pta

ke

. M

irta

zap

ine

, so

me

tim

es

cha

ract

eri

zed

as

an

SN

RI,

is

be

lie

ve

d t

o

en

ha

nce

ce

ntr

al

no

rad

ren

erg

ic a

nd

se

roto

ne

rgic

act

ivit

y a

s a

5-H

T2

an

d 5

-HT

3 r

ece

pto

r a

nta

go

nis

t, n

efa

zod

on

e i

s b

elie

ve

d t

o i

nh

ibit

ne

uro

na

l

up

take

of

sero

ton

in a

nd

no

rep

ine

prh

ine

, a

nd

bu

pro

pio

n i

s a

re

lati

ve

ly w

ea

k i

nh

ibit

or

of

the

ne

uro

na

l u

pta

ke

of

no

rep

ine

ph

rin

e,

sero

ton

in,

an

d

do

pa

min

e.

Th

e r

ece

ntl

y a

pp

rove

d a

nti

de

pre

ssa

nt,

vil

azo

do

ne

, co

mb

ine

s p

rop

ert

ies

of

a S

SR

I w

ith

5-h

yd

roxy

tryp

tam

ine

-1a

(5

-HT

1a)

pa

rtia

l a

go

nis

t

act

ivit

y.

Ho

we

ve

r, t

he

cli

nic

al

sig

nif

ica

nce

of

this

du

al

me

cha

nis

m i

s u

nkn

ow

n a

nd

it

ha

s n

ot

be

en

sh

ow

n t

o o

ffe

r a

ny u

niq

ue

eff

ica

cy o

r sa

fety

ad

va

nta

ge

ove

r cu

rre

ntl

y a

va

ila

ble

tre

atm

en

ts.

Vil

azo

do

ne

is

on

ly a

pp

rove

d a

nd

stu

die

d i

n t

he

tre

atm

en

t o

f M

DD

, w

hil

e o

the

r a

pp

rove

d s

eco

nd

ge

ne

rati

on

an

tid

ep

ress

an

ts h

ave

mu

ltip

le i

nd

ica

tio

ns

incl

ud

ing

GA

D,

soci

al

an

xie

ty d

iso

rde

r, p

an

ic d

iso

rde

r, o

bse

ssiv

e c

om

pu

lsiv

e d

iso

rde

r, a

nd

po

st t

rau

ma

tic

stre

ss d

iso

rde

r.

SS

RI’

s, S

NR

I’s,

an

d T

CA

’s a

re a

lso

fre

qu

en

tly r

eco

mm

en

de

d f

or

the

tre

atm

en

t o

f g

en

era

lize

d a

nxi

ety

dis

ord

er

(GA

D).

In

20

11

, th

e N

ati

on

al

Inst

itu

te

for

He

alt

h a

nd

Cli

nic

al

Exc

ell

en

ce (

NIC

E)

pu

bli

she

d a

gu

ide

lin

e o

n t

he

ma

na

ge

me

nt

of

ad

ult

s w

ith

GA

D i

n p

rim

ary

, se

con

da

ry a

nd

co

mm

un

ity

care

.7

Th

ese

gu

ide

lin

es

reco

mm

en

d t

ha

t if

dru

g t

rea

tme

nt

is n

ee

de

d,

the

mo

st c

ost

eff

ect

ive

SS

RI

sho

uld

be

pre

scri

be

d.

NIC

E s

pe

cifi

call

y r

eco

mm

en

ds

sert

ralin

e i

n t

he

UK

. I

f th

e f

irst

SS

RI

is n

ot

eff

ect

ive

, re

com

me

nd

ati

on

s in

clu

de

usi

ng

an

alt

ern

ati

ve S

SR

I o

r a

n S

NR

I, t

akin

g i

nto

acc

ou

nt

the

sid

e-

eff

ect

pro

file

an

d d

rug

in

tera

ctio

n p

ote

nti

al,

th

e r

isk o

f su

icid

e a

nd

to

xici

ty,

an

d t

he

te

nd

en

cy t

o p

rod

uce

a w

ith

dra

wa

l sy

nd

rom

e w

he

n c

ho

osi

ng

an

ap

pro

pri

ate

me

dic

ati

on

.

61 of 108

II.

Sy

ste

ma

tic

Re

vie

ws

AH

RQ

Co

mp

ara

tive

Eff

ect

ive

ne

ss R

evie

w

Th

e A

HR

Q r

evie

w a

sse

sse

d e

vid

en

ce o

n c

om

pa

rati

ve

be

ne

fits

an

d h

arm

s o

f se

con

d-g

en

era

tio

n a

nti

de

pre

ssa

nts

fo

r tr

ea

tin

g a

cute

, co

nti

nu

ati

on

,

an

d m

ain

ten

an

ce p

ha

ses

of

Ma

jor

De

pre

ssiv

e D

iso

rde

r.3

Ove

rall,

com

pa

rati

ve

eff

ica

cy a

nd

eff

ect

ive

ne

ss o

f se

con

d-g

en

era

tio

n a

nti

de

pre

ssa

nts

did

no

t d

iffe

r su

bst

an

tia

lly f

or

tre

ati

ng

pa

tie

nts

wit

h M

DD

. T

his

in

clu

de

d t

ho

se w

ith

acc

om

pa

nyin

g s

ymp

tom

clu

ste

rs;

an

d s

ub

gro

up

s d

efi

ne

d b

y a

ge

,

sex,

eth

nic

ity,

or

com

orb

id c

on

dit

ion

s, a

lth

ou

gh

on

ly s

pa

rse

evid

en

ce f

or

the

se f

ind

ing

s e

xist

s fo

r su

bg

rou

ps.

Th

ere

wa

s m

od

era

te q

ua

lity

of

evid

en

ce t

ha

t fo

r a

cute

ph

ase

tre

atm

en

t o

f M

DD

, cl

inic

al re

spo

nse

an

d r

em

issi

on

ra

tes

are

sim

ila

r a

mo

ng

se

con

d-

ge

ne

rati

on

an

tid

ep

ress

an

ts.

Co

nsi

ste

nt

resu

lts

fro

m 1

7 m

ost

ly f

air

-qu

ali

ty s

tud

ies

ind

ica

te t

ha

t th

e e

ffic

acy

of

seco

nd

-ge

ne

rati

on

an

tid

ep

ress

an

ts

reg

ard

ing

qu

ali

ty o

f li

fe d

oe

s n

ot

dif

fer

am

on

g d

rug

s. C

on

sist

en

t re

sult

s fr

om

7 f

air

-qu

ality

tri

als

su

gg

est

th

at

mir

taza

pin

e h

as

a s

tati

stic

all

y

sig

nif

ica

ntl

y f

ast

er

on

set

of

act

ion

th

an

cit

alo

pra

m,

flu

oxe

tin

e,

pa

roxe

tin

e,

an

d s

ert

ralin

e.

Wh

eth

er

this

dif

fere

nce

fa

vo

rin

g m

irta

zap

ine

ca

n b

e

ext

rap

ola

ted

to

oth

er

seco

nd

-ge

ne

rati

on

an

tid

ep

ress

an

ts is

un

cle

ar.

M

ost

oth

er

tria

ls d

o n

ot

ind

ica

te a

fa

ste

r o

nse

t o

f a

ctio

n o

f a

pa

rtic

ula

r

seco

nd

-ge

ne

rati

on

an

tid

ep

ress

an

t co

mp

are

d w

ith

an

oth

er.

T

he

re w

as

als

o m

od

era

te s

tre

ng

th e

vid

en

ce b

ase

d o

n 5

eff

ica

cy s

tud

ies

tha

t

de

mo

nst

rate

d n

o s

tati

stic

all

y s

ign

ific

an

t d

iffe

ren

ces

in p

reve

nti

ng

re

lap

se o

r re

curr

en

ce b

etw

ee

n e

scit

alo

pra

m a

nd

pa

roxe

tin

e,

flu

oxe

tin

e,

an

d

setr

ali

ne

, fl

uo

xeti

ng

an

d v

en

lafa

xin

e,

flu

vo

xam

ine

an

d s

ert

rali

ne

, a

nd

tra

zod

on

e a

nd

ve

nla

faxi

ne

. O

ve

rall

, th

ere

wa

s lo

w q

ua

lity

of

evid

en

ce

eva

lua

tin

g t

he

ma

na

ge

me

nt

of

tre

atm

en

t-re

sist

an

t d

ep

ress

ion

. R

esu

lts

fro

m 3

tri

als

su

pp

ort

mo

de

stly

be

tte

r re

spo

nse

an

d r

em

issi

on

ra

tes

for

ve

nla

faxi

ne

th

an

wit

h c

om

pa

rato

r, b

ut

dif

fere

nce

s w

ere

ge

ne

rall

y n

ot

sta

tist

ica

lly s

ign

ific

an

t.

Th

ere

wa

s h

igh

str

en

gth

of

evid

en

ce t

ha

t o

ve

rall

, a

dve

rse

eve

nts

pro

file

s a

re s

imil

ar

am

on

g s

eco

nd

-ge

ne

rati

on

an

tid

ep

ress

an

ts.

Dif

fere

nce

s e

xist

in

the

in

cid

en

ce o

f sp

eci

fic

ad

ve

rse

eve

nts

. D

isco

nti

nu

ati

on

ra

tes

we

re s

imila

r b

etw

ee

n S

SR

Is a

nd

oth

er

seco

nd

-ge

ne

rati

on

an

tid

ep

ress

an

ts (

15

% t

o

25

%).

D

ulo

xeti

ne

an

d v

en

lafa

xin

e h

ave

a h

igh

er

rate

of

dis

con

tin

ua

tio

n d

ue

to

ad

ve

rse

eve

nts

an

d v

en

lafa

xin

e h

as

a lo

we

r ra

te o

f d

isco

nti

nu

ati

on

du

e t

o l

ack

of

eff

ica

cy c

om

pa

red

to

th

e S

SR

I cl

ass

. T

he

re w

as

mo

de

rate

str

en

gth

evid

en

ce t

ha

t m

irta

zap

ine

ca

use

s g

rea

ter

we

igh

t g

ain

th

an

com

pa

rato

rs,

sert

ralin

e a

s a

hig

he

r in

cid

en

ce o

f d

iarr

he

a,

an

d t

razo

do

ne

ha

s a

hig

he

r ra

te o

f so

mn

ole

nce

th

an

co

mp

ara

tors

. T

he

re w

as

insu

ffic

ien

t

evid

en

ce t

o d

raw

co

ncl

usi

on

s o

n t

he

co

mp

ara

tive

ris

k f

or

suic

ida

lity

, ca

rdio

va

scu

lar

eve

nts

, o

r se

izu

res.

Li

mit

ati

on

s o

f th

is r

evie

w w

ere

th

at

mo

st

tria

ls w

ere

co

nd

uct

ed

in

hig

hly

se

lect

ed

po

pu

lati

on

s a

nd

we

re r

ela

tive

ly s

ho

rt-t

erm

tri

als

, p

ub

lica

tio

n b

ias

mig

ht

aff

ect

th

e e

stim

ate

s o

f so

me

com

pa

riso

ns,

an

d e

vid

en

ce w

ith

in s

ub

gro

up

s w

as

lim

ite

d.

Ove

rall

, 3

7%

of

pa

tie

nts

wit

h a

cute

-ph

ase

MD

D w

ho

re

ceiv

ed

fir

st-l

ine

tre

atm

en

t d

id n

ot

ach

ieve

re

spo

nse

wit

hin

6 t

o 1

2 w

ee

ks,

an

d 5

3%

did

no

t

ach

ieve

re

mis

sio

n.

Cu

rre

nt

evid

en

ce d

oe

s n

ot

wa

rra

nt

reco

mm

en

din

g a

pa

rtic

ula

r se

con

d-g

en

era

tio

n a

nti

de

pre

ssa

nt

on

th

e b

asi

s o

f d

iffe

ren

ces

in

eff

ica

cy o

r e

ffe

ctiv

en

ess

an

d d

iffe

ren

ces

in o

nse

t o

f a

ctio

n a

nd

ad

ve

rse

eve

nts

ma

y b

e c

on

sid

ere

d w

he

n c

ho

osi

ng

a m

ed

ica

tio

n.

A r

ece

nt

revie

w b

y t

he

Co

chra

ne

Co

lla

bo

rati

on

ass

ess

ed

th

e e

vid

en

ce o

n t

he

eff

ica

cy o

r m

irta

zap

ine

co

mp

are

d w

ith

oth

er

an

tid

ep

ress

ive

ag

en

ts in

the

acu

te-p

ha

se t

rea

tme

nt

of

MD

D a

nd

co

ncl

ud

ed

th

at

mir

taza

pin

e w

as

sig

nif

ica

ntl

y m

ore

eff

ect

ive

at

two

we

eks

tha

n S

SR

I’s

(OR

1.5

7,

95

% C

I 1

.3

to 1

.88

) a

nd

at

the

en

d o

f a

cute

-ph

ase

tre

atm

en

t (O

R 1

.19

, 9

5%

CI

1.0

1 t

o 1

.39

).

Mir

taza

pin

e w

as

als

o m

ore

eff

ect

ive

th

an

ve

nla

faxi

ne

at

two

62 of 108

we

eks

(OR

2.2

9,

95

% C

I 1

.45

to

3.5

9)

an

d a

t th

e e

nd

of

acu

te-p

ha

se t

rea

tme

nt

(OR

1.5

3,

95

% C

I 1

.03

to

2.2

5).

T

his

wa

s o

nly

ba

sed

on

tw

o t

ria

ls

wit

h a

to

tal

of

41

5 p

art

icip

an

ts.

Mir

taza

pin

e w

as

mo

re l

ike

ly t

o c

au

se w

eig

ht

ga

in,

incr

ea

sed

ap

pe

tite

, a

nd

so

mn

ole

nce

th

an

SS

RIs

bu

t le

ss l

ike

ly t

o

cau

se n

au

sea

or

vo

mit

ing

an

d s

exu

al d

ysf

un

ctio

n.

On

e p

ote

nti

al re

aso

n f

or

the

se d

iffe

ren

ces

in a

cute

-ph

ase

tre

atm

en

t o

f M

DD

is

a f

ast

er

on

set

of

act

ion

wh

en

co

mp

are

d t

o t

he

SS

RI’

s

III.

Ne

w D

rug

Re

vie

w

FD

A a

pp

rov

ed

in

dic

ati

on

s: V

ila

zod

on

e i

s a

se

lect

ive

se

roto

nin

re

up

take

in

hib

ito

r in

dic

ate

d f

or

the

tre

atm

en

t o

f m

ajo

r d

ep

ress

ive

dis

ord

er.

Cli

nic

al

Tri

al

Da

ta

Eff

ica

cy:

Th

e e

ffic

acy

of

vil

azo

do

ne

wa

s e

sta

bli

she

d in

tw

o P

ha

se I

II s

ho

rt t

erm

(e

igh

t-w

ee

k),

ra

nd

om

ize

d,

pla

ceb

o-c

on

tro

lle

d,

mu

ltic

en

ter

stu

die

s

usi

ng

a d

ose

tit

rate

d u

p t

o 4

0 m

g/d

ay.8

,9 T

he

tri

als

in

clu

de

d a

to

tal o

f 8

91

ad

ult

pa

tie

nts

(a

ge

s 1

8-7

0 y

ea

rs)

me

eti

ng

DSM

-IV

-TR

cri

teri

a f

or

MD

D,

sin

gle

ep

iso

de

or

recu

rre

nt.

T

ab

le 2

pro

vid

es

a s

um

ma

ry o

f th

e e

vid

en

ce f

ind

ing

s fo

r th

e t

wo

stu

die

s.

Th

ere

are

no

he

ad

-to

-he

ad

co

mp

ara

tive

tria

ls w

ith

an

y o

the

r a

nti

de

pre

ssa

nts

. T

he

pri

ma

ry m

ea

sure

use

d t

o e

va

lua

te e

ffic

acy

wa

s th

e M

on

tgo

me

ry-A

sbe

rg D

ep

ress

ion

Ra

tin

g S

cale

(MA

DR

S).

T

his

sca

le m

ea

sure

s th

e e

ffe

ct o

f tr

ea

tme

nt

on

de

pre

ssio

n s

eve

rity

by m

ea

suri

ng

th

e s

eve

rity

of

a n

um

be

r o

f sy

mp

tom

s a

t b

ase

lin

e a

nd

du

rin

g t

he

co

urs

e o

f tr

ea

tme

nt.

T

he

se s

ym

pto

ms

incl

ud

e m

oo

d a

nd

sa

dn

ess

, te

nsi

on

, sl

ee

p,

ap

pe

tite

, e

ne

rgy,

con

cen

tra

tio

n,

suic

ida

l id

ea

tio

n,

an

d

rest

less

ne

ss.

Lim

ite

d i

nfo

rma

tio

n i

s a

va

ila

ble

de

fin

ing

a c

lin

ica

lly m

ea

nin

gfu

l ch

an

ge

in

th

e M

AD

RA

S s

core

. M

ea

sure

me

nts

we

re c

on

du

cte

d a

t

ba

seli

ne

an

d w

ee

ks

1,

2,

3,

6 a

nd

8.

Bo

th s

tud

ies

de

mo

nst

rate

d a

sig

nif

ica

nt

imp

rove

me

nt

in p

ati

en

ts o

n v

ila

zod

on

e a

cco

rdin

g t

o t

he

MA

DR

S s

cale

com

pa

red

to

pla

ceb

. T

he

le

ast

-sq

ure

s m

ea

n d

iffe

ren

ce b

etw

ee

n g

rou

ps

in c

ha

ng

e f

rom

ba

selin

e in

on

e s

tud

y (t

ria

l 0

7)

wa

s -2

.5 (

SE

= 0

.96

; 9

5%

CI,

-

4.4

to

-0

.6;

p=

0.0

09

).

In t

he

se

con

d s

tud

y (

tria

l 0

4)

the

le

ast

sq

ua

res

me

an

dif

fere

nce

fro

m p

lace

bo

in

ch

an

ge

fro

m b

ase

lin

e w

as

-3.2

(S

E=

0.9

9;

95

%

CI,

-5

.1 t

o -

1.2

; p

=0

.00

1).

In

th

e s

eco

nd

tri

al,

pa

tie

nts

we

re a

llo

we

d t

o s

tay o

n t

he

20

mg

/da

y d

ose

if

the

y c

ou

ld n

ot

tole

rate

40

mg

/da

y.

Fo

rty-o

ne

pa

tie

nts

we

re m

ain

tain

ed

on

th

is d

ose

du

e t

o r

ea

son

s o

f in

tole

rab

ilit

y (

28

in

vil

azo

do

ne

gro

up

an

d 1

3 in

pla

ceb

o g

rou

p).

Vil

azo

do

ne

ha

s a

lso

be

en

stu

die

d in

fiv

e,

8-w

ee

k P

ha

se I

I st

ud

ies

in p

ati

en

ts w

ith

MD

D (

no

ne

are

fu

lly p

ub

lish

ed

). T

hre

e o

f th

ese

stu

die

s in

clu

de

d

act

ive

co

mp

ara

tors

(fl

uo

xeti

ne

or

cita

lop

ram

) a

nd

all

use

d t

he

ch

an

ge

fro

m b

ase

lin

e t

o e

nd

po

int

on

th

e H

am

ilto

n D

ep

ress

ion

Ra

tin

g S

cale

(H

AM

-

D1

7)

as

the

pri

ma

ry e

nd

po

int.

T

he

se s

tud

ies

eva

lua

ted

vil

azo

do

ne

do

ses

ran

gin

g f

rom

5 t

o 1

00

mg

/da

y,

wit

h m

ost

pa

tie

nts

do

sed

at !"#!$

%&'()

(ho

we

ve

r o

nly

tw

o u

sed

fix

ed

-do

se d

esi

gn

s th

at

we

re i

nfo

rma

tive

ab

ou

t d

ose

re

spo

nse

).

No

sta

tist

ica

lly s

ign

ific

an

t d

iffe

ren

ces

we

re o

bse

rve

d

be

twe

en

vil

azo

do

ne

an

d p

lace

bo

or

be

twe

en

th

e a

ctiv

e c

om

pa

rato

r a

nd

pla

ceb

o in

th

e I

TT

an

aly

ses.

Sa

fety

an

d T

ole

rab

ilit

y:

Co

mm

on

ly o

bse

rve

d a

dve

rse

eff

ect

s (i

nci

de

nce

*+,!(-'!(.!/0(1.!.2340!.50!6(.0!78!9/(40:7;

incl

ud

e:

dia

rrh

ea

(2

8%

vil

azo

do

ne

vs

9%

pla

ceb

o),

na

use

a (

23

% v

ila

zod

on

e v

s 5

% p

lace

bo

), v

om

itin

g (

5%

vil

azo

do

ne

vs

1%

pla

ceb

o),

an

d in

som

nia

(6

% v

ila

zod

on

e v

s 2

%

pla

ceb

o).

Th

e g

ast

roin

test

ina

l a

dve

rse

eve

nts

an

d i

nso

mn

ia t

en

d t

o o

ccu

r e

arl

y in

tre

atm

en

t.

Oth

er

ad

ve

rse

eve

nts

wit

h a

n i

nci

de

nce

of

at

lea

st 2

%

an

d a

t le

ast

tw

ice

th

e p

lace

bo

ra

te in

clu

de

: g

ast

roe

nte

riti

s, p

are

sth

esi

a,

tre

mo

r, a

bn

orm

al d

rea

ms,

re

stle

ssn

ess

, d

ecr

ea

sed

lib

ido

, a

bn

orm

al

org

asm

, d

ela

ye

d e

jacu

lati

on

, e

rect

ile

dysf

un

ctio

n,

fee

lin

g j

itte

ry,

pa

lpit

ati

on

s, a

nd

in

cre

ase

d a

pp

eti

te.

63 of 108

Ph

arm

aco

log

y:

Vil

azo

do

ne

is

an

in

do

lakly

lam

ine

th

at

bin

ds

wit

h h

igh

aff

init

y t

o t

he

se

roto

nin

re

up

take

sit

e (

SS

RI)

. I

t a

lso

ha

s h

igh

aff

init

y f

or

5H

T1

a R

ece

pto

rs a

nd

is

a 5

HT

1A

re

cep

tor

pa

rtia

l a

go

nis

t. T

he

me

cha

nis

m o

f a

nti

de

pre

ssa

nt

eff

ect

is

no

t kn

ow

n b

ut

is t

ho

ug

ht

to b

e r

ela

ted

to

en

ha

nce

me

nt

of

sero

ton

erg

ic a

ctiv

ity in

th

e c

en

tra

l n

erv

ou

s sy

ste

m t

hro

ug

h i

ts S

SR

I e

ffe

ct.

Th

e n

et

eff

ect

of

the

pa

rtia

l a

go

nis

t a

ctiv

ity i

s n

ot

kn

ow

n.

Co

nsi

de

rati

on

in

Su

bp

op

ula

tio

ns:

Pe

dia

tric

s: V

ila

zod

on

e h

as

no

t b

ee

n s

tud

ied

in

pa

tie

nts

le

ss t

ha

n 1

8 y

ea

rs o

f a

ge

.

Ge

ria

tric

s:

Vila

zod

on

e h

as

no

t b

ee

n s

tud

ied

in

pa

tie

nts

old

er

tha

n 7

0 y

ea

rs o

f a

ge

. N

o d

ose

ad

just

ed

is

ne

cess

ary

fo

r re

na

l im

pa

irm

en

t o

r m

ild

to

mo

de

rate

he

pa

tic

imp

air

me

nt.

P

ati

en

ts w

ith

se

vere

he

pa

tic

imp

air

me

nt

ha

ve

no

t ye

t b

ee

n s

tud

ied

.

Ge

nd

er,

ra

ce,

eth

nic

ity

: N

o s

ub

gro

up

an

aly

ses

ha

ve

be

en

pu

bli

she

d.

