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ProvenOutcomes

Make a

Proven Choicea

with

200,000,000 Patients Treated Worldwideb

FPO

FPO

FPO

FPO

FPO

a IMSNationalSales Perspective,February2009.1

b IMSPatientPerspectives,March2008.2

02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM

1/IMS National Sales Perspectives.

February.2009

2/IMS Patient Projections.March.2008



2

Make aProven Choice

with Proven Outcomes

ACS and DVT/PE are major public health crises,often with fatal complications3-5

All abbreviations are defined on page 41.

F P O

ACS patients with ischemia

Each year, more than 1.5 million patients with STEMI or UA/NSTEMI presentto emergency departments5

In the GRACE Registry, 30% of STEMI patients (N=1763) received no reperfusion therapywithin 12 hours of symptom onset6

34% and 36% of patients diagnosed on admission with UA or NSTEMI, respectively,experience recurrent ischemia in the hospital (N=8001)7

STEMI and UA/NSTEMI patients with in-hospital ischemia have a higher 6-monthmortality rate7

Patients at risk for DVT/PE

Up to 2 million Americans suffer from DVT annually8

Approximately 300,000 fatal PE events occur each year,9 the majority of whichresult from DVT 10

—Nearly 60% of patients die following undetected PE9

—34% of VTE-related deaths are sudden, fatal PE9

Complications from DVT kill more Americans each year than AIDS and breastcancer combined8

DVT-related PE is the most common cause of preventable hospital death11

Surgical patients at risk for DVT/PE

Certain surgeries carry a high risk of DVT/PE and require early prophylaxis12,13

Without prophylaxis, many postsurgical patients will develop DVT 11

—53% of all cases of symptomatic DVT/PE occurred after hospital discharge in abdominalsurgery patients without malignancy14

Cancer is one of the major risk factors for developing DVT after surgery15

—DVT/PE is the second leading cause of death in patients with overtmalignant disease16

—DVT/PE is the most common cause of death at 30 days after cancer surgery17


3/Anderson.J Am Coll Cardiol.August.2007/p657/c1/line 11

4/www.surgeongeneral.gov/p3/c1/line 5; p5/c1/line 12

5/Rosamond.Circulation.February.2007/pe92/c2/line 40

5/Rosamond.Circulation.

February.2007/pe92/c2/line 40

6/Eagle.Lancet.February.2002/p373/line A18

7/Armstrong.Circulation.

November.1998/p1862/figure 1

7/Armstrong.Circulation.

November.1998/p1863/c2/line 14

8/Gerotziafas.Curr Opin Pulm Med.2004/p356/c2/line 2

11/Geerts.Chest.June.2008/p388S/c2/line 29

9/Heit.Am Soc Hematol.December.2005/p1/table

10/Murin.Thromb Haemost.2002/p407/c1/line 31

9Heit.Am Soc Hematol.December.2005/p2/line 2

12/ENOXACAN Study Group.Br J Surg.

August.1997/p1099/c1/line 1

13/Bergqvist.Br J Surg.August.2004/p965/c1/line 1

11/Geerts.Chest.June.2008/p389S/c2/table 4

14/White.Thromb Haemost.April.2003/p448/table 1/

Gastrointestinal [NOTE:621÷1177=53%]

15/Kakkar.Hematol J.2004/pS20/c1/line 25

16/Donati.Haemostasis.1994/p128/line A1

17/Agnelli.Ann Surg.January.2006/p89/c2/line A9

9/Heit.Am Soc Hematol.December.2005/p2/line 2

8/Gerotziafas.Curr Opin Pulm Med.

2004/p356/c2/line 11



3

Please see important safety information on pages 8 and 9.

Please see accompanying full prescribing information,including boxedWARNING, inside pocket.

LOVENOX®—proven outcomes across multiplepatient types and indications

Multiple indications and patient types

Cardiology: across the spectrum of ACS—STEMI and UA/NSTEMI patients

Acutely ill medical patients: DVT prophylaxis in hospitalized patients at risk dueto severely restricted mobility during acute illness

DVT treatment: inpatient and outpatient

Hip- or knee-replacement surgery:patients undergoing hip- or knee-replacement surgery

Abdominal surgery: patients undergoing abdominal surgery, including those with cancer

LOVENOX®

indicationsTreatment of acute STEMI

LOVENOX® has been shown to reduce the rate of the combined endpoint of recurrent MIor death in patients with acute STEMI receiving thrombolysis and being managed medicallyor with PCI

Prophylaxis of ischemic complications of UA and non–Q-wave MI

LOVENOX® is indicated for the prophylaxis of ischemic complications of UA and non–Q-waveMI when concurrently administered with aspirin

Prophylaxis of DVT

LOVENOX® is indicated for th e prophylaxis of DVT, which may lead to PE:

—In medical patients who are at risk for thromboembolic complications due to severelyrestricted mobility during acute illness

—In patients undergoing hip-replacement surgery, during and following hospitalization

—In patients undergoing knee-replacement surgery

—In patients undergoing abdominal surgery who are at risk for

thromboembolic complications

Treatment of acute DVT

LOVENOX® is indicated for:

—The inpatient treatment of acute DVT, with or without PE, when administered inconjunction with warfarin sodium

—The outpatient treatment of acute DVT, without PE, when administered in conjunction

with warfarin sodium

F P O


NO ANNOTATIONS REQUIRED FOR

INDICATIONS

02977 M4 2009 MVA d L t 1 4/28/09 10 47 AM P 4



LOVENOX®—proven outcomes across

4 Please refer to pages 28–35 for full dosing and administration information.

ARR=absoluterisk reduction(thedifferencebetweena controlgroup’s event rateandthe treatment group’s event rate); CI=confidenceinterval;NNT=numberneededto treat (theestimated numberof patientswho needto betreatedwith LOVENOX® ratherthan a comparatorfor 1 additionalpatientto benefit);NS=notsignificant; OAD=observedabsolutedifference(the observed difference between 2 groups [NS]); RRR=relativerisk reduction.