Co

mp

ara

tiv

e C

lin

ica

l E

ffic

acy

:

Re

leva

nt

En

dp

oin

ts f

or

De

pre

ssio

n:

Re

spo

nse

*

Re

mis

sio

n*

Re

lap

se

Ho

spit

aliza

tio

n

Qu

ali

ty o

f Li

fe

Wit

hd

raw

als

du

e t

o a

dve

rse

eve

nts

Ma

jor

ad

ve

rse

eve

nts

Stu

dy

Pri

ma

ry E

nd

po

ints

:

Kh

an

, e

t a

l: C

ha

ng

e i

n b

ase

lin

e a

t w

ee

k 8

in

Mo

ntg

om

ery

-Asb

erg

De

pre

ssio

n R

ati

ng

Sca

le (

MA

DR

S)

Ric

ke

ls,

et

al:

Ch

an

ge

in

ba

seli

ne

at

we

ek 8

in

Mo

ntg

om

ery

-Asb

erg

De

pre

ssio

n R

ati

ng

Sca

le (

MA

DR

S)

*S

eco

nd

ary

en

dp

oin

ts i

n v

ila

zod

on

e t

ria

ls

Ta

ble

2.

Vil

azo

do

ne

Co

mp

ara

tiv

e E

vid

en

ce T

ab

le

Re

f./

Stu

dy

De

sig

n

Dru

g R

eg

ime

ns

Pa

tie

nt

Po

pu

lati

on

N

Du

rati

on

E

ffic

acy

Re

sult

s2

(CI,

p-v

alu

es)

AR

R /

NN

T3

S

afe

ty R

esu

lts^

(CI,

p-v

alu

es)

AR

R/

NN

H3

Q

ua

lity

Ra

tin

g4;

Co

mm

en

ts

Kh

an

, e

t a

l.

Mu

ltic

en

ter,

DB

, P

C,

PG

,

RC

T

Vil

azo

do

ne

vs

Pla

ceb

o

1.

Vil

azo

do

ne

40

mg

2.

Pla

ceb

o

Do

sed

QD

Ad

ult

pa

tie

nts

(1

8-

70

yrs

); D

SM

-IV

-TR

crit

eri

a f

or

MD

D,

sin

gle

ep

iso

de

or

recu

rre

nt

Me

an

ag

e 4

2 y

/o

56

% f

em

ale

Exc

lud

ed

:

24

0

24

1

8-w

ee

ks

MA

DR

S t

ota

l sc

ore

(ch

an

ge

fro

m

ba

seli

ne

to

we

ek

8):

Vil

azo

do

ne

40

mg

= -

13

.3

Pla

ceb

o =

-1

0.8

Me

an

dif

fere

nce

-2

.5

95

% C

I (-

4.4

to

-0

.6)

p-v

alu

e =

0.0

09

Re

spo

nse

Ra

te*

Vil

azo

do

ne

10

1 (

43

.7%

)

Pla

ceb

o 7

0 (

30

.3%

)

N/A

Re

spo

nse

:

AR

R 1

3.4

%

NN

T=

7.5

Dis

con

tin

ua

tio

ns

du

e t

o

ad

ve

rse

ev

en

ts:

Vil

azo

do

ne

: 1

2 (

5.1

%)

Pla

ceb

o:

4 (

1.7

%)

RR

3.0

, 9

5%

CI

(0.9

to

10

.9)

P=

0.0

42

Se

ve

re A

dv

ers

e e

ve

nts

:

Vil

azo

do

ne

: 1

5 (

6.4

%)

Pla

ceb

o:

13

(5

.6%

)

RR

1.1

, 9

5%

CI

(0.5

to

2.5

)

AR

I 3

.4%

NN

H 2

9

NS

Fa

ir;

Pla

ceb

o c

on

tro

lle

d,

sho

rt-

term

tri

al,

no

t h

ea

d-t

o-

he

ad

Ma

nu

fact

ure

r sp

on

sore

d

tria

l

No

in

form

ati

on

on

me

tho

ds

of

all

oca

tio

n c

on

cea

lme

nt

64 of 108

Exc

lud

ed

: h

isto

ry

of

sch

izo

ph

ren

ia,

bip

ola

r, o

r

sub

sta

nce

de

pe

nd

en

ce,

curr

en

t

psy

cho

the

rap

y

wit

hin

pre

vio

us

12

we

ek

s

RR

1.4

4 9

5%

CI

(1.1

-1.9

)

P=

0.0

03

Re

mis

sio

n R

ate

**

Vil

azo

do

ne

63

(2

7.3

%)

Pla

ceb

o 4

7 (

20

.3%

)

RR

1.3

95

% C

I (0

.95

-1.9

)

P=

0.0

8

*R

esp

on

se r

ate

de

fin

ed

as *+#,!

de

cre

ase

fro

m b

ase

line

in

MA

DR

S

**

Re

mis

sio

n r

ate

de

fin

ed

as

MA

DR

S

sco

re <

10

Re

mis

sio

n:

NS

P=

0.7

Pa

tie

nts

wit

h s

ign

ific

an

t

com

orb

id c

on

dit

ion

s th

at

mig

ht

inte

rfe

re w

ith

tri

al

pa

rtic

ipa

tio

n e

xclu

de

d a

t

the

in

vest

iga

tor’

s

dis

cre

tio

n

To

tal

Dis

con

tin

ua

tio

n R

ate

19

%(s

imil

ar

be

twe

en

gro

up

s)

No

me

asu

res

of

QO

L

Ric

ke

ls,

et

al.

Mu

ltic

en

ter,

DB

, P

C,

PG

,

RC

T

1.

Vil

azo

do

ne

40

mg

2.

Pla

ceb

o

Ad

ult

pa

tie

nts

(1

8-

70

yrs

); D

SM

-IV

-TR

crit

eri

a f

or

MD

D,

sin

gle

ep

iso

de

or

recu

rre

nt

Me

an

ag

e 4

0y

/o

63

% f

em

ale

Exc

lud

ed

: h

isto

ry

of

sch

izo

ph

ren

ia,

bip

ola

r, o

r

sub

sta

nce

de

pe

nd

en

ce,

curr

en

t

psy

cho

the

rap

y,

pa

tie

nts

wit

h

seri

ou

s su

icid

al

risk

, p

ati

en

ts w

ith

clin

ica

lly

sig

nif

ica

nt

card

iac,

re

na

l,

ne

uro

log

ic,

he

pa

tic,

me

tab

oli

c

or

pu

lmo

na

ry

dis

ea

se

20

5

20

5

8-w

ee

ks

MA

DR

S t

ota

l sc

ore

(ch

an

ge

fro

m

ba

seli

ne

to

we

ek

8):

Vil

azo

do

ne

40

mg

= -

12

.9

Pla

ceb

o =

-9

.6

Me

an

dif

fere

nce

-3

.2

95

% C

I (-

5.1

to

-1

.2)

p-v

alu

e =

0.0

01

Re

spo

nse

Ra

te*

Vil

azo

do

ne

: 8

0 (

40

%)

Pla

ceb

o :

56

(28

%)

RR

1.4

4 9

5%

CI

(1.0

7-1

.9)

P=

0.0

1

*R

esp

on

se r

ate

de

fin

ed

as *+#,!

de

cre

ase

fro

m b

ase

lin

e i

n

MA

DR

S

N/A

Re

spo

nse

AR

R 1

2%

NN

T=

8.1

Dis

con

tin

ua

tio

ns

du

e t

o

ad

ve

rse

ev

en

ts:

Vil

azo

do

ne

: 1

9 (

9.3

%)

Pla

ceb

o:

10

(4

.9%

)

RR

1.9

, 9

5%

CI(

0.9

-4.3

)

P=

0.0

85

Se

rio

us

ad

ve

rse

ev

en

ts:

Vil

azo

do

ne

: 5

(2

.4%

)

Pla

ceb

o:

5 (

2.5

%)

RR

1.0

95

% C

I (0

.3-4

.0)

P=

0.9

9

NS

NS

Fa

ir;

Pla

ceb

o c

on

tro

lle

d,

no

t

he

ad

-to

-he

ad

No

in

form

ati

on

on

me

tho

ds

of

all

oca

tio

n c

on

cea

lme

nt

Ma

nu

fact

ure

r sp

on

sore

d t

ria

l

Sh

ort

-te

rm t

ria

l

To

tal

Dro

po

ut

rate

25

%

(sim

ila

r b

etw

ee

n g

rou

ps)

Ext

en

sive

exc

lusi

on

cri

teri

a

No

me

asu

re o

f Q

OL

1S

tud

y d

esi

gn

ab

bre

via

tio

ns:

DB

= d

ou

ble

-bli

nd

, R

CT

= r

an

do

miz

ed

tri

al,

PC

= p

lace

bo

-co

ntr

oll

ed

, P

G =

pa

rall

el

-gro

up

, X

O =

cro

sso

ve

r.

2R

esu

lts

ab

bre

via

tio

ns:

RR

R =

re

lati

ve

ris

k r

ed

uct

ion

, R

R =

rela

tiv

e r

isk

, O

R=

Od

ds

Ra

tio

, H

R =

Ha

zard

Ra

tio

, A

RR

= a

bso

lute

ris

k r

ed

uct

ion

,

NN

T =

nu

mb

er

ne

ed

ed

to

tre

at,

NN

H =

nu

mb

er

ne

ed

ed

to

ha

rm,

CI

= c

on

fid

en

ce i

nte

rva

l 3N

NT

/NN

H a

re r

ep

ort

ed

on

ly f

or

sta

tist

ica

lly

sig

nif

ica

nt

resu

lts

4Q

ua

lity

Ra

tin

g:

(Go

od

- li

ke

ly v

ali

d,

Fa

ir-

lik

ely

va

lid

/po

ssib

ly v

ali

d,

Po

or-

fa

tal

fla

w-n

ot

va

lid

)

65 of 108

Ta

ble

3.

Vil

azo

do

ne

Do

se &

Av

ail

ab

ilit

y

ST

RE

NG

TH

F

OR

M

RO

UT

E

FR

EQ

UE

NC

Y

RE

NA

L A

DJ

HE

PA

TIC

AD

J P

ed

iatr

ic

Do

se

Eld

erl

y

Do

se

OT

HE

R D

OS

ING

CO

NS

IDE

RA

TIO

NS

10

mg

Ta

b

PO

D

ail

y N

/A

N/A

(n

ot

stu

die

d i

n

seve

re h

ep

ati

c

dis

ea

se)

No

t

Est

ab

lish

ed

No

t E

sta

bli

she

d

Sh

ou

ld b

e g

ive

n w

ith

fo

od

S

ho

uld

be

tit

rate

d (

10

mg

X 7

da

ys;

20

mg

X 7

da

ys;

th

en

40

mg

/da

y)

20

mg

Ta

b

PO

D

ail

y

40

mg

Ta

b

PO

D

ail

y

Ta

ble

4.

Vil

azo

do

ne

Ph

arm

aco

kin

eti

cs

Pa

ram

ete

r R

esu

lt

Ora

l B

ioa

va

ila

bil

ity

72

% w

/fo

od

Tm

ax

4-5

ho

urs

Pro

tein

Bin

din

g

96

-99

%

Eli

min

ati

on

Ext

en

siv

ely

me

tab

oli

zed

Fe

ces

2%

Uri

ne

1%

Ha

lf-L

ife

25

ho

urs

Me

tab

oli

sm

CY

P3

A4

(m

ajo

r);

2C

19

(m

ino

r);

2D

6 (

min

or)

No

act

ive

me

tab

oli

tes

IV.

Sa

fety

Ale

rt f

or

Cit

alo

pra

m

In A

ug

ust

20

11

, th

e F

DA

iss

ue

d a

Sa

fety

Ale

rt r

eg

ard

ing

th

e l

ink b

etw

ee

n a

bn

orm

al h

ea

rt r

hyt

hm

s a

nd

hig

h d

ose

cit

alo

pra

m (

Ce

lexa

).

Fu

rth

er

cla

rifi

cati

on

of

reco

mm

en

da

tio

ns

wa

s p

ost

ed

Ma

rch

20

12

.5,6

C

ha

ng

es

in t

he

ele

ctri

cal

act

ivit

y o

f th

e h

ea

rt (

pro

lon

ga

tio

n o

f th

e Q

T i

nte

rva

l) c

an

lea

d t

o a

n a

bn

orm

al h

ea

rt r

hyth

m (

incl

ud

ing

To

rsa

de

de

Po

inte

s),

wh

ich

ca

n b

e f

ata

l. P

ati

en

ts a

t p

art

icu

lar

risk

fo

r d

eve

lop

ing

pro

lon

ga

tio

n o

f th

e

QT

in

terv

al

incl

ud

e t

ho

se w

ith

un

de

rlyin

g h

ea

rt c

on

dit

ion

s a

nd

th

ose

wh

o a

re p

red

isp

ose

d t

o l

ow

le

ve

ls o

f p

ota

ssiu

m a

nd

ma

gn

esi

um

in

th

e b

loo

d.

Stu

die

s d

id n

ot

sho

w a

be

ne

fit

in t

he

tre

atm

en

t o

f d

ep

ress

ion

at

do

ses

hig

he

r th

an

40

mg

pe

r d

ay.

Pre

vio

usl

y,

the

cit

alo

pra

m d

rug

la

be

l st

ate

d t

ha

t

cert

ain

pa

tie

nts

ma

y r

eq

uir

e a

do

se o

f 6

0 m

g p

er

da

y.

Th

e c

ita

lop

ram

dru

g l

ab

el h

as

be

en

re

vis

ed

to

in

clu

de

th

e n

ew

dru

g d

osa

ge

an

d u

sag

e

reco

mm

en

da

tio

ns,

as

we

ll a

s in

form

ati

on

ab

ou

t th

e p

ote

nti

al fo

r Q

T i

nte

rva

l p

rolo

ng

ati

on

an

d T

ors

ad

e d

e P

oin

tes.

T

he

FD

A r

eco

mm

en

ds

the

foll

ow

ing

:

C

ita

lop

ram

ca

use

s d

ose

-de

pe

nd

en

t Q

T in

terv

al

pro

lon

ga

tio

n.

C

ita

lop

ram

sh

ou

ld n

o l

on

ge

r b

e p

resc

rib

ed

at

do

ses

gre

ate

r th

an

40

mg

pe

r d

ay.

C

ita

lop

ram

is

no

t re

com

me

nd

ed

fo

r u

se i

n p

ati

en

ts w

ith

co

ng

en

ita

l lo

ng

QT

syn

dro

me

, b

rad

yca

rdia

, h

yp

oka

lem

ia,

or

hyp

om

ag

ne

sem

ia,

rece

nt

acu

te m

yo

card

ial in

farc

tio

n,

or

un

com

pe

nsa

ted

he

art

fa

ilu

re.

C

ita

lop

ram

use

is

als

o n

ot

reco

mm

en

de

d i

n p

ati

en

ts w

ho

are

ta

kin

g o

the

r d

rug

s th

at

pro

lon

g t

he

QT

in

terv

al.

66 of 108

T

he

ma

xim

um

re

com

me

nd

ed

do

se o

f ci

talo

pra

m is

20

mg

pe

r d

ay f

or

pa

tie

nts

wit

h h

ep

ati

c im

pa

irm

en

t, p

ati

en

ts w

ho

are

old

er

tha

n 6

0

ye

ars

of

ag

e,

pa

tie

nts

wh

o a

re C

YP

2C

19

po

or

me

tab

oli

zers

, o

r p

ati

en

ts w

ho

are

ta

kin

g c

on

com

ita

nt

cim

eti

din

e (

Ta

ga

me

t) o

r a

no

the

r

CY

P2

C1

9 in

hib

ito

r, b

eca

use

th

ese

fa

cto

rs l

ea

d t

o in

cre

ase

d b

loo

d le

ve

ls o

f ci

talo

pra

m,

incr

ea

sin

g t

he

ris

k o

f Q

T in

terv

al

pro

lon

ga

tio

n a

nd

To

rsa

de

de

Po

inte

s.

67 of 108

Ap

pe

nd

ix 1

Pre

vio

us

Co

ncl

usi

on

s b

y H

RC

Se

con

d G

en

era

tio

n A

nti

de

pre

ssa

nts

1,2

:

Dru

g C

lass

es

incl

ud

ed

in

re

vie

w

S

SR

Is:

cit

alo

pra

m,

esc

ita

lop

ram

, fl

uo

xeti

ne

, fl

uv

oxa

min

e,

pa

roxe

tin

e,

an

d s

ert

ralin

e

S

NR

Is:

de

sve

nla

faxi

ne

, d

ulo

xeti

ne

, v

en

lafa

xin

e

O

the

rs:

bu

pro

pio

n,

mir

taza

pin

e,

ne

fazo

do

ne

, tr

azo

do

ne

Lim

ita

tio

n o

f th

e e

vid

en

ce:

S

tud

y d

ura

tio

ns

we

re s

ho

rt (

mo

stly

6-1

2 w

ee

ks)

com

pa

red

to

th

e u

sua

l d

ura

tio

n o

f tr

ea

tme

nt

(9-1

2 m

on

ths)

.

H

igh

dro

po

ut

rate

s

N

o e

ffe

ctiv

en

ess

stu

die

s

D

ep

ress

ion

in

ch

ild

ren

is

no

t a

s w

ell

stu

die

d a

s in

ad

ult

s

Co

ncl

usi

on

s:

G

oo

d E

vid

en

ce

Fa

ir E

vid

en

ce

Insu

ffic

ien

t E

vid

en

ce

Eff

ica

cy,

Ad

ult

s N

o s

ign

ific

an

t d

iffe

ren

ce i

n o

ve

rall

eff

ica

cy

am

on

g s

eco

nd

ge

ne

rati

on

an

tid

ep

ress

an

ts

in a

du

lts

wit

h M

DD

.

Se

con

d g

en

era

tio

n a

nti

de

pre

ssa

nts

we

re n

o b

ett

er

tha

n

pla

ceb

o f

or

MD

D i

n p

ati

en

ts w

ith

co

mo

rbid

co

nd

itio

ns

incl

ud

ing

me

tha

do

ne

ma

inta

ine

d o

pio

id a

dd

icti

on

,

coca

ine

ab

use

, H

IV,

mu

ltip

le s

cle

rosi

s, a

rth

riti

s, d

iab

ete

s,

can

cer

or

sub

sta

nce

ab

use

dis

ord

er.

To

de

term

ine

a c

om

pa

rati

ve d

iffe

ren

ce i

n

eff

ica

cy a

mo

ng

th

e s

tud

ied

ag

en

ts f

or

dy

sth

ym

ia,

ge

ne

rali

zed

an

xie

ty d

iso

rde

r, o

bse

ssiv

e-

com

pu

lsiv

e d

iso

rde

r, p

an

ic d

iso

rde

r, p

ost

-

tra

um

ati

c st

ress

dis

ord

er,

so

cia

l a

nxi

ety

dis

ord

er,

pre

me

nst

rua

l d

ysp

ho

ric

dis

ord

er

an

d l

ate

lu

tea

l

ph

ase

dy

sph

ori

c d

iso

rde

r.

Eff

ica

cy,

chil

dre

n

an

d a

do

lesc

en

ts

Cit

alo

pra

m a

nd

flu

oxe

tin

e a

re t

he

on

ly

two

ag

en

ts s

tud

ied

sh

ow

n t

o b

e b

ett

er

tha

n p

lace

bo

. S

ert

rali

ne

, ve

nla

faxi

ne

, a

nd

pa

roxe

tin

e w

ere

sh

ow

n t

o b

e n

o b

ett

er

tha

n p

lace

bo

.

In p

ati

en

ts <=!)0(61!.50!631>!78!10/8

-ha

rm

incr

ea

sed

wit

h S

SR

Is v

s. T

CA

s.

Th

ere

we

re

no

sta

tist

ica

lly

sig

nif

ica

nt

dif

fere

nce

s

am

on

g S

SR

Is.

A s

yst

em

ati

c re

vie

w o

f p

ub

lish

ed

an

d

un

pu

bli

she

d d

ata

su

gg

est

s th

at

on

ly

flu

oxe

tin

e h

as

a f

avo

rab

le r

isk

/be

ne

fit

pro

file

in

pe

dia

tric

po

pu

lati

on

s.

Se

con

d g

en

era

tio

n a

nti

de

pre

ssa

nts

we

re n

o b

ett

er

tha

n

pla

ceb

o f

or

com

orb

id a

lco

ho

l u

se d

iso

rde

r in

ad

ole

sce

nts

.

68 of 108

Ad

ve

rse

Eff

ect

s B

lack

Bo

x W

arn

ing

:

1.

Ne

fazo

ne

an

d a

ctiv

e l

ive

r d

ise

ase

.

2.

All

in

clu

de

d d

rug

s ca

rry

a b

lack

bo

x w

arn

ing

re

ga

rdin

g

suic

ida

lity

.

Th

e r

isk

of

suic

ida

lity

is

no

t in

cre

ase

d i

n

ad

ult

pa

tie

nts

*!(%0!<=?

Hig

he

r ra

te o

f n

au

sea

an

d v

om

itin

g w

ith

ven

lafa

xin

e.

Hig

he

r ra

te o

f d

isco

nti

nu

ati

on

wit

h

ven

lafa

xin

e a

nd

du

loxe

tin

e.

Se

xua

l S

ide

Eff

ect

s:

1.

Hig

he

r ri

sk:

pa

roxe

tin

e,

sert

ali

ne

an

d

mir

taza

pin

e

2.

Low

er

risk

: b

up

rop

ion

an

d n

efa

zod

on

e

Gre

ate

r w

eig

ht

ga

in w

ith

mir

taza

pin

e a

nd

pa

roxe

tin

e t

ha

n

wit

h s

ert

rali

ne

an

d f

luo

xeti

ne

.

Su

bg

rou

ps

A l

arg

e m

eta

-an

aly

sis

of

pa

roxe

tin

e v

s.

pla

ceb

o s

ug

ge

sts

tha

t th

e r

esp

on

se r

ate

is

low

er

in H

isp

an

ic a

nd

Asi

an

po

pu

lati

on

s

com

pa

red

to

Wh

ite

an

d B

lack

po

pu

lati

on

s

for

MD

Ds

in a

du

lts,

an

xie

ty d

iso

rde

rs,

an

d

po

st m

en

stru

al

dy

sph

ori

c d

iso

rde

r.

A r

etr

osp

ect

ive

co

ho

rt s

tud

y o

f w

om

en

*@

6 y

ea

rs w

ith

bre

ast

ca

nce

r sh

ow

s th

at

use

of

pa

roxe

tin

e i

ncr

ea

sed

th

e

risk

of

de

ath

fro

m b

rea

st c

an

cer

am

on

g w

om

en

ta

kin

g

tam

oxi

fen

. T

he

re i

s in

suff

icie

nt

da

ta t

o a

sse

ss t

he

ris

k f

or

oth

er

me

dic

ati

on

s in

th

is c

lass

.

To

de

term

ine

a c

om

pa

rati

ve d

iffe

ren

ce a

mo

ng

ag

en

ts i

n t

his

cla

ss b

ase

d o

n s

ub

po

pu

lati

on

s o

f

ag

e,

com

orb

idit

ies,

eth

nic

ity

or

ge

nd

er.

69 of 108

©C

op

yri

gh

t 20

12

Ore

gon

Sta

te U

niv

ersi

ty.

All

Rig

hts

Res

erved

Dru

g U

se R

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fety

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vise

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©C

op

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gh

t 20

12

Ore

gon

Sta

te U

niv

ersi

ty.

All

Rig

hts

Res

erved

Dru

g U

se R

ese

arch

& M

an

ag

em

en

t P

rogra

m

Ore

gon

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te U

niv

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mm

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tree

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To

ba

cco

Ce

ssa

tio

n M

ed

ica

tio

n R

ev

iew

M

on

th/Y

ea

r o

f R

ev

iew

: A

pri

l 2

01

2

FD

A A

pp

rov

ed

Me

dic

ati

on

s

No

n F

DA

-ap

pro

ve

d A

lte

rna

tiv

es

Nic

oti

ne

tra

nsd

erm

al p

atc

h

Nic

oti

ne

lo

zen

ge

Nic

oti

ne

gu

m

Nic

oti

ne

in

ha

ler

(Nic

otr

ol®

)

Nic

oti

ne

na

sal

spra

y (

Nic

otr

ol®

)

Bu

pro

pio

n s

ust

ain

ed

–re

lea

se

Va

ren

icli

ne

(C

ha

nti

x®)

Clo

nid

ine

No

rtri

pty

lin

e

*S

ee

Ap

pe

nd

ix 2

fo

r d

osi

ng

, d

ura

tio

n a

nd

ad

min

istr

ati

on

in

form

ati

on

Re

aso

n f

or

Re

vie

w:

Sm

okin

g i

s a

sig

nif

ica

nt

pu

bli

c h

ea

lth

pro

ble

m t

ha

t ca

n b

e a

sso

cia

ted

wit

h s

ub

sta

nti

al

he

alt

h c

are

co

sts

an

d c

an

ca

use

ma

ny p

reve

nta

ble

dis

ea

ses

incl

ud

ing

ca

nce

rs,

chro

nic

o

bst

ruct

ive

p

ulm

on

ary

d

ise

ase

(C

OP

D),

a

nd

ca

rdio

va

scu

lar

dis

ea

se.

T

his

re

vie

w

wil

l e

valu

ate

cu

rre

nt

com

pa

rati

ve

eff

ect

ive

ne

ss e

vid

en

ce t

o a

ssis

t in

est

ab

lish

ing

re

com

me

nd

ati

on

s fo

r th

e t

he

rap

eu

tic

ag

en

ts in

dic

ate

d f

or

smo

kin

g c

ess

ati

on

.

Issu

es:

1.

Wh

at

is t

he

co

mp

ara

tive

eff

ica

cy o

f sm

okin

g c

ess

ati

on

pro

du

cts

in p

rom

oti

ng

lo

ng

-te

rm t

ob

acc

o a

bst

ine

nce

?

2.

Is t

he

re a

ny e

vid

en

ce t

ha

t th

ere

is

a m

ea

nin

gfu

l d

iffe

ren

ce in

ag

en

ts i

n s

afe

ty t

ha

t w

ou

ld f

avo

r o

ne

ag

en

t o

ve

r a

no

the

r?

3.

Is t

he

re a

ny e

vid

en

ce t

ha

t th

ere

is

a d

iffe

ren

ce i

n e

ffic

acy

or

safe

ty in

sp

eci

al

po

pu

lati

on

s?

71 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

2

Auth

or:

Am

y B

urn

s, P

har

m.D

.

Me

tho

ds:

Se

arc

h S

tra

teg

y

An

Ovid

ME

DLI

NE

se

arc

h w

as

con

du

cte

d u

sin

g t

he

fo

llo

win

g s

ea

rch

te

rms:

Va

ren

icli

ne

; b

up

rop

ion

; n

ico

tin

e r

ep

lace

me

nt

the

rap

y;

nic

oti

ne

pa

tch

; n

ico

tin

e g

um

; n

ico

tin

e l

oze

ng

e;

nic

oti

ne

na

sal

spra

y;

nic

oti

ne

in

ha

ler;

sm

okin

g

cess

ati

on

; to

ba

cco

ab

stin

en

ce.

Th

e s

ea

rch

wa

s li

mit

ed

to

co

ntr

oll

ed

tri

als

co

nd

uct

ed

wit

h h

um

an

s in

En

gli

sh l

an

gu

ag

e p

ub

lica

tio

ns

fro

m 2

01

0 t

o

pre

sen

t. T

he

Ag

en

cy f

or

He

alt

hca

re R

ese

arc

h a

nd

Qu

ali

ty (

AH

RQ

), C

och

ran

e C

oll

ect

ion

, th

e D

ep

art

me

nt

of

Ve

tera

n A

ffa

irs,

an

d t

he

Ca

na

dia

n A

ge

ncy

for

Dru

gs

an

d T

ech

no

log

ies

in H

ea

lth

(C

AD

TH

) re

sou

rce

s w

ere

se

arc

he

d f

or

hig

h q

ua

lity

syst

em

ati

c re

vie

ws.

T

he

FD

A w

eb

site

wa

s se

arc

he

d f

or

ne

w

dru

gs,

in

dic

ati

on

s, a

nd

sa

fety

ale

rts,

an

d t

he

AH

RQ

Na

tio

na

l G

uid

eli

ne

Cle

ari

ng

ho

use

(N

GC

) w

as

sea

rch

ed

fo

r u

pd

ate

d a

nd

re

cen

t e

vid

en

ce-b

ase

d

gu

ide

lin

es.

Re

sult

s:

Th

e M

ED

LIN

E s

ea

rch

re

trie

ve

d 1

81

fu

ll c

ita

tio

ns.

Aft

er

a f

ull e

va

lua

tio

n o

f ci

tati

on

s a

nd

ab

stra

cts,

8 h

ea

d-t

o-h

ea

d t

ria

ls u

sin

g F

DA

ap

pro

ve

d a

ge

nts

we

re i

de

nti

fie

d f

or

furt

he

r re

vie

w a

nd

th

ree

po

ten

tia

lly r

ele

va

nt

art

icle

s w

ere

in

clu

de

d h

ere

. O

ne

tri

al

eva

lua

ted

th

e e

ffe

cts

of

va

ren

iclin

e o

n

card

iova

scu

lar

risk

a

nd

tw

o

art

icle

s e

va

lua

ted

va

ren

icli

ne

d

osi

ng

. T

he

m

ajo

rity

o

f th

e

RC

Ts

ide

nti

fie

d

we

re

exc

lud

ed

fo

r w

ron

g

stu

dy

typ

e

(ob

serv

ati

on

al,

ca

se s

tud

y),

th

e w

ron

g e

nd

po

int

(sm

okin

g r

ed

uct

ion

, d

ecr

ea

sed

dis

ea

se o

ccu

rre

nce

), w

ron

g d

ura

tio

n (

tria

ls l

ess

th

an

6 w

ee

ks)

, fo

r ve

ry

spe

cifi

c su

bp

op

ula

tio

ns

(ch

ron

ic b

ing

e d

rin

ke

rs,

Jap

an

ese

me

n o

ve

r 4

0)

or

for

du

pli

cati

on

(a

lre

ad

y in

clu

de

d in

an

oth

er

art

icle

or

revie

w).

Co

ncl

usi

on

s:

Th

e c

olle

ctiv

e c

on

clu

sio

ns

of

the

Ca

na

dia

n A

ge

ncy

fo

r D

rug

s a

nd

Te

chn

olo

gie

s in

He

alt

h1,

U.S

. D

ep

art

me

nt

of

He

alt

h a

nd

Hu

ma

n S

erv

ice

s2,

an

d t

he

Co

chra

ne

Co

lla

bo

rati

on

syst

em

ati

c re

vie

ws3

-8,

as

we

ll a

s th

e g

uid

eli

ne

s o

f th

e U

K’s

Na

tio

na

l In

stit

ute

fo

r C

lin

ica

l E

xce

lle

nce

9 a

nd

th

e U

S P

reve

nti

ve

Ta

sk F

orc

e1

0 s

ha

re m

an

y s

imil

ar

reco

mm

en

da

tio

ns.

Th

ere

is

stro

ng

evid

en

ce t

ha

t a

ll o

f th

e F

DA

ap

pro

ve

d s

mo

kin

g c

ess

ati

on

pro

du

cts

are

eff

ica

cio

us

com

pa

red

wit

h p

lace

bo

in

te

rms

of

ab

stin

en

ce r

ate

s.

Th

ere

is

stro

ng

evid

en

ce t

ha

t b

up

rop

ion

an

d n

ico

tin

e r

ep

lace

me

nt

the

rap

y (

NR

T)

form

ula

tio

ns

are

eq

ua

lly e

ffe

ctiv

e f

or

tob

acc

o a

bst

ine

nce

ra

tes.

T

he

re i

s m

od

era

te t

o s

tro

ng

evid

en

ce t

ha

t va

ren

icli

ne

ha

s th

e h

igh

er

rate

of

ab

stin

en

ce s

ucc

ess

wh

en

co

mp

are

d w

ith

bu

pro

pio

n o

r N

RT

s.

Th

ere

is

stro

ng

evid

en

ce t

ha

t co

mb

inin

g t

he

nic

oti

ne

pa

tch

wit

h a

no

the

r N

RT

th

era

py i

mp

rove

s a

bst

ine

nce

rate

s o

ve

r N

RT

mo

no

the

rap

y.

Th

ere

is

stro

ng

evi

de

nce

th

at

clo

nid

ine

is

eff

ica

cio

us

com

pa

red

wit

h p

lace

bo

fo

r to

ba

cco

ce

ssa

tio

n a

nd

mo

de

rate

to

stro

ng

evid

en

ce t

ha

t n

ort

rip

tyli

ne

is

eff

ect

ive

co

mp

are

d w

ith

pla

ceb

o f

or

tob

acc

o c

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on

. T

he

re i

s st

ron

g e

vid

en

ce t

ha

t co

mb

inin

g b

eh

avio

ral

the

rap

y w

ith

to

ba

cco

ce

ssa

tio

n m

ed

ica

tio

ns

incr

ea

se t

he

ra

te o

f lo

ng

-te

rm (

gre

ate

r th

an

6 m

on

ths)

ab

stin

en

ce.

Th

ere

is

inco

ncl

usi

ve

evid

en

ce t

ha

t

com

bin

ing

bu

pro

pio

n w

ith

NR

T i

s m

ore

eff

ect

ive

th

an

mo

no

the

rap

y a

nd

th

ere

is

insu

ffic

ien

t e

vid

en

ce t

o r

eco

mm

en

d a

ny m

ed

ica

tio

n f

or

spe

cia

l

po

pu

lati

on

s in

clu

din

g p

reg

na

nt

or

lact

ati

ng

wo

me

n,

ad

ole

sce

nts

or

the

me

nta

lly

ill.

Va

ren

icli

ne

ha

s so

me

sa

fety

iss

ue

s n

ot

see

n w

ith

bu

pro

pio

n o

r N

RT

pro

du

cts.

11

-12

Fro

m s

yst

em

ati

c re

vie

ws,

th

ere

is

stro

ng

evid

en

ce t

ha

t va

ren

icli

ne

is

safe

to

use

ove

r a

12

we

ek p

eri

od

, a

lth

ou

gh

lim

ita

tio

ns

ma

y b

e a

pp

rop

ria

te i

n p

ati

en

ts w

ith

a n

eu

rop

sych

iatr

ic o

r ca

rdio

va

scu

lar

his

tory

. A

sm

all

72 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

3

Auth

or:

Am

y B

urn

s, P

har

m.D

.

incr

ea

se i

n r

isk o

f se

rio

us

card

iova

scu

lar

eve

nts

ma

y e

xist

fo

r p

ati

en

ts w

ith

ca

rdio

va

scu

lar

dis

ea

se t

akin

g v

are

nic

lin

e;

ho

we

ve

r th

e e

vid

en

ce i

s

insu

ffic

ien

t to

fo

rm a

co

ncl

usi

on

. T

he

re i

s a

bla

ck b

ox

wa

rnin

g f

or

po

ten

tia

l se

rio

us

ne

uro

psy

chia

tric

eve

nts

(d

ep

ress

ion

an

d s

uic

ida

l te

nd

en

cie

s)

esp

eci

all

y i

n t

ho

se p

ati

en

ts w

ith

a h

isto

ry o

f m

en

tal

illn

ess

(b

up

rop

ion

als

o c

arr

ies

this

wa

rnin

g).

A

re

cen

t st

ud

y h

ow

eve

r, f

ou

nd

no

dif

fere

nce

in

th

e

rate

s o

f n

eu

rop

sych

iatr

ic h

osp

ita

liza

tio

ns

be

twe

en

NR

T a

nd

va

ren

icli

ne

pa

tie

nts

.13 P

ost

-ma

rke

tin

g t

ria

ls o

n p

sych

iatr

ic s

afe

ty o

f va

ren

iclin

e a

re

curr

en

tly o

ng

oin

g.

Re

com

me

nd

ati

on

s:

1.

Ad

d N

ico

tin

e r

ep

lace

me

nt

the

rap

y (

NR

T)

pro

du

cts

incl

ud

ing

th

e p

atc

h,

gu

m a

nd

lo

zen

ge

s a

s p

refe

rre

d d

rug

s o

n t

he

PD

L w

ith

an

ag

e r

est

rict

ion

to a

du

lts.

2.

Du

e t

o n

o d

iffe

ren

ces

in s

afe

ty o

r e

ffic

acy

be

twe

en

th

e N

RT

pro

du

cts,

eva

lua

te c

om

pa

rati

ve

co

sts

for

furt

he

r d

eci

sio

ns.

3.

Ma

ke

bu

pro

pri

on

su

sta

ine

d r

ele

ase

(g

en

eri

c Z

yba

n)

a p

refe

rre

d m

ed

ica

tio

n w

ith

an

ag

e r

est

rict

ion

fo

r a

du

lts.

4.

Ma

ke

va

ren

icli

ne

a p

refe

rre

d a

ge

nt

on

th

e P

DL

wit

h a

qu

an

tity

lim

it f

or

twe

lve

we

eks

of

tre

atm

en

t a

nd

wit

h r

est

rict

ion

to

ad

ult

s w

ith

ou

t a

his

tory

of

card

iova

scu

lar

or

ne

uro

psy

chia

tric

eve

nts

.

I.B

AC

KG

RO

UN

D/C

UR

RE

NT

LA

ND

SC

AP

E/S

UM

MA

RY

Cig

are

tte

s a

re r

esp

on

sib

le f

or

mo

re t

ha

n 4

43

,00

0 d

ea

ths

an

nu

all

y.

On

e i

n e

ve

ry f

ive

de

ath

s la

st y

ea

r w

as

smo

kin

g r

ela

ted

, a

nd

acc

ord

ing

to

th

e U

S

De

pa

rtm

en

t o

f H

ea

lth

an

d H

um

an

Se

rvic

es,

mo

re t

ha

n 5

0%

of

lon

g-t

erm

cig

are

tte

sm

oke

rs a

re k

ille

d f

rom

sm

okin

g-r

ela

ted

dis

ea

ses.

S

mo

kin

g

cig

are

tte

s ca

n n

eg

ati

ve

ly a

ffe

ct e

ve

ry p

hysi

olo

gic

al

syst

em

in

a s

mo

ke

r’s

bo

dy.

Un

fort

un

ate

ly,

smo

kin

g d

oe

sn’t

on

ly a

ffe

ct t

he

pe

rso

n s

mo

kin

g.

Th

ou

san

ds

of

no

n-s

mo

kin

g A

me

rica

ns

die

fro

m h

ea

rt a

nd

lu

ng

dis

ea

se a

sso

cia

ted

wit

h s

eco

nd

-ha

nd

sm

oke

. C

hil

dre

n e

xpo

sed

to

se

con

d-h

an

d s

mo

ke

are

at

hig

he

r ri

sk f

or

sud

de

n i

nfa

nt

de

ath

syn

dro

me

(S

IDS

), r

esp

ira

tory

dis

ea

ses,

lo

ng

te

rm e

ar

infe

ctio

ns

an

d o

the

r h

ea

lth

iss

ue

s.

M

ore

th

an

19

3

bil

lio

n d

oll

ars

in

he

alt

h c

are

co

sts

an

d l

ost

pro

du

ctiv

ity i

s sp

en

t a

nn

ua

lly o

n c

hro

nic

dis

ea

ses

cau

sed

by t

ob

acc

o u

se.1

4-1

5

Alt

ho

ug

h c

iga

rett

e s

mo

kin

g r

ate

s h

ave

dro

pp

ed

by m

ore

th

an

ha

lf s

ince

th

e 1

96

0s,

ap

pro

xim

ate

ly 2

0%

of

Am

eri

can

ad

ult

s a

nd

te

en

ag

ers

are

cu

rre

nt

smo

ke

rs.1

5

Am

on

g t

ho

se,

ab

ou

t 7

0%

exp

ress

an

in

tere

st i

n q

uit

tin

g.

In

20

10

, a

bo

ut

ha

lf o

f a

ll a

du

lt s

mo

ke

rs m

ad

e a

n a

tte

mp

t to

sto

p s

mo

kin

g,

bu

t

on

ly 6

.2%

re

po

rte

d r

em

ain

ing

sm

oke

-fre

e a

fte

r o

ne

ye

ar.

A

mo

ng

th

ose

wh

o a

tte

mp

ted

to

qu

it a

nd

th

ose

su

cce

ssfu

lly q

uit

in

th

e l

ast

tw

o y

ea

rs,

31

.7%

use

d e

ith

er

cou

nse

lin

g o

r m

ed

ica

tio

ns

an

d 4

.3%

use

d b

oth

.14

Th

e c

on

seq

ue

nce

s o

f to

ba

cco

ad

dic

tio

n a

re a

la

rge

pro

ble

m i

n t

he

Me

dic

aid

po

pu

lati

on

. T

he

pre

va

len

ce o

f sm

oke

rs i

n t

he

Me

dic

aid

po

pu

lati

on

is

ne

arl

y t

wic

e t

ha

t o

f th

e g

en

era

l p

op

ula

tio

n.

In

Ore

go

n,

thre

e t

ime

s a

s m

an

y a

du

lt M

ed

ica

id p

ati

en

ts s

mo

ke

co

mp

are

d w

ith

th

e g

en

era

l p

op

ula

tio

n.1

6

73 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

4

Auth

or:

Am

y B

urn

s, P

har

m.D

.

Ra

tes

of

tob

acc

o c

ess

ati

on

in

th

e M

ed

ica

id p

op

ula

tio

n r

em

ain

esp

eci

ally l

ow

. P

ati

en

ts w

ith

pri

va

te h

ea

lth

pla

ns

are

41

% m

ore

lik

ely

to

ha

ve

qu

it

smo

kin

g t

ha

n M

ed

ica

id p

ati

en

ts.1

4

Th

e e

stim

ate

d a

nn

ua

l co

st t

o t

he

sta

te i

s $

29

0 m

illi

on

do

lla

rs.1

6

A r

ece

nt

cost

-be

ne

fit

an

aly

sis

loo

ke

d a

t w

ha

t

savin

gs

smo

kin

g c

ess

ati

on

pro

gra

ms

mig

ht

bri

ng

st

ate

Me

dic

aid

pro

gra

ms.

T

he

an

aly

sis

est

ima

ted

th

e s

ho

rt-t

erm

re

turn

on

in

ve

stm

en

t o

f th

e s

avin

gs

att

ach

ed

to

re

du

ced

ca

rdio

va

scu

lar

ho

spit

al

ad

mis

sio

ns

an

d f

ou

nd

fo

r e

very

do

lla

r sp

en

t in

th

e s

mo

kin

g c

ess

ati

on

pro

gra

m (

me

dic

ati

on

s, c

ou

nse

lin

g,

etc

.) $

3.1

2 w

as

save

d f

rom

re

du

ced

ad

mis

sio

ns.

A

po

ten

tia

l a

nn

ua

l sa

vin

gs

of

$3

88

pe

r p

ati

en

t.1

7

Se

ve

n m

ed

ica

tio

ns

are

FD

A a

pp

rove

d f

or

tre

atm

en

t o

f to

ba

cco

de

pe

nd

en

ce.

Fiv

e a

re n

ico

tin

e r

ep

lace

me

nt

the

rap

y (

NR

T)

ava

ila

ble

in

va

rio

us

form

ula

tio

ns.

A

s th

e n

am

e i

mp

lie

s, N

RT

co

nta

in a

me

asu

red

am

ou

nt

of

nic

oti

ne

an

d a

re d

esi

gn

ed

to

he

lp a

sm

oke

r g

rad

ua

lly w

ea

n t

he

mse

lve

s o

ff

nic

oti

ne

wh

ile

ab

sta

inin

g f

rom

cig

are

tte

sm

okin

g.

De

pe

nd

ing

on

th

e f

orm

ula

tio

n,

the

se a

ge

nts

ca

n h

elp

wit

h t

he

wit

hd

raw

al

sym

pto

ms

(th

e p

atc

h,

gu

m a

nd

lo

zen

ge

) a

nd

he

lp w

ith

mo

re i

mm

ed

iate

nic

oti

ne

cra

vin

gs

(in

ha

ler,

na

sal

spra

y,

gu

m,

an

d l

oze

ng

e).

A

ll f

ive

are

me

an

t fo

r sh

ort

-te

rm u

se (

12

-

24

we

eks

or

less

).

Th

e n

asa

l sp

ray a

nd

in

ha

ler

ag

en

ts a

re a

va

ila

ble

by p

resc

rip

tio

n o

nly

. S

afe

ty c

on

cern

s in

clu

de

use

in

ca

rdio

va

scu

lar

pa

tie

nts

,

pre

gn

an

cy a

nd

bre

ast

-fe

ed

ing

wo

me

n,

an

d m

ino

rs.1

8

Th

ere

are

tw

o a

ge

nts

ap

pro

ve

d t

ha

t a

re n

on

-nic

oti

ne

pro

du

cts.

B

up

rop

ion

is

an

an

ti-d

ep

ress

an

t m

ed

ica

tio

n t

ha

t h

as

aff

ect

s o

n d

op

am

ine

re

cep

tors

in

the

ce

ntr

al

ne

rvo

us

syst

em

(C

NS

).

It i

s th

ou

gh

t to

aff

ect

th

e p

lea

sure

-se

ekin

g c

en

ter

in t

he

bra

in,

alt

ho

ug

h i

ts m

ech

an

ism

of

act

ion

in

sm

okin

g

cess

ati

on

is

un

kn

ow

n.

It

ha

s b

ee

n u

sed

in

co

mb

ina

tio

n w

ith

so

me

of

the

NR

T p

rod

uct

s.

Bu

pro

pio

n c

an

in

cre

ase

th

e s

eiz

ure

th

resh

old

an

d s

ho

uld

n’t

be

use

d i

n p

ati

en

ts p

ron

e t

o s

eiz

ure

s.

It a

lso

ha

s n

ot

be

en

ap

pro

ved

fo

r p

reg

na

ncy

/bre

ast

fee

din

g o

r m

ino

rs.

Va

ren

icli

ne

(C

ha

nti

x®)

is a

pa

rtia

l

nic

oti

nic

ag

on

ist

ap

pro

ve

d t

o t

rea

t sm

okin

g d

ep

en

de

nce

. I

t a

cts

at

the

sa

me

re

cep

tors

nic

oti

ne

occ

up

ies

bu

t w

ith

ou

t th

e r

ece

pto

r st

imu

lati

on

nic

oti

ne

pro

vid

es.

P

ati

en

ts t

he

refo

re e

xpe

rie

nce

le

ss c

ravin

g a

nd

wit

hd

raw

al

sym

pto

ms.

V

are

nic

lin

e i

s th

e n

ew

est

me

dic

ati

on

fo

r to

ba

cco

de

pe

nd

en

ce a

nd

ha

s le

ss s

afe

ty d

ata

th

an

th

e a

lte

rna

tive

ag

en

ts.

Ch

oo

sin

g a

mo

ng

me

dic

ati

on

s re

qu

ire

s co

nsi

de

rati

on

of

the

be

ne

fits

an

d r

isks,

wit

h a

tte

nti

on

to

ea

ch

pa

tie

nt’

s m

ed

ica

l a

nd

psy

chia

tric

sta

tus.

In

20

09

, th

e F

DA

iss

ue

d a

bo

xed

wa

rnin

g f

or

bo

th v

are

nic

lin

e a

nd

bu

pro

pio

n c

on

cern

ing

ne

uro

psy

chia

tric

sym

pto

ms,

de

pre

sse

d m

oo

d,

an

d s

uic

ida

l th

ou

gh

ts a

nd

be

ha

vio

r.1

9

Als

o,

a r

ece

nt

dru

g-s

afe

ty c

om

mu

nic

ati

on

no

ted

th

at

it m

ay b

e a

sso

cia

ted

wit

h a

sma

ll i

ncr

ea

se i

n t

he

ris

k o

f ca

rdio

va

scu

lar

eve

nts

. V

are

nic

lin

e s

ho

uld

no

t b

e u

sed

wit

h N

RT

ag

en

ts.1

8

Ma

ny m

ed

ica

tio

ns

ha

ve

be

en

pre

scri

be

d f

or

tob

acc

o d

ep

en

de

nce

as

off

-la

be

l a

ge

nts

. T

he

se n

on

-FD

A a

pp

rove

d m

ed

ica

tio

ns

ha

ve

a w

ide

ra

ng

e i

n t

he

am

ou

nt

of

evid

en

ce s

up

po

rtin

g t

he

ir u

se.

Tw

o m

ed

ica

tio

ns,

clo

nid

ine

(a

n a

nti

-hyp

ert

en

sive

) a

nd

no

rtri

pty

lin

e (

an

an

tid

ep

ress

an

t) h

ave

th

e m

ost

da

ta

sup

po

rtin

g t

he

ir u

se.

Ho

we

ve

r, e

vid

en

ce i

s lim

ite

d f

or

the

ir u

se a

nd

bo

th s

ho

uld

be

co

nsi

de

red

as

seco

nd

-lin

e a

ge

nts

aft

er

the

FD

A-a

pp

rove

d

me

dic

ati

on

s d

iscu

sse

d a

bo

ve

. O

the

r m

ed

ica

tio

ns

incl

ud

ing

th

e S

SR

Is (

i.e

. fl

uo

xeti

ne

) a

nd

na

ltre

xon

e h

ave

lit

tle

to

no

da

ta s

up

po

rtin

g t

he

ir u

se i

n

tob

acc

o d

ep

en

de

nce

an

d a

re n

ot

reco

mm

en

de

d f

or

use

.18

74 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

5

Auth

or:

Am

y B

urn

s, P

har

m.D

.

II.

Sy

ste

ma

tic

Re

vie

ws:

Ca

na

dia

n A

ge

ncy

fo

r D

rug

s a

nd

Te

chn

olo

gie

s in

He

alt

h (

CA

DT

H) 1

:

Th

e C

an

ad

ian

Ag

en

cy f

or

Dru

gs

an

d T

ech

no

log

ies

in H

ea

lth

(C

AD

TH

) p

rovid

ed

a t

ech

no

log

y r

ep

ort

in

Se

pte

mb

er

20

10

(u

pd

ate

d O

cto

be

r 2

01

1)

to

ass

ess

th

e

clin

ica

l e

ffe

ctiv

en

ess

a

nd

co

st

eff

ect

ive

ne

ss

of

me

dic

ati

on

s fo

r sm

okin

g

cess

ati

on

.

Th

e

revie

w

eva

lua

ted

th

e

com

pa

rati

ve

cl

inic

al

eff

ect

ive

ne

ss o

f va

ren

iclin

e,

bu

pro

pio

n a

nd

NR

T a

ge

nts

, th

e e

ffe

ctiv

en

ess

of

com

bin

ing

va

rio

us

ag

en

ts,

the

eff

ect

ive

ne

ss o

f a

dd

ing

be

ha

vio

ral

sup

po

rt

the

rap

y t

o d

rug

th

era

py,

an

d t

he

eff

ect

ive

ne

ss o

f tr

ea

tin

g s

pe

cia

l p

op

ula

tio

ns

(in

clu

din

g a

do

lesc

en

ts,

tho

se w

ho

are

pre

gn

an

t a

nd

th

ose

wit

h

psy

chia

tric

dis

ord

ers

).

Mo

re t

ha

n 3

50

0 c

ita

tio

ns

we

re o

rig

ina

lly i

de

nti

fie

d a

nd

14

3 i

ncl

ud

ed

in

th

e m

eta

-an

aly

sis.

A

rtic

les

we

re i

ncl

ud

ed

fo

r cl

inic

al

eva

lua

tio

n if

the

y m

et

the

foll

ow

ing

cri

teri

a:

the

art

icle

wa

s a

ra

nd

om

ize

d c

on

tro

l tr

ial

wit

h a

fo

llo

w u

p o

f a

t le

ast

six

mo

nth

s; t

he

po

pu

lati

on

wa

s sm

oke

rs t

ha

t m

irro

red

th

e

ge

ne

ral

po

pu

lati

on

(b

oth

ge

nd

ers

, a

ll a

ge

s, m

ult

iple

eth

nic

itie

s) u

nle

ss a

sp

eci

fic

po

pu

lati

on

wa

s st

ud

ied

(a

do

lesc

en

ts);

th

e i

nte

rve

nti

on

stu

die

d w

as

bu

pro

pio

n,

va

ren

icli

ne

, N

RT

or

be

ha

vio

ral

sup

po

rt t

he

rap

y w

ith

an

act

ive

or

pla

ceb

o c

om

pa

rato

r; a

nd

th

e o

utc

om

e w

as

bio

che

mic

all

y i

de

nti

fie

d

smo

kin

g a

bst

ine

nce

.

Aft

er

scre

en

ing

fo

r cr

ite

ria

, 1

43

art

icle

s w

ere

in

clu

de

d f

or

an

aly

sis.

Q

ua

lity

ra

tin

gs

we

re a

ssig

ne

d t

o e

ach

art

icle

aft

er

revie

w u

sin

g a

co

mb

ina

tio

n o

f

the

Ja

da

d a

nd

Ha

ile

y s

cale

s.

Ra

tin

gs

ran

ge

d f

rom

hig

h t

o p

oo

r q

ua

lity

, a

lth

ou

gh

th

e m

ajo

rity

of

art

icle

s (5

3%

we

re g

ive

n t

he

hig

he

st r

ati

ng

.

All

se

ve

n m

ed

ica

tio

ns

we

re m

ore

eff

ect

ive

th

an

pla

ceb

o a

t h

elp

ing

pa

tie

nts

re

ma

in t

ob

acc

o f

ree

aft

er

six

mo

nth

s a

nd

on

e y

ea

r.

Co

mp

ari

ng

bu

pro

pio

n

wit

h N

RT

tre

atm

en

t sh

ow

ed

no

dif

fere

nce

in

ab

stin

en

ce r

ate

s o

ne

ye

ar

aft

er

qu

itti

ng

(O

R 1

.03

, 9

5%

CI

0.8

4-1

.27

).

Am

on

g i

nd

ivid

ua

l n

ico

tin

e

rep

lace

me

nt

pro

du

cts,

no

dif

fere

nce

wa

s fo

un

d b

etw

ee

n a

bst

ine

nce

ra

tes

aft

er

on

e y

ea

r. P

ati

en

ts o

n v

are

nic

lin

e h

ad

th

e h

igh

est

od

ds

of

be

ing

tob

acc

o f

ree

on

e y

ea

r a

fte

r q

uit

tin

g v

ers

us

pla

ceb

o (

OR

2.7

, 9

5%

CI

2.2

5-

3.2

4),

bu

pro

pio

n (

OR

1.4

3,

95

% C

I 1

.11

-1.8

4)

, a

nd

NR

T (

OR

1.4

7,

95

% C

I 1

.2-

1.8

2).

M

ost

co

mb

ina

tio

ns

of

me

dic

ati

on

s sh

ow

ed

no

im

pro

ve

me

nt

ove

r m

on

oth

era

py i

n a

bst

ine

nce

ra

tes.

T

he

exc

ep

tio

n w

as

two

co

mb

ina

tio

ns

of

NR

T f

orm

ula

tio

ns:

usi

ng

th

e n

ico

tin

e p

atc

h w

ith

th

e n

ico

tin

e g

um

or

na

sal

spra

y w

as

mo

re e

ffe

ctiv

e t

ha

n t

he

pa

tch

alo

ne

(a

t si

x m

on

ths,

pa

tch

+ g

um

:

OR

2.1

, 9

5%

CI

1.1

8-

3.7

1;

pa

tch

+ s

pra

y:

OR

2.4

, 9

5%

CI

1.2

7-4

.5).

All

me

dic

ati

on

s w

ere

ass

oci

ate

d w

ith

hig

he

r n

um

be

rs o

f a

dve

rse

eve

nts

co

mp

are

d w

ith

pla

ceb

o a

nd

th

e n

ico

tin

e s

pra

y s

ee

me

d t

o b

e a

sso

cia

ted

wit

h

mo

re a

dve

rse

eve

nts

th

an

nic

oti

ne

pa

tch

(O

R 3

.83

, 9

5%

CrI

1.0

7 t

o 1

3.7

6)

or

nic

oti

ne

in

ha

ler

(OR

5.1

2,

95

% C

rI 1

.28

to

20

.48

).T

he

nic

oti

ne

pa

tch

,

bu

pro

pio

n,

an

d v

are

nic

lin

e s

ho

we

d a

hig

he

r p

rop

ort

ion

of

wit

hd

raw

als

du

e t

o a

dve

rse

eve

nts

co

mp

are

d w

ith

pla

ceb

o w

ith

po

ole

d O

R’s

of

1.4

1 (

95

%

CI

1.0

2 t

o 1

.94

), 1

.74

(9

5%

CI

1.3

1 t

o 2

.31

), a

nd

1.5

2 (

95

% C

I 1

.09

to

2.1

2)

resp

ect

ive

ly.

Mo

re s

tud

ies

are

ne

ed

ed

to

se

e w

ha

t th

era

py,

if a

ny w

ork

s

be

st i

n s

pe

cia

l p

op

ula

tio

ns

incl

ud

ing

pre

gn

an

cy a

nd

th

e m

en

tall

y i

ll;

on

e s

tud

y s

ho

we

d t

he

use

of

the

nic

oti

ne

pa

tch

in

ad

ole

sce

nts

im

pro

ve

d t

ob

acc

o

75 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

6

Auth

or:

Am

y B

urn

s, P

har

m.D

.

ab

stin

en

ce r

ate

co

mp

are

d w

ith

pla

ceb

o f

or

up

to

six

mo

nth

s (O

R 4

.93

, 9

5%

CI

0.9

5-

25

.57

).

Th

ere

wa

s n

o a

na

lysi

s fo

r sm

okin

g c

ess

ati

on

ag

en

ts i

n

pa

tie

nts

wit

h c

ard

iova

scu

lar

dis

ea

se.

Th

e e

vid

en

ce o

f h

ea

d-t

o-h

ea

d c

om

pa

riso

ns

be

twe

en

me

dic

ati

on

s is

lim

ite

d.

Co

ncl

usi

on

s:

1.

Th

ere

is

hig

h q

ua

lity

evid

en

ce N

RT

, b

up

rop

ion

an

d v

are

nic

lin

e a

re a

ll e

ffic

aci

ou

s co

mp

are

d w

ith

pla

ceb

o in

tre

ati

ng

to

ba

cco

de

pe

nd

en

ce a

nd

pro

mo

tin

g l

on

g-t

erm

ce

ssa

tio

n.

2.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t th

ere

is

no

dif

fere

nce

in

eff

ica

cy i

n v

are

nic

lin

e,

bu

pro

pio

n a

nd

NR

T i

n t

ob

acc

o a

bst

ine

nce

ra

tes.

3.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t th

ere

is

no

dif

fere

nce

be

twe

en

NR

T f

orm

ula

tio

ns

in s

mo

kin

g a

bst

ine

nce

ra

tes.

4.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t a

ll s

eve

n t

ob

acc

o c

ess

ati

on

pro

du

cts

ha

ve

hig

he

r re

lap

se r

ate

s th

an

pla

ceb

o.

5.

Th

ere

is

hig

h t

o g

oo

d q

ua

lity

evid

en

ce t

ha

t co

mb

inin

g t

he

nic

oti

ne

pa

tch

wit

h t

he

nic

oti

ne

gu

m o

r n

asa

l sp

ray w

as

mo

re e

ffic

aci

ou

s th

an

th

e

pa

tch

alo

ne

.

6.

Th

ere

is

go

od

to

fa

ir q

ua

lity

evid

en

ce t

ha

t a

dd

ing

th

e n

ico

tin

e p

atc

h o

r g

um

to

be

ha

vio

ral th

era

py w

as

mo

re e

ffe

ctiv

e t

ha

n b

eh

avio

ral th

era

py

alo

ne

.

7.

In s

pe

cia

l p

op

ula

tio

ns,

th

ere

is

hig

h t

o f

air

qu

ality

, li

mit

ed

evid

en

ce t

ha

t th

ere

is

no

dif

fere

nce

in

sm

okin

g a

bst

ine

nce

ra

tes

be

twe

en

NR

T,

NR

T +

be

ha

vio

ral th

era

py,

or

be

ha

vio

ral th

era

py

alo

ne

vs.

pla

ceb

o i

n p

reg

na

nt

wo

ma

n

8.

In s

pe

cia

l p

op

ula

tio

ns,

th

ere

is

go

od

to

fa

ir q

ua

lity

, li

mit

ed

evid

en

ce t

ha

t th

e n

ico

tin

e p

atc

h i

s m

ore

eff

ect

ive

th

an

pla

ceb

o i

n a

do

lesc

en

ts.

9.

In s

pe

cia

l p

op

ula

tio

ns,

th

ere

is

go

od

to

po

or

qu

ality

evid

en

ce t

ha

t n

on

e o

f th

e c

urr

en

t m

ed

ica

tio

ns

ava

ila

ble

are

mo

re e

ffe

ctiv

e t

ha

n p

lace

bo

in

pa

tie

nts

wit

h m

en

tal

illn

ess

.

US D

ep

art

me

nt

of

He

alt

h a

nd

Hu

ma

n S

erv

ice

s2:

A m

eta

-an

aly

sis

by t

he

US

De

pa

rtm

en

t o

f H

ea

lth

an

d H

um

an

Se

rvic

es

ass

ess

ed

ra

nd

om

ize

d t

ria

ls t

o c

rea

te a

pu

bli

c h

ea

lth

se

rvic

e-s

po

nso

red

clin

ica

l

pra

ctic

e g

uid

eli

ne

in

Ma

y 2

00

8.

Th

is c

lin

ica

l p

ract

ice

gu

ide

lin

e a

nd

syst

em

ati

c re

vie

w w

as

spo

nso

red

by a

gro

up

eff

ort

of

Fe

de

ral

Go

ve

rnm

en

t a

ge

nci

es

an

d n

on

pro

fit

org

an

iza

tio

ns

incl

ud

ing

th

e A

ge

ncy

fo

r H

ea

lth

care

Re

sea

rch

an

d Q

ua

lity

(A

HR

Q),

th

e C

en

ters

fo

r D

ise

ase

Co

ntr

ol

(CD

C),

th

e N

ati

on

al

He

art

, Lu

ng

an

d B

loo

d I

nst

itu

te (

NH

LBI)

, a

nd

th

e N

ati

on

al

Ca

nce

r In

stit

ute

(N

CI)

. T

he

re

vie

w f

ocu

ses

on

ele

ve

n t

op

ics

incl

ud

ing

th

e e

ffe

ctiv

en

ess

of

com

bin

ing

co

un

seli

ng

an

d m

ed

ica

tio

n r

ela

tive

to

eit

he

r co

un

selin

g a

nd

me

dic

ati

on

alo

ne

, e

ffe

ctiv

en

ess

of

va

ren

icli

ne

, e

ffe

ctiv

en

ess

of

me

dic

ati

on

com

bin

ati

on

s, e

ffe

ctiv

en

ess

of

lon

g-t

erm

use

, a

nd

eff

ect

ive

ne

ss i

n s

pe

cia

l p

op

ula

tio

ns

(in

clu

din

g a

do

lesc

en

ts,

tho

se w

ho

are

pre

gn

an

t a

nd

th

ose

wit

h

psy

chia

tric

dis

ord

ers

).

Art

icle

s w

ere

in

clu

de

d i

f th

ey w

ere

a r

an

do

miz

ed

, p

lace

bo

/co

mp

ari

son

co

ntr

olle

d t

ria

l o

f a

to

ba

cco

use

tre

atm

en

t in

terv

en

tio

n w

ith

fo

llo

w-u

p r

esu

lts

at

lea

st 5

mo

nth

s a

fte

r th

e q

uit

da

te;

wa

s p

ub

lish

ed

be

twe

en

Ja

nu

ary

19

75

an

d J

un

e 2

00

7 i

n E

ng

lish

in

a p

ee

r-re

vie

we

d j

ou

rna

l; a

nd

ad

dre

sse

d o

ne

of

76 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

7

Auth

or:

Am

y B

urn

s, P

har

m.D

.

the

11

to

pic

s ch

ose

n f

or

revie

w.

Re

com

me

nd

ati

on

s b

ase

d o

n t

he

art

icle

s w

ere

giv

en

a s

tre

ng

th o

f e

vid

en

ce (

A,

B,

or

C)

rati

ng

ba

sed

on

th

e q

ua

lity

an

d

qu

an

tity

of

da

ta.

Se

ve

n F

DA

in

dic

ate

d m

ed

ica

tio

ns

we

re e

va

lua

ted

in

th

e s

yst

em

ati

c re

vie

w.

Oth

er

me

dic

ati

on

s u

sed

off

-la

be

l fo

r to

ba

cco

de

pe

nd

en

ce w

ere

als

o

incl

ud

ed

. 8

3 t

ria

ls w

ere

in

clu

de

d i

n a

me

ta-a

na

lysi

s co

mp

ari

ng

th

e e

ffe

ctiv

en

ess

of

smo

kin

g c

ess

ati

on

me

dic

ati

on

s w

ith

re

spe

ct t

o t

he

ra

te o

f

ab

stin

en

ce 6

mo

nth

s a

fte

r tr

ea

tme

nt.

T

his

re

vie

w i

de

nti

fie

d a

ll s

eve

n m

ed

ica

tio

ns

eff

ect

ive

in

in

cre

asi

ng

th

e o

dd

s o

f a

chie

vin

g a

bst

ine

nce

co

mp

are

d

to p

lace

bo

. A

me

ta-a

na

lysi

s w

as

pe

rfo

rme

d t

o a

llo

w f

or

com

pa

riso

ns

of

me

dic

ati

on

s b

etw

ee

n o

the

r a

ctiv

e m

ed

ica

tio

ns.

V

are

nic

lin

e 2

mg

/da

y

(nu

mb

er

of

tria

ls,

N=

5)

de

mo

nst

rate

d t

he

gre

ate

st o

dd

s o

f re

ma

inin

g t

ob

acc

o f

ree

six

mo

nth

s a

fte

r q

uit

tin

g (

OR

3.1

, 9

5%

CI

2.5

-3.8

) a

nd

wa

s

ass

oci

ate

d w

ith

an

est

ima

ted

ab

stin

en

ce r

ate

of

33

%.

Co

mb

ina

tio

n N

RT

wa

s a

lso

ass

oci

ate

d w

ith

a h

igh

er

est

ima

ted

ab

stin

en

ce r

ate

of

37

% (

mo

st

ph

arm

aco

the

rap

ies

sho

we

d a

n e

stim

ate

d r

ate

of

19

% t

o 2

6%

). S

ub

ject

s o

n a

ll f

orm

s o

f N

RT

, e

xce

pt

for

the

lo

zen

ge

fo

rmu

lati

on

, w

ere

mo

re l

ike

ly t

o

be

to

ba

cco

fre

e c

om

pa

red

to

pla

ceb

o.

Th

e n

ico

tin

e n

asa

l sp

ray a

nd

th

e h

igh

do

se (

>2

5m

g)

nic

oti

ne

pa

tch

sh

are

d t

he

se

con

d h

igh

est

od

ds

aft

er

va

ren

icli

ne

(b

oth

: O

R 2

.3,

95

% C

I 1

.7-3

.0).

B

up

rop

ion

SR

(N

=2

6)

use

wa

s a

lso

ass

oci

ate

d w

ith

gre

ate

r o

dd

s o

f b

ein

g t

ob

acc

o f

ree

co

mp

are

d w

ith

pla

ceb

o a

t si

x m

on

ths

(OR

2.0

, 9

5%

CI

1.8

-2.2

).

Clo

nid

ine

(N

=3

) a

nd

no

rtri

pty

lin

e (

N=

5)

are

use

d o

ff-l

ab

el

to t

rea

t to

ba

cco

de

pe

nd

en

ce;

pa

tie

nts

in

bo

th t

rea

tme

nt

arm

s w

ere

mo

re l

ike

ly t

o s

till

be

to

ba

cco

fre

e a

t si

x m

on

ths

tha

n t

he

ir p

lace

bo

co

un

terp

art

s.

Co

mb

ina

tio

n t

he

rap

y t

ha

t in

clu

de

d t

he

nic

oti

ne

pa

tch

wa

s sh

ow

n t

o b

e v

ery

eff

ect

ive

. T

he

pa

tch

wh

en

co

mb

ine

d w

ith

th

e n

ico

tin

e i

nh

ale

r (O

R 2

.2,

95

%C

I 1

.3-3

.6),

bu

pro

pio

n S

R (

OR

2.5

,

95

%C

I 1

.9-3

.4),

no

rtri

pty

lin

e (

OR

2.3

, 9

5%

CI

1.3

-4.2

), o

r th

e n

ico

tin

e g

um

/in

ha

ler

(OR

3.6

, 9

5%

CI

2.5

-5.2

) sh

ow

ed

im

pro

ve

d e

ffe

ctiv

en

ess

at

6 m

on

ths

com

pa

red

wit

h p

lace

bo

.

Co

ncl

usi

on

s:

1.

Th

ere

is

evid

en

ce t

ha

t fi

rst-

lin

e m

ed

ica

tio

ns

va

ren

icli

ne

, b

up

rop

ion

, n

ico

tin

e p

atc

h,

gu

m,

inh

ale

r a

nd

na

sal

spra

y a

pp

ea

r to

be

eff

ect

ive

smo

kin

g c

ess

ati

on

tre

atm

en

ts.

(Str

en

gth

of

evid

en

ce A

)

2.

Th

ere

is

evid

en

ce t

ha

t th

e n

ico

tin

e l

oze

ng

e i

s a

n e

ffe

ctiv

e s

mo

kin

g c

ess

ati

on

tre

atm

en

t. (

Str

en

gth

of

evid

en

ce B

)

3.

Th

ere

is

evid

en

ce t

ha

t se

con

d-l

ine

sm

okin

g c

ess

ati

on

me

dic

ati

on

s, c

lon

idin

e a

nd

no

rtri

pty

lin

e,

ap

pe

ar

to b

e e

ffe

ctiv

e s

mo

kin

g c

ess

ati

on

tre

atm

en

ts w

he

n u

sed

un

de

r a

ph

ysi

cia

n’s

su

pe

rvis

ion

. (S

tre

ng

th o

f e

vid

en

ce A

)

4.

Th

ere

is

evid

en

ce t

ha

t u

sin

g a

co

mb

ina

tio

n o

f th

e n

ico

tin

e p

atc

h a

nd

oth

er

NR

T o

r b

up

rop

ion

ap

pe

ar

to b

e e

ffe

ctiv

e s

mo

kin

g c

ess

ati

on

tre

atm

en

ts.

(Str

en

gth

of

evid

en

ce A

)

5.

Th

ere

is

evid

en

ce t

ha

t th

e c

om

bin

ati

on

of

cou

nse

lin

g a

nd

me

dic

ati

on

is

mo

re e

ffe

ctiv

e f

or

smo

kin

g c

ess

ati

on

th

an

eit

he

r m

ed

ica

tio

n o

r

cou

nse

lin

g a

lon

e.

(Str

en

gth

of

evid

en

ce A

)

6.

Th

ere

is

insu

ffic

ien

t e

vid

en

ce s

up

po

rtin

g t

he

use

of

smo

kin

g c

ess

ati

on

me

dic

ati

on

s in

th

e f

oll

ow

ing

sp

eci

al

po

pu

lati

on

s: p

reg

na

nt

wo

me

n,

ad

ole

sce

nts

, sm

oke

-le

ss t

ob

acc

o u

sers

, a

nd

lig

ht

smo

ke

rs w

ho

sm

oke

le

ss t

ha

n 1

0 c

iga

rett

es

pe

r d

ay.

77 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

8

Auth

or:

Am

y B

urn

s, P

har

m.D

.

Th

e C

och

ran

e C

oll

ab

ora

tio

n3

-8:

In 2

00

8,

a s

yst

em

ati

c re

vie

w e

va

lua

ted

if

nic

oti

ne

re

pla

cem

en

t th

era

py i

s m

ore

eff

ect

ive

th

an

pla

ceb

o a

t a

chie

vin

g a

bst

ine

nce

fro

m s

mo

kin

g.

Th

irte

en

oth

er

ob

ject

ive

s w

ere

an

aly

zed

in

clu

din

g i

f o

ne

NR

T f

orm

ula

tio

n i

s m

ore

eff

ect

ive

th

an

th

e o

the

rs,

if c

om

bin

ati

on

NR

T i

s m

ore

eff

ect

ive

th

an

mo

no

the

rap

y,

or

if N

RT

is

mo

re e

ffe

ctiv

e t

ha

n o

the

r sm

okin

g c

ess

ati

on

tre

atm

en

t.

Art

icle

s w

ere

in

clu

de

d i

f th

ey w

ere

an

RC

T w

he

re a

NR

T w

as

com

pa

red

wit

h p

lace

bo

, a

n a

ctiv

e c

om

pa

rato

r, o

r n

o t

rea

tme

nt

at

all

. T

he

pri

ma

ry

ou

tco

me

wa

s a

bst

ine

nce

fro

m s

mo

kin

g w

ith

a f

ollo

w u

p o

f a

t le

ast

six

mo

nth

s.

A m

eta

-an

aly

sis

wa

s p

erf

orm

ed

on

th

e 1

11

art

icle

s se

lect

ed

fo

r re

vie

w.

All

fo

rms

of

NR

T w

ere

sh

ow

n t

o b

e m

ore

eff

ect

ive

th

an

pla

ceb

o i

n m

ain

tain

ing

to

ba

cco

ab

stin

en

ce (

RR

1.5

8,

95

% C

I 1

.5-1

.66

) a

t si

x m

on

ths.

O

f th

e

five

fo

rms

of

nic

oti

ne

pro

du

cts,

pa

tie

nts

on

th

e n

asa

l sp

ray (

nu

mb

er

of

tria

ls,

N=

4)

an

d t

he

lo

zen

ge

(N

=6

) h

ad

th

e g

rea

test

pro

ba

bil

ity o

f re

ma

inin

g

smo

ke

-fre

e (

RR

2.0

2,

95

% C

I 1

.49

-3.7

3;

RR

2.0

, 9

5%

CI

1.6

3-2

.45

re

spe

ctiv

ely

).

Th

e i

nh

ale

r (N

=4

; R

R 1

.9,

95

% C

I 1

.36

-2.6

7),

th

e p

atc

h (

N=

41

; R

R 1

.66

,

95

% C

I 1

.53

-1.8

1),

an

d t

he

gu

m (

N=

53

; R

R 1

.43

, 9

5%

CI

1.3

3-1

.53

) w

ere

als

o f

ou

nd

mo

re e

ffic

aci

ou

s th

an

pla

ceb

o.

On

ly t

hre

e t

ria

ls d

ire

ctly

co

mp

are

d

NR

T t

he

rap

ies;

no

ne

of

the

th

ree

fo

un

d a

ny s

ign

ific

an

t d

iffe

ren

ce b

etw

ee

n f

orm

ula

tio

ns.

T

wo

tri

als

lo

oke

d a

t N

RT

ve

rsu

s b

up

rop

ion

bu

t n

eit

he

r fo

un

d

a s

ign

ific

an

t d

iffe

ren

ce i

n s

ust

ain

ed

qu

it r

ate

s.

Se

ve

n t

ria

ls c

om

pa

red

co

mb

ina

tio

n t

he

rap

y (

pa

tch

+ a

no

the

r N

RT

ag

en

t) w

ith

NR

T m

on

oth

era

py.

Pa

tie

nts

usi

ng

co

mb

ina

tio

n t

he

rap

y h

ad

hig

he

r ra

tes

of

ab

stin

en

ce a

t si

x m

on

ths

tha

n p

ati

en

ts u

sin

g o

ne

NR

T (

RR

1.3

5,

95

% C

I 1

.11

to

1.6

3).

A 2

00

9 r

evie

w l

oo

ke

d a

t w

he

the

r a

nti

-de

pre

ssa

nt

use

he

lps

in q

uit

tin

g t

ob

acc

o.

Tw

elv

e a

nti

de

pre

ssa

nts

we

re a

sse

sse

d i

n t

his

syst

em

ati

c re

vie

w f

or

eff

ect

ive

ne

ss i

n t

ob

acc

o c

ess

ati

on

. F

DA

-ap

pro

ved

aty

pic

al

an

tid

ep

ress

an

t b

up

rop

ion

; S

SR

Is f

luo

xeti

ne

, se

rtra

lin

e a

nd

pa

roxe

tin

e;

MA

O i

nh

ibit

ors

mo

colo

be

mid

e,

an

d s

ele

gil

ine

; tr

icycl

ics

no

rtri

pty

lin

e,

do

xep

in a

nd

im

ipra

min

e;

ve

nla

faxi

ne

; tr

yp

top

ha

n;

an

d S

t. J

oh

n’s

Wo

rt w

ere

all i

ncl

ud

ed

. O

the

r

incl

usi

on

cri

teri

a w

ere

RC

T w

ith

a p

lace

bo

or

act

ive

co

mp

ara

tor

an

d a

t le

ast

six

mo

nth

s fo

llo

w u

p.

A m

eta

-an

aly

sis

wa

s co

nd

uct

ed

wit

h t

he

da

ta g

ath

ere

d f

rom

th

e 6

6 a

rtic

les

wh

ich

me

t cr

ite

ria

.

Th

e m

ajo

rity

of

art

icle

s e

va

lua

ted

bu

pro

pio

n (

nu

mb

er

of

art

icle

s, N

=4

9)

or

no

rtri

pty

lin

e (

N=

9).

B

oth

we

re f

ou

nd

to

be

eff

ica

cio

us

in h

elp

ing

pa

tie

nts

re

ma

in t

ob

acc

o f

ree

at

six

mo

nth

s (b

up

rop

ion

RR

1.6

9,

95

%C

I 1

.53

-1.8

5;

no

rtri

pty

lin

e R

R 2

.03

95

%C

I 1

.48

-2.7

8).

A

dd

ing

bu

pro

pio

n o

r n

ort

rip

tyli

ne

to

NR

T w

as

no

t m

ore

eff

ect

ive

th

an

eit

he

r a

nti

-de

pre

ssa

nt

alo

ne

, a

nd

in

dir

ect

co

mp

ara

tor

tria

ls b

oth

we

re a

s e

ffe

ctiv

e a

s N

RT

as

mo

no

the

rap

y.

Th

ree

tri

als

co

mp

are

d b

up

rop

ion

to

va

ren

icli

ne

. P

ati

en

ts i

n t

he

bu

pro

pio

n a

rms

ha

d l

ow

er

qu

it r

ate

s a

t si

x m

on

ths

tha

n t

ho

se i

n t

he

va

ren

icli

ne

gro

up

s (R

R 0

.66

, 9

5%

CI

0.5

3-0

.82

).

No

tre

atm

en

t e

ffe

cts

we

re s

ee

n

wit

h v

en

lafa

xin

e,

the

SS

RIs

or

the

MA

O in

hib

ito

rs.

No

lo

ng

-te

rm d

ata

wa

s fo

un

d f

or

St.

Jo

hn

’s W

ort

, tr

yp

top

ha

n,

do

xep

in a

nd

im

ipra

min

e.

In 2

01

1 a

syst

em

ati

c re

vie

w e

xam

ine

d v

are

nic

lin

e a

nd

its

eff

ect

ive

ne

ss a

s a

sm

okin

g c

ess

ati

on

ag

en

t.

Art

icle

s w

ere

in

clu

de

d i

f th

ey w

ere

a R

CT

wh

ich

com

pa

red

va

ren

icli

ne

to

pla

ceb

o,

bu

pro

pio

n o

r N

RT

. A

ll t

ria

ls w

ere

re

qu

ire

d t

o h

ave

a f

oll

ow

-up

pe

rio

d o

f a

t le

ast

six

mo

nth

s.

Fo

urt

ee

n t

ria

ls w

ere

ide

nti

fie

d f

or

incl

usi

on

; th

e m

ajo

rity

ha

d a

pla

ceb

o c

on

tro

l (n

um

be

r o

f tr

ials

, N

=1

1),

th

ree

tri

als

co

mp

are

d v

are

nic

lin

e t

o b

up

rop

ion

an

d t

wo

op

en

-

lab

el

tria

ls h

ad

a N

RT

co

mp

ara

tor.

T

he

va

ren

iclin

e p

ati

en

ts i

n a

ll c

om

pa

rato

r tr

ials

ha

d h

igh

er

rate

s o

f to

ba

cco

ab

stin

en

ce:

vs.

pla

ceb

o a

t si

x m

on

ths

(RR

2.3

1,

95

% C

I 2

.01

-2.6

6),

vs.

bu

pro

pio

n a

t o

ne

ye

ar

(RR

1.5

2,

95

% C

I 1

.22

-1.8

8),

an

d v

s. N

RT

at

six

mo

nth

s (R

R 1

.13

, 9

5%

CI

0.9

4-1

.35

; n

ot

sig

nif

ica

nt)

.

78 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

9

Auth

or:

Am

y B

urn

s, P

har

m.D

.

Clo

nid

ine

, a

n a

lph

a-2

re

cep

tor

ag

on

ist,

is

oft

en

use

d o

ff-l

ab

el

for

smo

kin

g c

ess

ati

on

. A

20

08

up

da

ted

syst

em

ati

c re

vie

w a

na

lyze

d t

he

eff

ect

ive

ne

ss o

f

clo

nid

ine

fo

r th

is.

Six

tri

als

we

re i

ncl

ud

ed

fo

r m

eta

-an

aly

sis;

th

ree

use

d t

ran

sde

rma

l cl

on

idin

e a

nd

th

ree

use

d t

he

ora

l fo

rm.

All

tri

als

we

re R

CT

,

pla

ceb

o c

on

tro

lle

d w

ith

at

lea

st s

ix m

on

ths

foll

ow

-up

. P

ati

en

ts u

sin

g c

lon

idin

e h

ad

hig

he

r ra

tes

of

qu

itti

ng

at

six

mo

nth

s th

an

th

ose

re

ceiv

ing

pla

ceb

o

(RR

1.6

3,

95

% C

I 1

.22

-2.1

8).

Pa

tie

nts

wit

h m

en

tal

illn

ess

ha

ve

hig

he

r ra

tes

of

tob

acc

o d

ep

en

de

nce

th

an

th

e g

en

era

l p

op

ula

tio

n.

Th

ey a

re a

lso

mo

re d

iffi

cult

to

tre

at

be

cau

se o

f

the

ir m

en

tal

illn

ess

. A

20

10

syst

em

ati

c re

vie

w e

va

lua

ted

sm

okin

g c

ess

ati

on

tri

als

in

sch

izo

ph

ren

ic p

op

ula

tio

ns.

A

rtic

les

we

re i

ncl

ud

ed

if

the

y w

ere

a

RC

T w

ith

a s

chiz

op

hre

nic

or

sch

izo

aff

ect

ive

ad

ult

sm

oke

r p

op

ula

tio

n.

An

y t

ob

acc

o i

nte

rve

nti

on

wa

s a

cce

pta

ble

fo

r in

clu

sio

n,

alt

ho

ug

h a

pla

ceb

o o

r

act

ive

co

ntr

ol

wa

s re

qu

ire

d.

Un

like

ma

ny t

ob

acc

o c

ess

ati

on

re

vie

ws,

re

du

ctio

n i

n s

mo

kin

g w

as

an

ou

tco

me

alo

ng

wit

h a

bst

ine

nce

.

A t

ota

l o

f 2

1

art

icle

s w

ere

in

clu

de

d f

or

an

aly

sis;

11

tri

als

use

d s

mo

kin

g c

ess

ati

on

as

an

ou

tco

me

. O

f th

ose

, se

ve

n c

om

pa

red

bu

pro

pio

n w

ith

pla

ceb

o a

nd

fo

un

d

bu

pro

pio

n u

se w

as

ass

oci

ate

d w

ith

hig

he

r q

uit

ra

tes

at

the

en

d o

f tr

ea

tme

nt

(RR

2.8

4,

95

% C

I 1

.66

-4.9

9)

an

d a

t si

x m

on

ths

foll

ow

-up

(n

um

be

r o

f tr

ials

,

N=

5),

(R

R 2

.78

, 9

5%

CI

1.0

2-7

.58

).

No

sig

nif

ica

nt

dif

fere

nce

s w

ere

se

en

in

sch

izo

ph

ren

ic s

ym

pto

ms

(po

siti

ve

or

ne

ga

tive

) b

etw

ee

n t

he

pla

ceb

o a

nd

bu

pro

pio

n g

rou

ps.

T

hre

e t

ria

ls c

om

pa

red

NR

T p

lus

be

ha

vio

ral

the

rap

y v

ers

us

rou

tin

e c

are

or

pla

ceb

o.

No

sig

nif

ica

nt

dif

fere

nce

in

ce

ssa

tio

n o

r

smo

kin

g r

ed

uct

ion

wa

s se

en

. R

esu

lts

we

re s

imila

r in

tw

o c

ross

-ove

r n

ico

tin

e p

atc

h s

tud

ies:

no

dif

fere

nce

wa

s se

en

be

twe

en

th

e p

atc

h a

nd

pla

ceb

o

gro

up

s.

Oth

er

ph

arm

aco

log

ica

l in

terv

en

tio

ns

exa

min

ed

: to

pir

am

ate

, cl

oza

pin

e,

ato

mo

xeti

ne

, a

nd

ga

lan

tam

ine

we

re f

ou

nd

to

be

eit

he

r in

con

clu

sive

or

ine

ffe

ctiv

e.

Pre

gn

an

t sm

oke

rs a

re a

n o

fte

n t

arg

ete

d p

op

ula

tio

n f

or

smo

kin

g c

ess

ati

on

s in

terv

en

tio

ns.

Sm

okin

g d

uri

ng

pre

gn

an

cy c

an

ca

use

de

mo

nst

rate

d h

arm

to

the

fe

tus

an

d m

oth

er.

Use

of

ph

arm

aco

log

ica

l to

ba

cco

ab

stin

en

ce a

ge

nts

is

con

tro

ve

rsia

l d

uri

ng

pre

gn

an

cy,

lea

vin

g b

eh

avio

ral

the

rap

y a

s th

e

tre

atm

en

t o

f ch

oic

e.

A 2

00

9 s

yst

em

ati

c re

vie

w e

xam

ine

d s

mo

kin

g c

ess

ati

on

in

terv

en

tio

ns

du

rin

g p

reg

na

ncy

an

d t

he

ir s

ucc

ess

ra

tes.

A

rtic

les

we

re

incl

ud

ed

if

the

y w

ere

a R

CT

wit

h p

reg

na

nt

ad

ult

sm

oke

rs a

nd

ha

d a

pri

ma

ry o

utc

om

e o

f sm

okin

g c

ess

ati

on

.

In

th

e 6

5 a

rtic

les

incl

ud

ed

fo

r a

na

lysi

s,

pa

tie

nts

wh

o w

ere

ta

rge

ted

wit

h a

sm

okin

g c

ess

ati

on

in

terv

en

tio

n w

ere

le

ss l

ike

ly t

o c

on

tin

ue

sm

okin

g i

n t

he

th

ird

tri

me

ste

r th

an

th

ose

wit

h n

o

inte

rve

nti

on

(R

R 0

.94

, 9

5%

CI

0.9

2-0

.96

).

Fiv

e o

f th

e t

ria

ls e

mp

loye

d N

RT

as

the

in

terv

en

tio

n.

Usi

ng

NR

T d

id n

ot

ap

pe

ar

to h

ave

an

y m

ore

eff

ica

cy

tha

n o

the

r n

on

-ph

arm

aco

log

ic i

nte

rve

nti

on

s, b

ut

did

ca

use

gre

ate

r sa

fety

co

nce

rns.

O

ne

NR

T t

ria

l w

as

dis

con

tin

ue

d e

arl

y d

ue

to

la

rge

sta

tist

ica

lly

sig

nif

ica

nt

dif

fere

nce

be

twe

en

th

e N

RT

an

d p

lace

bo

gro

up

s in

ad

ve

rse

eve

nts

, in

clu

din

g f

eta

l d

ea

th.

Co

ncl

usi

on

s:

1.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t th

e n

ico

tin

e i

nh

ale

r, n

asa

l sp

ray a

nd

pa

tch

are

eff

ect

ive

me

dic

ati

on

s fo

r sm

okin

g c

ess

ati

on

.

2.

Th

ere

is

go

od

qu

ality

evid

en

ce t

ha

t th

e n

ico

tin

e g

um

an

d lo

zen

ge

are

eff

ect

ive

me

dic

ati

on

s fo

r sm

okin

g c

ess

ati

on

.

3.

Th

ere

is

go

od

qu

ality

evid

en

ce t

o c

on

clu

de

th

at

com

bin

ati

on

NR

T t

ha

t in

clu

de

s th

e n

ico

tin

e p

atc

h is

mo

re e

ffe

ctiv

e t

ha

n m

on

oth

era

py.

4.

Th

ere

is

insu

ffic

ien

t e

vid

en

ce t

o c

on

clu

de

if

bu

pro

pio

n i

s m

ore

eff

ect

ive

th

an

NR

T.

5.

Th

ere

is

go

od

qu

ality

evid

en

ce t

ha

t b

up

rop

ion

is

an

eff

ect

ive

me

dic

ati

on

fo

r sm

okin

g c

ess

ati

on

.

6.

Th

ere

is

go

od

qu

ality

evid

en

ce t

ha

t n

ort

rip

tyli

ne

is

an

eff

ect

ive

me

dic

ati

on

fo

r sm

okin

g c

ess

ati

on

.

79 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

10

Auth

or:

Am

y B

urn

s, P

har

m.D

.

7.

Th

ere

is

lim

ite

d g

oo

d-t

o-f

air

qu

ality

evid

en

ce t

ha

t S

SR

Is f

luo

xeti

ne

, p

aro

xeti

ne

, a

nd

se

rtra

lin

e a

re n

ot

eff

ect

ive

me

dic

ati

on

s fo

r sm

okin

g

cess

ati

on

.

8.

Th

ere

is

go

od

qu

ality

evid

en

ce t

ha

t va

ren

iclin

e i

s a

n e

ffe

ctiv

e m

ed

ica

tio

n f

or

smo

kin

g c

ess

ati

on

.

9.

Th

ere

is

lim

ite

d g

oo

d q

ua

lity

evid

en

ce t

ha

t va

ren

icli

ne

is

a m

ore

eff

ect

ive

me

dic

ati

on

fo

r sm

okin

g c

ess

ati

on

th

an

bu

pro

pio

n.

10

.T

he

re i

s li

mit

ed

fa

ir-t

o-p

oo

r q

ua

lity

evid

en

ce t

ha

t va

ren

icli

ne

is

a m

ore

eff

ect

ive

me

dic

ati

on

fo

r sm

okin

g c

ess

ati

on

th

an

NR

T.

11

.T

he

re i

s li

mit

ed

go

od

-to

-fa

ir q

ua

lity

evid

en

ce t

ha

t cl

on

idin

e i

s a

n e

ffe

ctiv

e m

ed

ica

tio

n f

or

smo

kin

g c

ess

ati

on

.

12

.T

he

re i

s fa

ir q

ua

lity

evid

en

ce t

ha

t b

up

rop

ion

is

an

eff

ect

ive

me

dic

ati

on

fo

r sm

okin

g c

ess

ati

on

in

sch

izo

ph

ren

ic a

nd

sch

izo

aff

ect

ive

po

pu

lati

on

s.

13

.T

he

re i

s in

suff

icie

nt

evid

en

ce t

o c

on

clu

de

if

NR

T is

an

eff

ect

ive

sm

okin

g c

ess

ati

on

th

era

py

in s

chiz

op

hre

nic

an

d s

chiz

oa

ffe

ctiv

e p

op

ula

tio

ns.

14

.T

he

re i

s fa

ir-t

o-p

oo

r q

ua

lity

evid

en

ce t

ha

t sm

okin

g c

ess

ati

on

in

terv

en

tio

ns

in p

reg

na

nt

wo

me

n d

ecr

ea

se s

mo

kin

g r

ate

s.

15

. T

he

re i

s in

suff

icie

nt

evid

en

ce t

o c

on

clu

de

if

NR

T is

a s

afe

or

eff

ect

ive

sm

okin

g c

ess

ati

on

th

era

py i

n p

reg

na

nt

po

pu

lati

on

s.

Re

ma

inin

g I

ssu

es:

F

urt

he

r st

ud

ies

are

ne

ed

ed

to

ass

ess

th

e r

ela

tive

eff

ect

ive

ne

ss a

nd

sa

fety

of

the

se

ve

n F

DA

-ap

pro

ve

d m

ed

ica

tio

ns

for

lon

g-t

erm

tre

atm

en

t,

in g

en

era

l a

nd

fo

r sp

eci

fic

sub

po

pu

lati

on

s (w

om

en

; a

do

lesc

en

ts;

old

er

smo

ke

rs;

smo

ke

less

to

ba

cco

u

sers

; in

div

idu

als

w

ith

p

sych

iatr

ic

dis

ord

ers

, in

clu

din

g s

ub

sta

nce

use

dis

ord

ers

; p

ost

-myo

card

ial in

farc

tio

n p

ati

en

ts).

F

urt

he

r st

ud

ies

are

ne

ed

ed

to

eva

lua

te t

he

use

of

com

bin

ed

to

ba

cco

de

pe

nd

en

ce m

ed

ica

tio

ns

in g

en

era

l a

nd

fo

r sp

eci

fic

sub

po

pu

lati

on

s

(e.g

. h

igh

ly d

ep

en

de

nt

smo

ke

rs).

F

urt

he

r st

ud

ies

are

ne

ed

ed

to

ass

ess

th

e e

ffe

ctiv

en

ess

of

pre

-qu

it N

RT

use

in

in

cre

asi

ng

ab

stin

en

ce r

ate

s.

F

urt

he

r st

ud

ies

are

ne

ed

ed

to

ad

dre

ss t

he

co

mp

ara

tive

eff

ica

cy o

f O

TC

tre

atm

en

ts v

ers

us

pre

scri

pti

on

tre

atm

en

t

F

urt

he

r st

ud

y i

s n

ee

de

d t

o d

ete

rmin

e i

f sm

okin

g f

or

a l

on

ge

r d

ura

tio

n a

fte

r st

art

ing

va

ren

icli

ne

is

mo

re e

ffe

ctiv

e a

t im

pro

vin

g l

on

g-t

erm

ab

stin

en

ce t

ha

n t

he

ori

gin

al

va

ren

icli

ne

pa

cka

gin

g r

eco

mm

en

da

tio

n o

f o

ne

we

ek.

III.

Gu

ide

lin

es

1.

Sm

okin

g c

ess

ati

on

se

rvic

es

in p

rim

ary

ca

re,

ph

arm

aci

es,

lo

cal

au

tho

riti

es

an

d w

ork

pla

ces,

pa

rtic

ula

rly f

or

ma

nu

al

wo

rkin

g g

rou

ps,

pre

gn

an

t

wo

me

n a

nd

ha

rd t

o r

ea

ch c

om

mu

nit

ies .

9

80 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

11

Auth

or:

Am

y B

urn

s, P

har

m.D

.

De

ve

lop

er:

P

ub

lish

ed

:

Na

tio

na

l In

stit

ute

fo

r H

ea

lth

an

d C

lin

ica

l E

xce

lle

nce

2

00

8

Re

com

me

nd

ati

on

s:

i.T

he

re i

s h

igh

qu

ali

ty e

vid

en

ce t

ha

t b

rie

f in

terv

en

tio

ns

by h

ea

lth

care

pro

fess

ion

als

to

ad

vis

e a

nd

dis

cuss

sm

okin

g a

re e

ffe

ctiv

e i

n h

elp

ing

smo

kin

g c

ess

ati

on

.

ii.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t in

div

idu

al o

r g

rou

p b

eh

avio

ral co

un

seli

ng

is

eff

ect

ive

in

aid

ing

to

ba

cco

ce

ssa

tio

n.

iii.

Th

ere

is

hig

h q

ua

lity

evid

en

ce t

ha

t m

ed

ica

tio

ns

ava

ila

ble

fo

r to

ba

cco

de

pe

nd

en

ce (

bu

pro

pio

n,

va

ren

icli

ne

, a

nd

nic

oti

ne

re

pla

cem

en

t th

era

py)

are

eff

ect

ive

in

ass

isti

ng

sm

okin

g c

ess

ati

on

.

iv.

Th

e g

uid

elin

e r

eco

mm

en

ds

usi

ng

pro

fess

ion

al

jud

gm

en

t w

he

n p

resc

rib

ing

to

ba

cco

ce

ssa

tio

n m

ed

ica

tio

n i

n s

pe

cia

l p

op

ula

tio

ns

incl

ud

ing

pre

gn

an

t o

r b

rea

stfe

ed

ing

mo

the

rs a

nd

ad

ole

sce

nts

.

Cri

tiq

ue

:

Th

e N

ICE

sm

okin

g c

ess

ati

on

gu

ide

lin

e is

aim

ed

at

a l

arg

e t

arg

et

au

die

nce

an

d i

s e

xpa

nsi

ve

in

sco

pe

.

Se

arc

h c

rite

ria

are

giv

en

in

bro

ad

de

scri

pti

on

s, b

ut

wit

h d

ire

ctio

n t

o a

pp

en

dic

es

wit

h m

ore

de

taile

d i

nfo

rma

tio

n.

In

tern

al

an

d e

xte

rna

l p

ee

r re

vie

ws

we

re c

on

du

cte

d t

o v

alid

ate

th

e g

uid

elin

e.

A h

iera

rch

y o

f E

vid

en

ce R

ati

ng

syst

em

wa

s u

sed

to

ass

ess

th

e q

ua

lity

an

d s

tre

ng

th o

f th

e e

vid

en

ce

Th

is g

uid

elin

e i

s fu

nd

ed

by t

he

Go

ve

rnm

en

t o

f th

e U

nit

ed

Kin

gd

om

.

2.

Co

un

selin

g a

nd

in

terv

en

tio

ns

to p

reve

nt

tob

acc

o u

se a

nd

to

ba

cco

-ca

use

d d

ise

ase

in

ad

ult

s a

nd

pre

gn

an

t w

om

en

: U

.S.

Pre

ve

nti

ve

Se

rvic

es

Ta

sk

Fo

rce

re

aff

irm

ati

on

re

com

me

nd

ati

on

sta

tem

en

t10

De

ve

lop

er:

P

ub

lish

ed

:

U.S

. P

reve

nti

ve

Se

rvic

es

Ta

sk F

orc

e

U

pd

ate

20

09

Re

com

me

nd

ati

on

s:

i.T

he

re i

s h

igh

qu

ali

ty e

vid

en

ce t

ha

t cl

inic

ian

s a

sk a

ll a

du

lts

ab

ou

t to

ba

cco

use

an

d p

rovid

e t

ob

acc

o c

ess

ati

on

in

terv

en

tio

ns

for

tho

se w

ho

use

tob

acc

o p

rod

uct

s

ii.

Th

ere

is

hig

h q

ua

lity

evi

de

nce

th

at

clin

icia

ns

ask

all

pre

gn

an

t w

om

en

ab

ou

t to

ba

cco

use

an

d p

rovid

e a

ug

me

nte

d,

pre

gn

an

cy t

ail

ore

d

cou

nse

lin

g f

or

tho

se w

ho

sm

oke

.

81 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

12

Auth

or:

Am

y B

urn

s, P

har

m.D

.

iii.

Th

ere

is

evid

en

ce t

ha

t co

mb

ina

tio

n o

f m

ed

ica

tio

n a

nd

co

un

seli

ng

th

era

py is

mo

re e

ffe

ctiv

e a

t in

cre

asi

ng

ce

ssa

tio

n r

ate

s o

f e

ith

er

alo

ne

.

Cri

tiq

ue

:

Th

e T

ask

Fo

rce

is

an

in

de

pe

nd

en

t e

xpe

rt p

an

el

fun

de

d b

y t

he

US

Go

ve

rnm

en

t.

Th

e t

arg

et

au

die

nce

s fo

r th

is g

uid

eli

ne

are

he

alt

hca

re p

rovid

ers

in

th

e

pri

ma

ry c

are

se

ttin

g.

Exp

ert

op

inio

n c

on

sen

sus

is g

ive

n g

rea

t w

eig

ht

in t

he

gu

ide

lin

e,

pa

rtic

ula

rly f

or

sub

ject

s su

ch a

s sc

ree

nin

g w

hic

h a

re d

iffi

cult

to

qu

an

tify

usi

ng

RC

Ts.

Evid

en

ce i

s ra

nke

d o

n t

he

str

en

gth

an

d s

ou

rce

of

da

ta a

s “h

igh

, m

od

era

te a

nd

lo

w c

ert

ain

ty o

f n

et

be

ne

fit”

an

d t

he

n g

rad

ed

thro

ug

h t

he

pa

ne

ls c

on

sen

sus

on

th

e d

eg

ree

of

ma

gn

itu

de

of

tha

t b

en

efi

t: g

rad

e A

is

tho

ug

ht

to p

rovid

e s

ub

sta

nti

al

be

ne

fit

wh

ile

gra

de

D p

rovid

es

no

be

ne

fit.

IV.

FD

A S

afe

ty A

lert

s

In 2

01

1,

the

FD

A r

evie

we

d n

ew

sa

fety

in

form

ati

on

fo

r va

ren

icli

ne

co

nce

rnin

g c

ard

iova

scu

lar

an

d n

eu

rop

sych

iatr

ic a

dve

rse

eve

nts

.11

-12

Va

ren

iclin

e

(Ch

an

tix

®)

ma

y b

e a

sso

cia

ted

wit

h a

n i

ncr

ea

sed

ris

k o

f ca

rdio

va

scu

lar

ad

vers

e e

ve

nts

. T

he

ne

w d

ata

on

ca

rdio

va

scu

lar

safe

ty c

am

e f

rom

a r

ece

nt

RC

T

eva

lua

tin

g t

he

sa

fety

an

d e

ffic

acy

of

va

ren

icli

ne

. T

he

tri

al

wa

s tw

elv

e w

ee

ks

of

tre

atm

en

t w

ith

va

ren

icli

ne

or

pla

ceb

o a

nd

th

en

40

we

eks

of

foll

ow

-up

in a

po

pu

lati

on

of

sta

ble

ca

rdio

va

scu

lar

dis

ea

se p

ati

en

ts.

Th

e c

on

tin

uo

us

ab

stin

en

ce r

ate

fro

m w

ee

k 9

to

we

ek 5

2 s

ho

we

d t

he

va

ren

icli

ne

arm

wa

s

sig

nif

ica

ntl

y m

ore

lik

ely

to

re

ma

in t

ob

acc

o f

ree

(O

R 3

.14

, 9

5%

CI

1.9

3-

5.1

1;

P=

0.0

00

1).

H

ow

eve

r, a

sm

all

nu

mb

er

of

pa

rtic

ipa

nts

exp

eri

en

ced

a

seri

ou

s ca

rdio

va

scu

lar

ad

ve

rse

e

ve

nt,

m

ore

o

fte

n

to

the

va

ren

icli

ne

g

rou

p

tha

n

the

co

ntr

ol:

n

on

fata

l M

I 2

.0%

vs.

0

.9%

, n

ee

d

for

coro

na

ry

reva

scu

lari

zati

on

2.3

% v

s. 0

.9%

, n

ew

dia

gn

osi

s o

f P

VD

1.4

% v

s. 0

.9%

. T

he

tri

al

wa

s n

ot

po

we

red

to

qu

an

tify

th

e s

tati

stic

al

dif

fere

nce

s se

en

.13

Th

e

FD

A

inst

ruct

ed

P

fize

r to

a

dd

th

e

ne

w

card

iac

safe

ty

info

rma

tio

n

to

the

“W

arn

ing

s a

nd

P

reca

uti

on

s”

in

Ch

an

tix

lab

eli

ng

a

nd

p

resc

rib

ing

info

rma

tio

n.

G

ive

n t

he

ris

k o

f se

rio

us

card

iova

scu

lar

eve

nts

occ

urr

ing

in

th

is p

op

ula

tio

n (

pa

tie

nts

wit

h c

ard

iova

scu

lar

dis

ea

se w

ho

co

nti

nu

e t

o

smo

ke

), t

he

FD

A a

dvis

es

we

igh

ing

th

e r

isks

an

d b

en

efi

ts f

or

ind

ivid

ua

l p

ati

en

ts b

efo

re t

rea

tin

g C

VD

pa

tie

nts

wit

h v

are

nic

lin

e.

Th

ey h

ave

in

stru

cte

d

Pfi

zer

to c

on

du

ct a

la

rge

me

ta-a

na

lysi

s o

f R

CT

an

d w

ill

issu

e a

no

the

r u

pd

ate

wh

en

re

vie

we

d.1

2

Th

e F

DA

did

no

t re

qu

ire

Pfi

zer

to a

lte

r la

be

lin

g f

or

the

ris

k o

f n

eu

rop

sych

iatr

ic a

dve

rse

eve

nts

. T

wo

la

rge

VA

an

d D

ep

art

me

nt

of

De

fen

se s

po

nso

red

ob

serv

ati

on

al

stu

die

s w

ere

re

cen

tly r

evie

we

d b

y t

he

FD

A.

Bo

th s

tud

ies

com

pa

red

va

ren

icli

ne

an

d n

ico

tin

e r

ep

lace

me

nt

the

rap

y (

NR

T);

ad

ve

rse

sa

fety

ou

tco

me

s in

clu

de

d h

osp

ita

liza

tio

ns

du

e t

o n

eu

rop

sych

iatr

ic e

ve

nts

. N

eit

he

r st

ud

y f

ou

nd

a d

iffe

ren

ce i

n r

ate

s o

f n

eu

rop

sych

iatr

ic h

osp

ita

liza

tio

ns

be

twe

en

va

ren

icli

ne

an

d N

RT

; b

eca

use

of

this

, th

e F

DA

did

no

t a

dvis

e a

ny c

ha

ng

e t

o t

he

la

be

lin

g o

f C

ha

nti

x.

Th

e F

DA

no

ted

so

me

co

nce

rns

wit

h t

he

two

stu

die

s.

Th

ey w

ere

no

t p

ow

ere

d t

o d

ete

ct v

ery

ra

re a

dve

rse

eve

nts

an

d a

dve

rse

eve

nts

we

re t

rack

ed

on

ly w

he

n t

he

y r

esu

lte

d i

n h

osp

ita

liza

tio

ns.

Pfi

zer

is c

urr

en

tly c

on

du

ctin

g a

la

rge

cli

nic

al tr

ial fo

cuse

d o

n n

eu

rop

sych

iatr

ic s

afe

ty.

Re

sult

s a

re a

nti

cip

ate

d in

20

17

.13

82 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

13

Auth

or:

Am

y B

urn

s, P

har

m.D

.

A r

ece

nt

clin

ica

l tr

ial

wa

s th

e i

mp

etu

s fo

r a

ch

an

ge

in

th

e d

osi

ng

re

com

me

nd

ati

on

s fo

r va

ren

icli

ne

by P

fize

r.

Pre

vio

usl

y v

are

nic

lin

e h

as

be

en

do

sed

so

to a

llo

w t

he

pa

tie

nt

to s

mo

ke

co

ncu

rre

ntl

y w

ith

th

e f

irst

we

ek o

f ta

kin

g v

are

nic

lin

e a

nd

in

stru

ct p

ati

en

ts t

o q

uit

on

th

e e

igh

th d

ay o

f va

ren

iclin

e u

se.

Th

e n

ew

alt

ern

ati

ve

in

stru

ctio

ns

all

ow

pa

tie

nts

to

qu

it a

nyt

ime

be

twe

en

da

y 8

an

d d

ay 3

5 a

fte

r va

ren

icli

ne

is

sta

rte

d.

20

Th

e t

ria

l w

as

a d

ou

ble

-bli

nd

ra

nd

om

ize

d c

on

tro

lle

d t

ria

l (n

=6

59

) co

mp

ari

ng

va

ren

icli

ne

or

pla

ceb

o.

Su

bje

cts

rece

ive

d t

rea

tme

nt

for

12

we

eks

an

d

we

re f

oll

ow

ed

fo

r a

n a

dd

itio

na

l 2

4 w

ee

ks.

T

he

y w

ere

in

stru

cte

d t

o q

uit

sm

okin

g s

om

eti

me

be

twe

en

da

y 8

an

d d

ay 3

5;

en

dp

oin

ts w

ere

ab

stin

en

ce a

t

we

eks

9 t

o 1

2 a

nd

we

eks

9 t

o 2

4.

P

ati

en

ts i

n t

he

va

ren

icli

ne

gro

up

we

re m

ore

lik

ely

th

an

th

e p

lace

bo

su

bje

cts

to b

e t

ob

acc

o a

bst

ine

nt

thro

ug

h w

ee

ks

9 t

o 1

2 (

53

.1%

vs.

19

.3%

; O

R 5

.9,

95

% C

I 3

.7-9

.4)

an

d w

ee

ks

9 t

o 2

4 (

34

.7%

vs.

12

.7%

; O

R 4

.4,

95

% C

I 2

.6-7

.5).

A

dve

rse

eve

nts

we

re m

ino

r a

nd

we

re

sim

ila

r a

mo

ng

bo

th a

rms.

T

he

tri

al

wa

s o

f g

oo

d t

o f

air

qu

ali

ty.2

1

On

th

e b

asi

s o

f th

e s

ucc

ess

of

the

fle

xib

le-d

ate

tri

al,

a s

ma

ll U

K s

tud

y s

et

ou

t to

se

e i

f co

nti

nu

ed

to

ba

cco

use

fo

r a

n a

dd

itio

na

l th

ree

we

eks

aft

er

sta

rtin

g v

are

nic

lin

e i

mp

rove

d o

utc

om

es.

U

nli

ke

th

e p

revio

us

tria

l, t

his

stu

dy h

ad

se

t q

uit

da

tes.

P

ati

en

ts w

ere

ra

nd

om

ize

d t

o r

ece

ive

va

ren

icli

ne

(n=

52

) o

r p

lace

bo

(n

=4

8)

for

the

in

itia

l th

ree

we

eks

of

tre

atm

en

t, d

uri

ng

th

is t

ime

th

ey c

on

tin

ue

d s

mo

kin

g.

Aft

er

we

ek t

hre

e,

all

su

bje

cts

we

re

rece

ivin

g v

are

nic

lin

e a

nd

at

the

en

d w

ee

k f

ou

r a

ll s

ub

ject

we

re t

o s

top

sm

okin

g.

P

ati

en

ts w

ho

sm

oke

d d

uri

ng

th

e i

nit

ial

fou

r w

ee

ks

of

va

ren

iclin

e h

ad

an

in

cre

ase

d s

ust

ain

ed

ab

stin

en

ce r

ate

at

12

we

eks

(47

.2%

vs.

20

.8%

, p

=0

.00

5)

tha

n t

he

pla

ceb

o s

ub

ject

s.2

2

Alt

ho

ug

h s

ma

ll,

this

tri

al

wa

s o

f g

oo

d t

o

fair

qu

ality

. M

ore

stu

die

s a

re n

ee

de

d,

ho

we

ve

r, t

o e

sta

bli

sh i

f th

is d

osi

ng

re

gim

en

or

fle

xib

le d

osi

ng

im

pro

ve

s th

e e

ffe

ctiv

en

ess

of

va

ren

icli

ne

.

RE

FE

RE

NC

ES

1.

Tra

n K

, A

sak

aw

a K

, C

imo

n K

, M

ou

lto

n K

, K

au

ne

lis

D,

Pip

e A

, S

elb

y P

. P

ha

rma

colo

gic

-ba

sed

Str

ate

gie

s fo

r S

mo

kin

g C

ess

ati

on

: C

lin

ica

l a

nd

Co

st-E

ffe

ctiv

en

ess

An

aly

ses

[In

tern

et]

. O

tta

wa

: C

an

ad

ian

Ag

en

cy f

or

Dru

gs

an

d T

ech

no

log

ies

in H

ea

lth

; 2

01

0.

(Te

chn

olo

gy

Re

po

rt;

no

. 1

30

). A

cce

sse

s 1

/30

/12

. A

vail

ab

le f

rom

:

htt

p:/

/ww

w.c

ad

th.c

a/i

nd

ex.

ph

p/e

n/h

ta/r

ep

ort

s-p

ub

lica

tio

ns/

sea

rch

?&

typ

e=

16

2.

Fio

re M

C,

Jaé

n C

R,

Ba

ke

r T

B,

et

al.

Tre

ati

ng

To

ba

cco

Use

an

d D

ep

en

de

nce

: 2

00

8 U

pd

ate

. C

lin

ica

l P

ract

ice

Gu

ide

lin

e.

Ro

ckvi

lle

, M

D:

U.S

. D

ep

art

me

nt

of

He

alt

h a

nd

Hu

ma

n

Se

rvic

es.

Pu

bli

c H

ea

lth

Se

rvic

e.

Ma

y 2

00

8.

3.

Ste

ad

LF

, P

ere

ra R

, B

ull

en

C,M

an

t D

, La

nca

ste

r T

. N

ico

tin

e r

ep

lace

me

nt

the

rap

y f

or

smo

kin

g c

ess

ati

on

. C

och

ran

e D

ata

ba

se o

f S

yste

ma

tic

Re

vie

ws

20

08

, Is

sue

1.

Art

. N

o.:

CD

00

01

46

. D

OI:

10

.10

02

/14

65

18

58

.CD

00

01

46

.pu

b3

4.

Hu

gh

es

JR,

Ste

ad

LF

, La

nca

ste

r T

. A

nti

de

pre

ssa

nts

fo

r sm

ok

ing

ce

ssa

tio

n.

Co

chra

ne

Da

tab

ase

of

Sys

tem

ati

c R

evi

ew

s 2

00

7,I

ssu

e 1

. A

rt.

No

.: C

D0

00

03

1.

DO

I:

10

.10

02

/14

65

18

58

.CD

00

00

31

.pu

b3

5.

Ca

hil

l K

, S

tea

d L

F,

Lan

cast

er

T.

Nic

oti

ne

re

cep

tor

pa

rtia

l a

go

nis

ts f

or

smo

kin

g c

ess

ati

on

. C

och

ran

e D

ata

ba

se o

f S

yste

ma

tic

Re

vie

ws

20

11

, Is

sue

2.

Art

. N

o.:

CD

00

61

03

. D

OI:

10

.10

02

/14

65

18

58

.CD

00

61

03

.pu

b5

6.

Go

url

ay

SG

, S

tea

d L

F,

Be

no

wit

z N

. C

lon

idin

e f

or

smo

kin

g c

ess

ati

on

. C

och

ran

e D

ata

ba

se o

f S

yste

ma

tic

Re

vie

ws

20

04

, Is

sue

3.

Art

. N

o.:

CD

00

00

58

. D

OI:

10

.10

02

/14

65

18

58

.CD

00

00

58

.pu

b2

7.

Tso

i D

T,

Po

rwa

l M

, W

eb

ste

r A

C.

Inte

rve

nti

on

s fo

r sm

ok

ing

ce

ssa

tio

n a

nd

re

du

ctio

n i

n i

nd

ivid

ua

ls w

ith

sch

izo

ph

ren

ia.

Co

chra

ne

Da

tab

ase

of

Sys

tem

ati

c R

evi

ew

s 2

01

0,

Issu

e 6

. A

rt.

No

.: C

D0

07

25

3.

DO

I: 1

0.1

00

2/1

46

51

85

8.C

D0

07

25

3.p

ub

2.

83 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

14

Auth

or:

Am

y B

urn

s, P

har

m.D

.

8.

Lum

ley

J,

Ch

am

be

rla

in C

,Do

wsw

ell

T,O

liv

er

S,O

ak

ley

L,W

ats

on

L.

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rve

nti

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oti

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gn

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cy.

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chra

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tab

ase

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tem

ati

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vie

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09

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84 of 108

Sm

okin

g C

essa

tion

Rev

iew

Dat

e: A

pri

l 2012

15

Auth

or:

Am

y B

urn

s, P

har

m.D

.

Ap

pe

nd

ix 2

: M

ed

ica

tio

n I

nfo

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n

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ME

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EN

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R

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oti

ne

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da

y:

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g p

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ay

fo

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k,

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se o

ne

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Drug Use Research & Management Program

Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

1

Month/Year of Review: April 2012 Date of Last Review: September 2010 PDL Classes: Pulmonary Arterial Hypertension Agents Source Document: Provider Synergies

Current Preferred Agents: Current Non-Preferred Agents*: Oral Agents Bosentan (Tracleer) Sildenafil (Revatio) Tadalafil (Adcirca)

Oral Agents Ambrisentan (Letairis) Inhalation Agents Iloprost (Ventavis) Treprostinil (Tyvaso)

* Home administered IV’s are non-preferred (Epoprostadil, Revatio, Veletri, Flolan, Remodulin) Previous Recommendations: 1. There is no evidence found to support a difference in efficacy/effectiveness between members of this class. 2. There was no evidence found to support a difference in harms between members of this class. 3. Consideration should be given to including at least on medication from each dosage form (oral and inhalation). 4. Prior Authorization (PA) criteria should be considered for appropriate patient selection. PA Criteria/QL: Prior Authorization is required for non preferred agents on PDL to ensure appropriate use for pulmonary arterial hypertension (Appendix 1). This requires the patient have a World Health Organization Functional Class (WHO-FC) of II-IV and the drug prescribed by a pulmonologist or cardiologist. Revatio and Adcirca have the FDA indication for pulmonary hypertension and should not be used for erectile dysfunction. Methods: A MEDLINE OVID search was conducted using all included oral and inhalation drugs in pulmonary arterial hypertension and limits for humans, English language, and controlled clinical trials or meta-analysis from 2010 to current. The Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, the Department of Veteran Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were searched for high quality systematic reviews. The FDA website was searched for new drugs, indications, and safety alerts, and the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence-based guidelines. New Systematic Reviews: A Meta -analysis was performed and reviewed by the Centre for Reviews and Dissemination and met their criteria for inclusion.1 Twenty-four RCTs (3,758 participants) were included. This review concluded that prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors all had benefits in people with pulmonary arterial hypertension. Only intravenous prostanoids had a proven benefit on mortality, particularly in people with severe disease (RR 0.49, 95% CI 0.29 to 0.82; 10 trials). Compared to placebo, endothelin receptor antagonists (8 studies) and PDE5 inhibitors (3 trials) had no statistically significant effect on mortality. Endothelin receptor antagonists were associated with statistically significant improvements in six-minute walk distance (38 meters, 95% CI 27.2 to 48.7; seven trials), functional class (six trials), Borg score (five trials) and most hemodynamic changes (five trials). PDE5 inhibitors were associated with statistically significant improvements in six-minute walk distance (33.7 meters, 95% CI 22.5 to 44.8; three trials) and all reported hemodynamic parameters (two trials). Available data was based on studies of short duration (12 -16 weeks) and authors agreed that longer term studies were needed to confirm results.

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New Trials: A total of 30 citations resulted from the initial MEDLINE search and after review for inclusion, four potentially relevant clinical trials were identified (Appendix 2). These trials are briefly described in Table 1. Table 1: Study details

Study Comparison Population Primary Outcome

Results

McLaughlin, 20102 DB, MC, PC, RCT TRIUMPH-1

Treprostinil inhaled four times daily vs. placebo in patients already on either bosentan or sildenafil therapy

Adults with PAH, baseline 6MWD between 200 and 450m, receiving bosentan 125mg daily or any prescribed dose of sildenafil for at least 3 months N=235

Change in 6MWD measured at peak (10 to 60 minutes after inhalation)

Change in 6MWD at 12 weeks: • Between-treatment median difference in change

from baseline in peak 6MWD was 20 m (P=0.0004). • Between-treatment median difference in change in

peak 6MWD was 25 m (P=0.0002) in patients receiving background bosentan therapy and 9 m in patients taking sildenafil background therapy (P value not significant).

• There was no difference in time to clinical worsening between treatment groups

Barst, 20113 DB, PC

Tadalafil 2.5mg vs. 10mg vs. 20mg vs. 40mg vs. placebo stratified by background bosentan

Patients with PAH with the option of background bosentan

Change in 6-minute walk distance (6MWD)

PBO-adjusted change in 6MWD from baseline at week 16 (meters) Bosentan background 20mg: 22.6; 95 % CI (-0.5 to 45.7), p=NS 40mg: 22.7; 95% CI (-2.4 to 47.8), p=NS Treatment-naïve 20mg: 32.4; 95% CI (6.8 to 58.1), p=NS 40mg: 44.3; 95% CI (19.7 to 69.0), p<0.01

Sun, 20114 Open-label, uncontrolled, prospective

Low dose iloprost (2.5 ug per inhalation, 6 x daily) x 24 weeks

Adults patients with PAH (n=62), 95% in WHO-FC classes II and III

Change in 6-minute walk distance (6MWD)

Change in 6MWD from baseline + 57 meters; 95% CI (26.59-87.82), p<0.001 *The WHO_FC was improved significantly (p=0.006), no significant in change in systemic arterial oxygen saturation and systemic arterial pressure **14 patients (22.6%) discontinued the study prematurely

Barst, 20125 DB, PC, RCT

Low-dose vs. medium-dose vs. high-dose sildenafil vs. placebo

Treatment-naïve children, aged 1-17

% change from baseline in peak oxygen consumption (PVo2) to week 16

% change from baseline inPVo2 Low: 3.8+5.0% [95% CI, -6.1% to 13.7%] Med: 11.3 + 4.8% [95% CI, 1.7–20.9%] high: 8.0 + 4.9% [95% CI, -1.6% to 17.6%] Combined sildenafil: 7.7 + 4.0% (95% CI, -0.2% to 15.6%);p=0.056

New drugs: None New Formulations: None New FDA safety alerts: On March 4, 2011, the Food and Drug Administration removed a boxed warning about a potential for liver injury from the prescribing information for ambrisentan based on the review of post-marketing data; monthly liver function monitoring is no longer required.6 Healthcare professionals should still order liver enzyme tests when they consider it clinically necessary. Bosentan, however, is still not recommended in patients with liver impairment.

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References: 1. Ryerson CJ, Nayar S, Swiston JR, Sin DD. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir. Res. 2010;11:12.

2. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J. Am. Coll. Cardiol. 2010;55(18):1915–1922.

3. Barst RJ, Oudiz RJ, Beardsworth A, et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J. Heart Lung Transplant. 2011;30(6):632–643.

4. Sun Y-J, Xiong C-M, Shan G-L, et al. Inhaled Low-Dose Iloprost for Pulmonary Hypertension: A Prospective, Multicenter, Open-Label Study. Clinical Cardiology. 2012. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22488211. Accessed April 20, 2012.

5. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125(2):324–334.

6. FDA Drug Safety Communication. Liver injury warning to be removed from Letairis (ambrisentan) tablets. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm245852.htm. Accessed April 24, 2012.

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Appendix 1: Current PA Pulmonary Arterial Hypertension

Goal(s): To ensure appropriate drug use for pulmonary arterial hypertension (PAH) by utilization in specified patient population.

Length of Authorization: 1 year Preferred Alternatives: See PDL options: http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml * Note: Revatio and Adcirca have the FDA indication for pulmonary hypertension and should not be used for Erectile Dysfunction (ED). Viagra® and Cialis® are FDA-approved for ED and not covered by OHP. Requires PA:

GSN Drug Name Brand Name Bosentan Tracleer Iloprost Ventavis Treprostinil Tyvaso

Approval Criteria

1. What is the diagnosis?

Record ICD9 code.

2. Is this an OHP covered diagnosis?

Yes: Go to #3

No: Pass to RPh, DENY (Not covered by the OHP)

3. Does the patient have a diagnosis of pulmonary

arterial hypertension (PAH)?

Yes: Go to #4

No: Pass to RPh. RPh go to #8

4. Is this renewal of current therapy? Yes: Go to bottom section titled “renewal”

No: go to #5

5. Will the prescriber consider a change to a preferred

product?

Message: • Preferred products do not require a PA. • Preferred products are evidence-based reviewed

for comparative effectiveness and safety by the Health Resource Commission (HRC). Reports are available at: http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Yes: Inform provider of covered alternatives in class. http://www.oregon.gov/DHS/healthplan/tools_prov/dl.shtml. Approve for 1 year.

No: Go to #6

6. Does the patient have a WHO FC Classification of

II-IV?

Yes: Go to #7

No: Deny (Medical Appropriateness)

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7. Is the drug being prescribed by a pulmonologist or

a cardiologist?

Yes: Approve for 1 year

No: Deny (Medical Appropriateness)

8. RPh Only; All other indications need to be evaluated as to whether they are above the line or below the line diagnosis.

• If above the line or clinic provides supporting literature: approve for length of treatment.

• If below the line: Deny, (Not Covered by the OHP).

Renewal

1. Does the patient have PAH with a WHO FC

Classification of II-IV?

Yes: Go to #2

No: Deny (Medical Appropriateness)

2. Is the drug being prescribed by a pulmonologist or

a cardiologist?

Yes: Approve for 1 year

No: Deny (Medical Appropriateness)

DUR Board Action: 9/16/10 (KS) Revision(s):

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Appendix 2: Trial Abstracts

1. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, Robbins IM, Olschewski H, Rubenfire M, Seeger W. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010 May 4;55(18):1915-22.

OBJECTIVES: This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil. BACKGROUND: There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies. METHODS: Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 mug) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed. RESULTS: Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated. CONCLUSIONS: This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199).

2. Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, Sundin DP, Galiè N; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.

BACKGROUND: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups.METHODS: Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW.RESULTS: At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar.CONCLUSION: Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.

3. Sun YJ, Xiong CM, Shan GL, Gu Q, Zeng WJ, Lu XL, Zhu F, Liu ZH, Ni XH, He JG; on behalf of the Iloprost Therapy on Pulmonary Hypertension Study Group. Inhaled Low-Dose Iloprost for Pulmonary Hypertension: A Prospective, Multicenter, Open-Label Study. Clin Cardiol. 2012 Apr 9. doi: 10.1002/clc.21987. [Epub ahead of print]

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BACKGROUND: Inhaled iloprost (average >30 µg/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low-dose iloprost given intravenously was equally effective as high-dose iloprost in the therapy of systemic sclerosis. HYPOTHESIS: Patients with pulmonary hypertension will benefit from inhalation of low-dose iloprost. METHODS: Sixty-two patients with PH were enrolled and initiated with neubulizedlow-dose iloprost (2.5 µg per inhalation, 6× daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), and hemodynamic parameters.RESULTS: Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO-FCIII-IV at baseline), 4 because of protocol change, and 2 patients lost during follow-up. In the remaining 48 patients, 6MWD was increased from 356 ± 98 meters to 414 ± 99 meters (P < 0.001) and WHO-FC improved significantly (P = 0.006) after 24-week inhalation therapy. Cardiac output, cardiac index, and mixed venous oxygen saturation improved significantly compared with baseline (n = 34, P < 0.05). Most of the hemodynamic parameters improved significantly in patients in WHO-FC II (P < 0.05) but not in patients in WHO-FCIII-IV. CONCLUSIONS: Low-dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO-FCI-II but not in patients with WHO-FCIII-IV, suggesting the importance of early treatment in patients with advanced disease stages. Clin. Cardiol. 2012 DOI: 10.1002/clc.21987 This study was supported by National Grant from the Ministry of Science and Technology (Beijing, China, project number 2006BAI01A07) and the Capital Development Scientific Fund (Beijing, China, project number 2005-1018). The authors have no other funding, financial relationships, or conflicts of interest to disclose.

4. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.

BACKGROUND: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. METHODS AND RESULTS: Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. CONCLUSIONS: Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight.

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Drug Use Research & Management Program

Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

1

Month/Year of Review: April 2012 Date of Last Review: June 2009 PDL Classes: DPP4 Inhibitors Source Document: DERP Report (June 2009) GLP-1 agonists and analogs Oral Hypoglycemics Thiazolidinediones

Current Preferred Agents: Current Non-Preferred Agents: Dipeptidyl peptidase (DPP4 ) Inhibitors Sitagliptan/metformin (Janumet) Sitagliptan (Januvia) Glucagon-like peptide (GLP)-1 Analogs Pramlintide (Symlinpen 60 and 120) Thiazolidinediones (TZD’s)_ Pioglitazone (Actos) Oral hypoglycemics Glimepiride Glipizide Glyburide Metformin Metformin ER

Oral hypoglycemics Glyburide micronized Chlorpropamide Tolbutamide Repaglinide (Prandin) Nateglinide (Starlix) Tolazamide Thiazolidinediones Rosiglitazone (Avandia) DPP4 Inhibitors Linagliptan (Tradjenta) Saxagliptan (Onglyza)

GLP-1 Analogs Exenatide (Byetta) Liraglutide (Victoza) Combination Products Rosiglitazone/Glimepiride (Avandaryl) Pioglitazone/Glimepiride (Duetact) Pioglitazone/metformin (Actoplus Met) Rosiglitazone/metformin (Avandamet) Glyburide/metformin Glipizide/metformin Repaglinide/metformin (Prandimet) Saxagliptan /metformin (Kombiglyze XR) Linagliptan/metformin (Jentadueto) Sitagliptan/metformin (Janumet XR)

Previous Recommendations: Oral Hypoglycemics 1. There is no clinically significant difference between any of the agents in these two drug classes (oral sulfonylureas

and non-sulfonylurea secretagogues) in their ability to lower hemoglobin A1c (HbAlc). 2. There is no statistically significant difference between glyburide and chlorpropamide in the progression or

occurrence of clinically relevant outcomes with the exception of retinopathy. Patients on glyburide had greater risk reduction of progression of retinopathy than those on chlorpropamide.

3. There is insufficient evidence on other sulfonylureas and nonsulfonylureas secretagogues to identify a difference in progression or occurrence of clinically relevant outcomes.

4. Chlorpropamide has a less favorable adverse effect profile compared to glyburide. There is no difference in safety or adverse effect profiles for other oral sulfonylureas and non-sulfonylureas secretagogues. Glimepiride, glipizide, glyburide, micronized glyburide and repaglinide do not differ in safety or adverse effect profile. No evidence exists for evaluation of tolbutamide, tolazamide or nateglinide.

TZDs 1. Good quality evidence shows that pioglitazone and rosiglitazone have similar effects on A1C, yielding a decrease of

approximately 1%. There are no significant differences between these two drugs for effect on A1c . 2. TZDs have a similar effect on A1C as metformin, glibenclamide, or glimepiride.

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2

3. There is no difference between TZDs and metformin or sulfonylureas in their ability to lower A1c.

DPP4-Inhibitors 1. Data are insufficient to determine the long term clinical effectiveness of sitagliptin. 2. No studies provided evidence on benefits or harms for follow-up periods longer than 52 weeks. 3. There was no evidence of increased adverse events for sitagliptin vs. placebo. 4. Sitagliptin had lower rates of abdominal pain, nausea, vomiting and diarrhea than metformin. 5. Sitagliptin and metformin as monotherapy or in combination have a lower incidence of hypoglycemia than glipizide.

GLP-1 agonists and analogs 1. Data are insufficient to determine long term effectiveness of pramlintide in achieving glycemic control when added

to prandial insulin compared with conventional insulin therapy. 2. Pramlintide + insulin treated patients had an increased incidence of nausea, vomiting and anorexia than insulin

treated patients. 3. Data are insufficient to determine long term clinical effectiveness of pramlintide in Type 2 Diabetes when added to

prandial insulin compared to conventional insulin therapy with or without concurrent oral agents. 4. No studies meeting inclusion criteria examined exenatide as monotherapy or combined therapy for long term health

outcomes. 5. Nausea and vomiting were more common in exenatide vs. insulin groups. PA Criteria/QL: Prior Authorization criteria for incretin enhancers, incretin mimetics, and amylin analogs to promote use of preferred agents and require a trial of metformin and sulfonylurea therapy or have contraindications before approval of a non-preferred agent in these classes. Methods: A MEDLINE OVID search was conducted using all included drugs in adults and limits for humans, English language, and controlled clinical trials or meta-analysis from July 2010 (end of literature search in recent systematic review) to current. The Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, the Department of Veteran Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were searched for high quality systematic reviews. The FDA website was searched for new drugs, indications, and safety alerts, and the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence-based guidelines. New Systematic Reviews: The Oregon Evidence-based Practice Center (EPC) for the Drug Effectiveness Review Project (DERP) produced an original report on newer diabetes medications, TZD’s, and combinations in February 2011.1

The full report can be found on the Evidence-based Practice Center website: http://derp.ohsu.edu/about/final-document-display.cfm. This review compared the effectiveness and adverse event profiles of amlyin agonists, DDP-4 inhibitors, incretin mimetics, TZDs, and certain combination products for people with type 2 diabetes and for people with type 1 diabetes for pramlintide only. Most of the evidence was limited to adult populations which evaluated intermediate outcomes, such as HbA1c or weight. Very few studies reported health outcomes or were longer than 6 months. All of the included medications were found to be efficacious for reducing HbA1c and none of the newer medications appeared to cause weight gain. Little data was available to evaluate the long-term effectiveness of the newer medications compared with more established treatments. Overall, there was insufficient evidence to determine how fixed-dose combination products (FDCPs) compared with other treatments for their impact on health outcomes and there were no head-to-head trials that compared 2 FDCPs. There was insufficient evidence to draw conclusions based on subgroups of patients based on demographics, comorbidities, or other medications. The following additional conclusions were made for each drug class.

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Amylin Agonists There was insufficient evidence to determine how pramlintide compares with other treatments for their impact on health outcomes. There was moderate strength evidence that a greater reduction in HbA1c was demonstrated with pramlinitde added to fixed doses of insulin compared with placebo and insulin (range 0.13% to 0.4%) and low evidence that there is no statistically significant differences when added to insulin glargine or determir compared with rapid acting insulin (1.1% vs. 1.3%, p=0.46).1 There was moderate strength evidence demonstrating nausea as the most commonly reported adverse event which occurred more frequently with pramlintide plus insulin than with placebo plus insulin. DPP-IV Inhibitors There was insufficient evidence to compare the direct effectiveness of sitagliptan and saxagliptin and all included studies focused on intermediate outcomes.. There was low quality evidence that sitagliptin monotherapy resulted in slightly less HbA1c reduction than either metformin monotherapy over 54 weeks (between group difference −0.16 for metformin 1000 and −0.47 for metformin 2000 mg/d) or glipizide monotherapy over 12 weeks (between group difference −0.22%). 1 There was moderate strength evidence that there is no significant difference in reduction in HbA1c between rosiglitazone and sitagliptin when added to metformin therapy. GLP-1 Agonists No studies examined the impact of treatment on health outcomes as the primary outcomes. One head-to-head trial demonstrated low quality evidence that liraglutide 1.8mg once daily reduced mean HbA1c significantly more than exenatide 10 mcg twice daily (treatment difference -0.33%; 95% CI -0.47 to -0.18) and resulted in similar weight loss.1 This trial also demonstrated no significant difference in withdrawal rates between groups. There is moderate strength evidence that there is no significant difference in reduction in HbA1c between exenatide and insulin when also taking oral diabetic agents (exenatide range -1.0% to -1.4%, insulin range -0.9% to -1.4%) TZDs: Moderate evidence from a meta-analysis of 8 head-to-head randomized controlled trials suggests no statistically significant difference between pioglitazone and rosiglitazone for their ability to improve glycemic control (mean difference in reduction in HbA1c -0.09, 95% CI -0.23 to 0.05) when used in either monotherapy or combination therapy.1 There is also moderate strength evidence that there is no difference between pioglitazone or rosiglitazone and sulfonylureas for reduction in HbA1c and high quality evidence for no difference between pioglitazone and metformin. There is high quality evidence that both TZDs increase the risk of heart failure (Odds ratio from 1.32 to 2.18) and the risk of edema (Odds ratio from 2.26 to 2.18).1 There is low strength evidence that there is no increased all-cause mortality or cardiovascular mortality with pioglitazone. There is also moderate strength evidence that the risk of fractures is increased among patients exposed to TZDs (OR 1.45, 95% CI 1.18 to 1.79, from meta-analysis of 10 randomized controlled trials with 13,715 patients). This risk appears to be increased among women compared to men.1

Agency for Healthcare Research and Quality The Agency for Healthcare Research and Quality (AHRQ) published an update to the comparative effectiveness review on Oral Diabetes Medications for Adults with Type 2 Diabetes in March 2011 to summarize the benefits and harms of medications as monotherapy and in combination, for the treatment of adults with type 2 diabetes.2 There was low or insufficient evidence for all comparisons when focusing on long term clinical outcomes of all-cause mortality, cardiovascular disease, nephropathy, and neuropathy, as most studies were generally of short duration and had few long-term events. Metformin was associated with slightly lower all-cause mortality and cardiovascular disease mortality than the sulfonylureas. There was moderate strength evidence from two larger trials that pioglitazone is better than metformin at reducing short-term nephropathy. In both trials, the urinary

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albumin-to-creatinine ratio declined in patients receiving pioglitazone by 15 percent and 19 percent, respectively but remained unchanged in patients with metformin with statistically significant differences between groups in both trials.2 Intermediate outcomes were the most frequently evaluated outcomes. Most diabetes medications reduced HbA1c to a similar degree, by about 1 absolute percentage point (moderate to high strength of evidence). There was moderate strength of evidence that metformin was more efficacious than the DPP-4 inhibitors in lowering HbA1c (by about 0.4 absolute percentage points, 95% CI -0.5% to -0.2%) based on three randomized controlled trials.2 There was high strength of evidence that TZD’s and sulfonylureas had a more unfavorable effect on weight compared to metformin (mean difference of -2.6kg; 95% CI -4.1 kg to -1.2 kg, mean difference of -2.7kg; 95% CI -3.5 kg to -1.9 kg for TZDs and sulfonylureas, respectively).2 Three RCTs comparing rosiglitazone directly with pioglitazone showed a greater increase in LDL with rosiglitazone, (pooled between-group difference of 14.3 mg/dL, 95 percent CI 5.8 mg/dL to 22.7 mg/dL) and that pioglitazone increased HDL more than rosiglitazone (pooled between group difference of -2.3 mg/dL, 95 percent CI -3.5 mg/dL to -1.2 mg/dL).2 All comparisons with the GLP-1 agonists were based on insufficient or low evidence. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events. Metformin was associated with high risk of gastrointestinal side effects than all other medications and there was high strength of evidence that TZDs were associated with a 1.5-fold higher risk of bone fractures than was with metformin alone or in combination with a sulfonylurea and women were taking rosiglitazone were at higher risk for bone fractures than men.2 No other conclusions regarding differences in subgroups of patients could be made. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus TZDs. TZDs also had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Other Another meta-analysis was performed that included 43 randomized (n=19,101) controlled trials lasting at least 12 weeks involving DPP-4 inhibitors.3 Of participants evaluated for the primary endpoint, 10,467 were treated with a DPP-4 inhibitor and 8,634 treated with placebo or a comparator drug. DPP-4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40 percent of participants achieved the HbA1c goal of < 7 percent, which was associated with weight neutrality and no greater hypoglycemia. Baseline HbA1c was the best predictor for achievement of HbA1C target (p<0.001).3 New Trials: A total of 233 citations resulted from the original Medline literature search. After title and abstract review, 43 citations resulted and after further review for inclusion of population and outcomes, eleven potentially relevant clinical trials were identified (Appendix 1). Four trials evaluated linagliptin and are included in the individual drug monograph. The table below briefly describes the identified clinical trials.

Study Comparison Population Primary Outcome

Results

Yang, 20114 R, PC, DB

saxagliptin 5mg + metformin vs. placebo + metformin (n = 570).

Asian patients with type 2 diabetes with inadequate control on metformin alone

HbA1c change from baseline to week 24

Adjusted mean decrease in HbA1c: Sax/Met: -0.78% Pla/met: -0.37% P<0.0052

Nowicki, 20115 RCT, DB

Saxagliptin 2.5 mg vs. placebo added to other

Type 2 diabetes and renal impairment

Change in HbA1c and fasting plasma glucose

mean decrease in HbA1c: Sax: -1.08%; 95% CI (-1.37 to -0.8%) Pla: -0.36%%; 95% CI (-0.63 to -0.08%)

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antidiabetic drugs (n=170)

(FPG) at week 52 Diff -0.73%; 95% CI -1.11% to -0.34% P<0.001 Reductions similar in patients with ESRD

Borges, 20116 RCT, PG, DB

Avandamet (AVM) vs. metformin N=688

Type 2 diabetes, drug naive

Two hour pain relief

Reduction in HbA1c: AVM: Met: P<0.0001

Reduction in FPG: AVM: Met: P<0.001

Goke, 20107 RCT

saxagliptin 5 mg or glipizide from 5 to 20 mg x 52 weeks.

Type 2 diabetes with inadequate control on metformin alone N=858

Change from baseline in HbA1c; Non-inferiority

Adjusted mean decrease in HbA1c: Sax/Met: -0.74% Glp/Met: -0.80% Diff 0.06% (95% CI -0.05% to 0.16) *Discontinuation rates due to adverse events similar between groups (~4%)

Reasner, 20108 RCT, DB

Sitagliptin/ Metformin 50/500 bid vs. metformin 500 bid (N=1250)

Type 2 diabetes, drug naïve Mean baseline HbA1c 9.9%

Mean reduction in HbA1c at week 18

Mean change in HbA1c Sita/met: -2.4% Met: -1.8% p < 0.001

Hollander, 20119 DB, PC

Saxagliptin (SX) 2.5mg vs. SX 5mg vs. placebo added to TZD

Type 2 diabetes with inadequate control on TZD monotherapy N=565

Mean reduction in HbA1c at week 18 at 76 weeks

Mean change in HbA1c SX 2.5mg: -0.59% SX 5 mg: -1.09% PLA: -0.2% P=0.0019 for SX 2.5mg vs. placebo p < 0.0001 for SX 5 mg vs. placebo *Only 63.8% of patients completed the study

Buse, 201110 RCT, DB, PC

Exenatide vs. placebo

Type 2 diabetes, HbA1c 7.1 to 10.5% on insulin glargine alone or in combination with metformin and/or pioglitazone

Mean reduction in HbA1c at week 30 weeks

Mean change in HbA1c Exen: -1.74% Pla: -1.04% P<0.001 Achieved HbA1c <7.0% Exen: 60% Pla: 35% * Thirteen exenatide patients and one placebo patient discontinued due to adverse events (p<0.010).

New drugs: Linagliptin (Tradjenta) is a dipeptidyl peptidase-4 (DPP-4) Inhibitor FDA approved in 2011 and used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. See full drug monograph for further information and details (http://pharmacy.oregonstate.edu/drug_policy/meetings). New Formulations: Exenatide extended–release (Bydureon), once weekly injection (EQW) is a glucagon-like peptide-1 (GLP-1) agonist approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. EQW is an extended release formulation of the twice daily injectable product exenatide (Byetta) which was FDA approved in 2005. See full drug summary for further information and details (http://pharmacy.oregonstate.edu/drug_policy/meetings). New Combination Products: Sitagliptin/simvastatin (Juvisync) is a new combination product that combines a DPP-4 Inhibitor with the cholesterol lowering agent, simvastatin. It was FDA approved in October 2011 for patients in whom treatment with

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both sitagliptin and simvastatin is appropriate.11 Sitagliptin/simvastatin was approved based on studies demonstrating its bioequivalence to the single agents administered together. In a randomized open-label, crossover study ( n=29), steady-state sitagliptin did not alter the pharmacokinetics of a single dose of simvastatin. This study did not specifically evaluate the effects of simvastatin on sitagliptin pharmacokinetics, although none is expected. It has not been studied in patients with a history of pancreatitis and use is not recommended in patients with moderate or severe renal impairment or end stage renal disease (ESRD) since doses appropriate for these patients are not available in this combination product.11 Linagliptan/metformin (Jentadueto) is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product approved in January, 2012 and indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.12 It is not indicated for the treatment of type 1 diabetes or diabetic ketoacidosis. Jentadueto has not been studied with insulin. There have been no clinical efficacy studies performed with linagliptin/metformin (Jentadueto). However, coadministration of the single entity medications has been studied in type 2 diabetes mellitus patients who were not well controlled in their diet and exercise and in combination with a sulfonylurea.12 The bioequivalence of Jentadueto to linagliptin and metformin administered together as single entities was demonstrated in healthy subjects. There are currently three additional biguanide/DDP-4 combination products available. New FDA safety alerts: In September 2010, the FDA restricted access for rosiglitazone and combination products that contain rosiglitazone due to an increased risk of cardiovascular adverse events as a result of review of cardiovascular safety data from the long-term clinical study, Rosiglitazone Evaluted for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD).13 In May 2011, the FDA outlined the risk evaluation and mitigation strategy (REMS), which applies to all rosiglitazone-containing products.14 Under the REMS, healthcare providers and patients must enroll in a special program in order to prescribe and receive these drugs. The REMS, called the Avandia-Rosiglitazone Medicines Access Program, limits the use of rosiglitazone medicines to patients already being successfully treated with these medicines and patients whose blood sugar cannot be controlled with other anti-diabetic medicines and who, after consulting with their healthcare provider, do not wish to use pioglitazone-containing medicines. As of November 18, 2011, rosiglitazone medicines are no longer available through retail pharmacies. In June 2011, the FDA issued a safety announcement that the use of pioglitazone (Actos) for more than one year may be associated with an increased risk of bladder cancer based on two three-year trials demonstrating increased reports of bladder cancer in patients taking pioglitazone compared to placebo or glyburide (44% vs. 14%).15

Consequently, pioglitazone should not be used in patients with active bladder cancer and should be used with caution in those with a prior history of bladder cancer. The benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of bladder cancer. In 2011, the REMS requirement for exenatide, sitagliptin and sitagliptin/metformin were removed by the FDA.

Recommendations: 1) No further review or research needed. 2) Maintain new combination products sitaglipin/simvastatin and linagliptin/metformin as non-preferred

agents on the PDL.

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References:

1. Jonas DD, Van Scoyoc EE, Gerrald KK, et al. Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations. 2011. Available at: http://derp.ohsu.edu/about/final-document-display.cfm.

2. Bennett W, Wilson L, Bolen S, et al. Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 27. (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-0018.) AHRQ Publication No. 11-EHC038-EF. Rockville, MD: Agency for Healthcare Research and Quality. 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

3. Esposito K, Cozzolino D, Bellastella G, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2011;13(7):594–603.

4. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res. Clin. Pract. 2011;94(2):217–224.

5. Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int. J. Clin. Pract. 2011;65(12):1230–1239.

6. Borges JLC, Bilezikian JP, Jones-Leone AR, et al. A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011;13(11):1036–1046.

7. Göke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int. J. Clin. Pract. 2010;64(12):1619–1631.

8. Reasner C, Olansky L, Seck TL, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13(7):644–652.

9. Hollander PL, Li J, Frederich R, Allen E, Chen R. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011;8(2):125–135.

10. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann. Intern. Med. 2011;154(2):103–112.

11. Juvisync. Prescribing Information. Merck & Co., Inc. Available at: http://www.merck.com/product/usa/pi_circulars/j/juvisync/juvisync_pi.pdf.

12. Jentadueto prescribing information. Ridgefield, CT; Boehringer Ingelheim Pharmaeuticals.

13. FDA Drug Safety Communication. Ongoing review of Avandia (rosiglitazone) and cardiovascular safety. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm201418.htm.

14. FDA Drug Safety Communication. Updated Risk Evaluation and Migitation Strategy (REMS) to Restrict access to rosiglitazone-containing medicines ncluding Avandia, Avandamet, and Avandaryl. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm.

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15. FDA Drug Safety Communication. Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm.

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Appendix 1: New Trials

1. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract. 2011 Nov;94(2):217-24. Epub 2011 Aug 26.

To assess efficacy and safety of saxagliptin added to metformin versus placebo plus metformin in Asian patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin alone. METHODS: Adults (HbA(1c) 7.0-10.0%, on stable metformin ≥ 1500 mg/day) were randomized 1:1 to saxagliptin 5mg daily plus metformin (n = 283) or placebo plus metformin (n = 287). The primary end point was HbA(1c) change from baseline to Week 24. RESULTS: Saxagliptin plus metformin provided significant adjusted mean decreases versus placebo plus metformin (p ≤ 0.0052) in HbA(1c) (-0.78% versus -0.37%), fasting plasma glucose (-1.14 mmol/L versus -0.58 mmol/L), and postprandial glucose area under the curve from 0 to 180 min (-315 mmol min/L versus -160 mmol min/L). Significantly more saxagliptin-treated patients achieved a therapeutic glycemic response (HbA(1c)<7.0%) (46.5% versus 30.5%; p = 0.0001). The proportion of patients experiencing adverse events (excluding hypoglycemia) was similar for saxagliptin plus metformin (42.8%) versus placebo plus metformin (40.8%). Hypoglycemic events were reported in 1.4% of patients in each group. CONCLUSION: Saxagliptin added to metformin significantly improved glycemic control and was well tolerated in Asian patients with T2DM who had inadequate glycemic control with metformin and diet and lifestyle modification.

2. Nowicki M, Rychlik I, Haller H, Warren M, Suchower L, Gause-Nilsson I, Schützer KM. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract. 2011 Dec;65(12):1230-9. doi: 10.1111/j.1742-1241.2011.02812.x. Epub 2011 Oct 7.

OBJECTIVE: Therapeutic options are limited for diabetes patients with renal disease. This report presents 52-week results from a study assessing the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus (T2DM) and renal impairment. DESIGN: Double-blind study in patients stratified by baseline renal impairment (moderate, severe or end-stage renal disease [ESRD] on haemodialysis) randomised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline, including insulin.PATIENTS: A total of 170 adults with glycated haemoglobin (HbA(1c) ) 7-11% and creatinine clearance < 50 ml/min or ESRD were randomised and treated. Absolute changes in HbA(1c) and fasting plasma glucose (FPG) from baseline to week 52 were evaluated using analysis of covariance (ANCOVA) with last observation carried forward. Repeated-measures analyses were also performed. RESULTS: Adjusted mean decrease in HbA(1c) was greater with saxagliptin than placebo (difference, -0.73%, p < 0.001 [ANCOVA]). Reductions in adjusted mean HbA(1c) were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate (-0.94% vs. 0.19% respectively) or severe (-0.81% vs. -0.49%), but similar to placebo for those with ESRD (-1.13% vs. -0.99%). Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment. Saxagliptin was generally well tolerated; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events (28% and 29% respectively). CONCLUSIONS: Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment

3. Borges JL, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ, Grosse M, Fitzpatrick LA, Cobitz AR. A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011 Nov;13(11):1036-46. doi: 10.1111/j.1463-1326.2011.01461.x.

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The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. METHODS: This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET.RESULTS: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD. CONCLUSION: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.

4. Göke B, Gallwitz B, Eriksson J, Hellqvist A, Gause-Nilsson I; D1680C00001 Investigators. Saxagliptin is non-

inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010 Nov;64(12):1619-31. doi: 10.1111/j.1742-1241.2010.02510.x. Epub 2010 Sep 16.

Purpose: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS: A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA(1c) ) > 6.5 - 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < 0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < 0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (∼4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia.

5. Reasner C, Olansky L, Seck TL, Williams-Herman DE, Chen M, Terranella L, Johnson-Levonas AO, Kaufman KD,

Goldstein BJ. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011 Jul;13(7):644-52. doi: 10.1111/j.1463-1326.2011.01390.x.

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This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed-dose combination of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes. METHODS: This double-blind study (18-week Phase A and 26-week Phase B) randomized 1250 drug-naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. RESULTS: At week 18, mean change from baseline HbA1c was -2.4% for sitagliptin/metformin FDC and -1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (-3.8 mmol/l) versus metformin monotherapy (-3.0 mmol/l; p < 0.001). Homeostasis model assessment of β-cell function (HOMA-β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. CONCLUSION: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea

6. Hollander PL, Li J, Frederich R, Allen E, Chen R; CV181013 Investigators. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011 Apr;8(2):125-35.

To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione monotherapy, 565 patients were randomised to saxagliptin (2.5 mg or 5 mg) or placebo added to thiazolidinedione over 76 weeks (24-week short-term + 52-week long-term extension period) in this phase 3, double-blind, placebo-controlled trial; 360 patients completed the study. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model; 95% CI) for saxagliptin 2.5 mg, 5 mg, and placebo were -0.59% (-0.75, -0.43), -1.09% (-1.26, -0.93), and -0.20% (-0.39, -0.01), respectively (post hoc and nominal p=0.0019 and p<0.0001 for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively). Adverse event frequency was similar between groups. Confirmed hypoglycaemic events were 1.0% and 0% vs. 0.5% for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively. Results should be interpreted with caution given the proportion of patients who discontinued or required glycaemic rescue therapy during the 76-week course of study. Saxagliptin added to thiazolidinedione provided sustained incremental efficacy vs. placebo with little hypoglycaemia for up to 76 weeks and was generally well tolerated.

7. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin–treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154

Objective: To test whether twice-daily exenatide injections reduce HbA₁(c) levels more than placebo in people receiving insulin glargine. DESIGN: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA₁(c) level at site,performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) Adults with type 2 diabetes and an HbA₁(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks. The primary outcome was change in HbA₁(c) level. Secondary outcomes included the percentage of participants with HbA₁(c) values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. RESULTS: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study.

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The HbA₁(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. CONCLUSION: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation.

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Drug Use Research & Management Program

Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079

Phone 503-947-5220 | Fax 503-947-1119

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Month/Year of Review: April 2012 Date of Last Review: September 2010 PDL Class: DM - Insulin Source Document: Provider Synergies

Current Preferred Agents: Current Non-Preferred Agents: Short-Acting Human insulin regular (Humulin R) Human insulin regular (Novolin R) Rapid-Acting Insulin aspart (Novolog) Insulin lispro (Humalog)

Rapid/Intermediate-Acting Combination Insulin aspart 70/30 (Novolog Mix) Insulin lispro 50/50, 75/25 (Humalog Mix) Intermediate-Acting Human insulin NPH (Humulin N) Human insulin NPH (Novolin N) Long-Acting Insulin glargine (Lantus)

Rapid-Acting Insulin glulisine (Apidra and Apidra Solostar) Long-Acting Insulin detemir (Levemir)

Previous Recommendations: 1. Evidence does not support a difference in efficacy/effectiveness 2. Evidence does not support a difference in harms or adverse events 3. Insulin aspart and lispro are both listed as Pregnancy Category B while insulin determir, glargine, and glulisine are

listed as Pregnancy Category C 4. Recommend inclusion of at least one agent from each subgroup: Short acting, rapid acting, rapid/intermediate

acting combination products, intermediate acting, long acting

PA Criteria/QL: Clinical criteria to approve insulin pens/cartridges. Requests for PA for school-aged children should be reviewed on a client specific basis. Methods: A MEDLINE OVID search was conducted using all included drugs in subjects with diabetes and limits for humans, English language, and controlled clinical trials or meta-analysis from September 2010 to current. The Agency for Healthcare Research and Quality (AHRQ), Cochrane Collection, the Department of Veteran Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were searched for high quality systematic reviews. The FDA website was searched for new drugs, indications, and safety alerts, and the AHRQ National Guideline Clearinghouse (NGC) was searched for updated and recent evidence-based guidelines. New Trials: A total of 318 citations resulted and after review for inclusions, five potentially relevant clinical trials were identified and brief details are described in table 1.

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Table 1: Potentially relevant comparative trials Study Comparison Population Primary Outcome Results Thalange , 20111 RCT, open-label

Detemir vs. NPH + insulin aspart with meals and snacks

Aged 2-16 yr with type 1 diabetes (n=348)

HbA1c at week 52 Mean HbA1c was similar between groups at baseline (8.2 vs. 8.1%), and changed little over 1 yr (8.1 vs. 8.3%).

Swinnen, 20102 Non-inferiority, open-label, RCT

Insulin glargine once daily vs. insulin detemir twice daily

Insulin-naïve type 2 diabetic patients on stable oral drugs, HbA1c 7.5-10% N=973

Percentage of patients reaching A1C <7% without symptomatic hypoglycemia @24 weeks

% reaching A1C<% Glargine: 27.5% Detemir: 25.6% difference: 1.85% [95% CI 3.78 to7.48%] *7 patients on glargine and 22 on detemir dropped out of the study due to adverse events (P < 0.005)

Fogelfeld, 20103 RCT, open-label, non-inferiority

Insulin lispro vs. insulin detemir

Insulin-naïve, type 2 diabetes, on ≥2 oral diabetic meds, HbA1c 7.5-10% N=442

Change from baseline in HbA1c (non-inferiority margin of 0.4%) @ week 24

Change from baseline in HbA1c Lispro: -1.47 ± 1.01% Detemir: -1.24 ± 1.11% LS difference: -0.21% [95% CI -0.39 to -0.03%]

Hsia, 20114 RCT, open-label

Bedtime NPH vs. bedtime glargine vs. morning glargine N=85

Adults with type 2 diabetes, HbA1c 7.5-12% despite treatment with oral medications, from inner city population

Between-group difference in the change of HbA1c from baseline.

Change from baseline in HbA1c NPH: -1.4 ± 1.7% Glar(PM): -1.3 ± 1.2% Glar (AM): -1.9 ± 1.4% differences between groups = -0.06%; 95% CI (-0.24 to 0.12), confirming noninferiority

Philotheou, 20115 RCT, open-label

Insulin glulisine vs. insulin lispro

4-17 years old, type 1 diabetes, HbA1c 6.0-11% (n=572)

Non-inferiority of glulisine to lispro in HbA1c at 26 week

Change from baseline in HbA1c Glulisine: +0.1 ± 0.08% Lispro: +0.16 ± 0.07% Glar (AM): -1.9 ± 1.4% • differences between groups = NS

HbA1c = hemoglobin A1c, NPH = neutral protamine Hagedorn, RCT = randomized controlled trial, NS = nonsignificant

Systematic Reviews: A Cochrane review from 2011 evaluated the comparative efficacy of insulin detemir and insulin glargine in the treatment of type 2 diabetes and identified four randomized trials directly comparing determir to glargine lasting 24 to 52 weeks. 6 Overall, risk of bias in the trials was high, mainly because all trials were open-label and neither participants nor study personnel were blinded. For the majority of efficacy outcomes, there was statistical heterogeneity between the studies. Overall, there was low quality evidence that there was no significant difference in efficacy in terms of change in HbA1c or hypoglycemic events. The mean difference in the endpoint of HBA1c between the agents was not statistically different (0.08%; 95% CI -.10 to 0.27). The percentage of patients achieving good glycemic control at study endpoint was similar between the two insulins (RR 0.96; 95%CI 0.81 to 1.14). There was also low quality evidence that there was no difference in safety between the two insulins. There was no difference in the relative risk of having at least once hypoglycemic event (RR 0.98; 95% CI 0.92 to 1.05), without evidence for statistically heterogeneity. There was high quality evidence that there was a difference in weight gain. Insulin detemir was associated with a statistically significant less weight gain than insulin glargine (mean difference of 0.91kg; 95% CI -1.21 to -0.61). There was insufficient evidence to make conclusions regarding quality of life, cost effectiveness, or mortality. To achieve the same glycemic control, it

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was found that insulin detemir was often injected twice daily in a higher dose but with less weight gain, while insulin glargine was only injected once daily. New drugs: None New FDA Indications: In May 2011, the FDA approved insulin lispro (Humalog) use in a continuous insulin infusion pump in the pediatric population. New FDA safety alerts: None Guidelines: The American Association of Clinical Endocrinologists (AACE) 2011 Diabetes Care Plan Guidelines state that insulin is required in all patients with type 1 diabetes, and it should be considered for patients with type 2 diabetes, when noninsulin antihyperglycemic therapy fails to achieve target glycemic control or when a patient, whether drug naïve or not, has symptomatic hyperglycemia.7 When insulin therapy is indicated in patients with type 2 diabetes, therapy with long-acting basal insulin should be the initial choice in most cases; insulin analogues glargine and determir are preferred over intermediate-acting NPH because they are associated with less hypoglycemia. Short- or rapid-acting insulin may considered if postprandial hyperglycemia is present; rapid-acting insulin analogues being the prefer agent of the two because they have a more rapid onset and offset of action and are associated with less hypoglycemia. Premixed insulin analogue therapy may be appropriate for patients in whom adherence to a drug regimen is problematic; although, these preparations lack component dosage flexibility and may increase the risk for hypoglycemia compared with basal insulin or basal-bolus insulin. Basal-bolus insulin therapy is flexible and is recommended for intensive insulin therapy.7 According to the AACE, the preferred treatment for postprandial hyperglycemia in pregnant women is regular or rapid-acting insulin analogues. Basal insulin can be controlled with the use of rapid-acting insulin via infusion pump therapy or long-acting insulin.7

Recommendations:

• No further research or review needed at this time.

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References: 1. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes. 2011;12(7):632–641.

2. Swinnen SG, Dain M-P, Aronson R, et al. A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. Diabetes Care. 2010;33(6):1176–1178.

3. Fogelfeld L, Dharmalingam M, Robling K, et al. A randomized, treat-to-target trial comparing insulin lispro protamine suspension and insulin detemir in insulin-naive patients with Type 2 diabetes. Diabet. Med. 2010;27(2):181–188.

4. Hsia SH. Insulin glargine compared to NPH among insulin-naïve, U.S. inner city, ethnic minority type 2 diabetic patients. Diabetes Res. Clin. Pract. 2011;91(3):293–299.

5. Philotheou A, Arslanian S, Blatniczky L, et al. Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a Basal-bolus insulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. Diabetes Technol. Ther. 2011;13(3):327–334.

6. Swinnen SG, Simon AC, Holleman F, Hoekstra JB, Devries JH. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(7):CD006383.

7. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 Suppl 2:1–53.

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Research & Management Program Oregon State University, 500 Summer Street NE, E35, Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-1119

Hepatitis B Antivirals PA Criteria Month/Year of Review: February 2012 Last Oregon Review: September 2010 (Provider Synergies) The Oregon Health Resources Commission reviewed this class of agents for Chronic Hepatitis B (CHB) for addition to the Oregon PDL last September. The full source document can be found on the HRC website: http://www.oregon.gov/OHA/pharmacy/therapeutics/docs/ps-2009-11-hep-b.pdf. Previous Recommendations: 1. Evidence does not support a difference in efficacy/effectiveness 2. Evidence does not support a difference in harms/adverse events 3. Recommend including this class on the PDL and consider including entecavir (Baraclude) and tenefovir disoproxil fumarate (Viread) 4. Recommend establishing PA criteria for non-preferred products Summary: There are currently five oral nucleoside/nucleotide analogues (NA) available: lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir disoproxil fumarate. The long term clinical goals of antiviral therapy in CHB include reducing the development of cirrhosis, hepatocellular carcinoma, and death. There is moderate evidence suggesting that all of the NA have positive effects on one or more intermediate biomarkers associated with CHB including suppression of Hepatitis B Virus (HBV) DNA, normalization of serum alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg) loss or seroconversion, and hematologic response of improved necroinflammatory and fibrosis scores but no one treatment has shown to improve all biomarkers and there remains controversy over how these intermediate outcomes are related and if they predict clinical long term outcomes. The high-quality systematic review prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Minnesota Evidence-based Practice center concluded that observational studies suggest that male gender, coinfection with Hepatitis C, D, or HIV, increased HBV DNA, and cirrhosis were associated with an increased risk of hepatocellular carcinoma and death.1 Although, there is limited direct evidence that any anti-HBV therapies have a beneficial impact on these clinical outcomes, there is growing evidence that prolonged and effective suppression of HBV DNA can decrease the risk of cirrhosis and hepatocellular carcinoma. This supports the current trend to use long term antiviral therapy. 2 In addition to comparative efficacy evaluated in the Provider Synergies review,3 randomized controlled trials demonstrated that tenofovir treatment resulted in statistically significant improvements in Hepatitis B viral suppression compared to adefovir in both HBeAg+ (76% vs. 13%, RR 5.8, 95% CI 3.35,9.73) and HBeAg- patients (93% vs. 63%, RR 1.5, 95% CI 1.28, 1.69).4 It was also reviewed and recommended by the Canadian Agency for Drugs and

Technologies in Health (CADTH) as well as recommended in current treatment guidelines.5 Guidelines from the Association for the Study of Liver (EASL), the American Association for the Study of Liver Disease (AASLD), the National Institute of Health (NIH), and a panel of US expert hepatologists have all published guidelines or consensus statements for the management of CHB. These all recommend peginterferon alfa, entecavir, and tenofovir as preferred first-line drugs for CHB based largely on efficacy and a lower risk of the development of drug resistance.6–8 While these newer antiviral agents have the potential for prolonged effective viral suppression, more studies on the safety profiles and efficacy on long term use of these newer agents are needed. Future clinical trials should incorporate long term outcomes to align treatment with the surrogate markers and whether these markers reflect important clinical outcomes. Other Considerations: • Lamivudine has the most robust long term safety data and still has a place in therapy in those with favorable parameters and low risk of resistance. It

can also be recommended in clinical situations which a finite prophylaxis course is needed. • Combination therapy with NA has not has not proven to be superior to monotherapy in inducing a higher rate of sustained response. Recommendations: Consider establishing prior authorization criteria for the non-preferred agents in this class to promote the use of the preferred and recommended products when feasible. REFERENCES 1. Wilt T, Shamliyan T, Shaukat A, et al. Management of Chronic Hepatitis B. Evidence Report/Technology Assessment No. 174. (Prepared by the Minnesota Evidence-based Practice Center). AHRQ Publication No. 09-E002. Rockville, MD. Agency for Healthcare Research and Quality. 2008. Available at: http://www.ncbi.nlm.nih.gov/books/NBK38701/. Accessed November 10, 2011

2. Lam Y-F, Yuen M-F, Seto W-K, Lai C-L. Current antiviral therapy of chronic hepatitis B: Efficacy and safety. Current Hepatitis Reports. 2011;10(4):235-243.

3. Provider Synergies, L.L.C. Hepatitis B Agents Review. 2009. http://www.oregon.gov/OHA/pharmacy/therapeutics/docs/ps-2009-11-hep-b.pdf

4. Zhao S-S, Tang L-H, Dai X-H, et al. Comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B: a systematic review. Virol. J. 2011;8:111.

5. Common Drug Review: TENOFOVIR DISOPROXIL FUMARATE. Final Recommendation and Reasons for Recommendation. Candadian Agency for Drugs and Technologies in Health (CADTH). Available at: http://www.cadth.ca/media/cdr/complete/cdr_complete_Viread-HBV_March-18-2009.pdf.

6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B. Journal of Hepatology. 2009;50(2):227-242.

7. Belongia E, Costa J, Gareen I, et al. National Institutes of Health Consensus Development Conference Statement : managemen t of hepatitis B. Ann Intern Med. 2009;150:104-110.

8. Tong MJ, Hsu L, Chang PW, Blatt LM. Evaluation of current treatment recommendations for chronic hepatitis B: a 2011 update. J. Gastroenterol. Hepatol. 2011;26(5):829-835.

Suggested PA Criteria

Hepatitis B Antivirals Goal(s):

Cover hepatitis B agents according to OHP guidelines. Cover preferred products when feasible for covered diagnosis. Preferred products are selected based on evidence based reviews.

Length of Authorization: Up to 1 year. Quantity limited to a 30 day supply per dispensing. Pediatric age restrictions: A. lamivudine (Epivir HBV)-2 years and up B. adefovir dipivoxil (Hepsera)-12-17 years C. entecavir (Baraclude)-16 years and up D. telbivudine (Tyzeka)-safety and effectiveness not approved in pediatrics Covered Alternatives that do not require a PA: See PDL list at; http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml

Approval Criteria

1. What is the diagnosis?

Record ICD-9 code

2. Is the diagnosis an OHP covered diagnosis? Yes: Go to #3. No: Pass to RPh, Deny for OHP Coverage.

3. Is the request for treatment of Chronic Hepatitis B? Yes: Go to #4 No: Pass to RPh, Deny for Appropriateness

4. Is this a continuation of current therapy (i.e. filled prescription within prior 90 days)? Verify via pharmacy claims. ***If request is for Pegasys, refer to PA criteria “Pegylated Interferon and Ribavirin.”***

Yes: Go to Renewal Criteria

No: Go to #5

5. Has the client tried and is intolerant to, resistant to, or has a contraindication to the preferred products?

Yes: Document intolerance or contraindication. Approve requested treatment for 6 months with monthly quantity limit of 30 days supply.

No: Go to #6

6. Will the prescriber consider a change to a preferred product? Message: • Preferred products are evidence-based reviewed for comparative effectiveness &

Yes: Inform provider of covered alternatives in class. http://www.oregon.gov/DHS/healthplan/tools_prov/pdl.shtml.

No: Approve requested treatment for 6 months with monthly quantity limit of 30 days supply.

safety by the Health Resources Commission (HRC). Reports are available at: http://www.oregon.gov/OHPPR/HRC/Evidence_Based_Reports.shtml.

Renewal Criteria

1. Is client compliant with requested treatment? (see refill history). Yes: Go to 2. No: Deny. Forward to RPH for provider consult.

2. Is HBV DNA undetectable?

Yes: Approve for up to 1 year with monthly quantity limit of 30 days supply

No: Deny. Forward to RPH for provider consult.