200,000,000 PatientsTreated Worldwide2

F P O

STEMI18,19

ExTRACT–TIMI 25 wasarandomized, double-blind,

double-dummy,parallel-

group, multinational, active-controlledclinicaltrial

comparing LOVENOX®

with UFHin acuteSTEMIpatients

UA/NSTEMI21

ESSENCE wasaprospective, randomized,

double-blind, parallel-group,

multicenter,multinational trialcomparingLOVENOX®

withUFH in UA/NSTEMI

patients

Acutely illmedical patients22

MEDENOXwas amulticenter, multinational,

double-blindstudy of

hospitalizedacutely illmedicalpatients randomized

toLOVENOX® orplacebo

DVT outpatienttreatment23

This studywas a

randomized, open-label

trialcomparing LOVENOX®

outpatient treatmentof

DVTwith inpatientIV UFH,

eachin conjunctionwithwarfarin

Major hemorrhage:

2.1% vs 1.4%

P <0.001

ICH:

0.8% vs 0.7%

P =0.14

Overall hemorrhage:

18.4% vs 14.2%

P =0.001

Major hemorrhage:

6.5% vs 7.0%

P =NS

Major hemorrhage:

1.7% vs 1.1%

P =NS

Thrombocytopenia:

2.2% vs 3.6%

P =NS

Major hemorrhage:

2.0% vs 1.2%

P =NS

Basedon trialresults,

LOVENOX® would havean estimated21 fewer

deathsor MIsper1000

STEMIpatients vs UFH,with7 additional

majorbleeds20,a


LOVENOX® would have

an estimated32 fewerdeaths, MIs,or recurrent

angina events per1000

UA/NSTEMIpatients vsUFH,with comparable

majorbleeding20,a


LOVENOX® would havean estimated94 fewer

DVT/PE events per1000acutely ill medicalpatientsvs placebo,

with comparable

majorbleeding20,a


LOVENOX® would have

an estimated14 fewerrecurrent symptomatic

VTEeventsper 1000DVT

outpatients vs UFH,with

comparable major

bleeding(NS)20,a

17% RRRARR=2.1%

in death or MI

LOVENOX® vs UFH(9.9% vs 12.0%)

95% CI; P <0.001

N=20,479NNT=4820,a

16% RRRARR=3.2%

in death, MI, and

recurrent anginaLOVENOX® vs UFH

(16.6% vs 19.8%)

95% CI; P =0.019N=3171

NNT=3220,a

63% RRRARR=9.4%

in DVT/PE eventsLOVENOX®

vs placebo(5.5% vs 14.9%)

95% CI; P <0.001N=579

NNT=1120,a

1.4% OADin recurrent

symptomatic

thromboembolism

LOVENOX® vs UFH(5.3% vs 6.7%)

95% CI; P =NS

N=500

Primary efficacyoutcome

(LOVENOX® vs comparator)

Patient type/study design

Safetyendpoints


Duration oftreatment

Benefit/riskprofile

(ARR x 1000patients)

8 days oruntil

hospital discharge,whichevercame first

48hoursto 8 days;

median: 2.6 days

In-hospital treatment

for 6 to14 days;median: 7 days

Meandurationof:

LOVENOX®

5.8± 1.8days;

UFH

5.5 ± 1.2days

aTheNNT andbenefit/riskprofilewere calculatedbased uponthe reported ARRresults.20


18/Antman.N Engl J Med.April.2006/p1482/table 2

(Efficacy)

18/Antman.N Engl J Med.April.2006/p1483/c1/line 18

(Safety)


(Duration)

19/Antman.Am Heart J.February.2005/p218/c2/line 24;

p219/c2/line 52 (Design)

20/DOF-ARR.NNT calculations

21/Cohen.N Engl J Med.August.1997/p449/c1/line 14

(Efficacy)

21/Cohen.N Engl J Med.1997/p450/c1/line 1; p451/

c2/table 5 (Safety)

21/Cohen.N Engl J Med.1997/p448/c1/line 37; c2/line

50 (Duration)

21/Cohen.N Engl J Med.1997/p448/c1/line 20; p447/

c2/line 32 (Design)


22/Samama.N Engl J Med.September.

1999/p795/c2/line 11 (Efficacy)


1999/p798/c1/table 5 (Safety)22/Samama.N Engl J Med.September.

1999/p794/c1/line 34; p795/c2/line 6 (Duration)

22/Samama.N Engl J Med.September.1999/p794/c1/

line33; p973/c1/line A7; p795/c1/line 8 (Design)


23/Levine.N Engl J Med.March.1996/p679/c2/line27;

p680/C1/Table 2 (Efficacy)

23/Levine.N Engl J Med.March.1996/p680/c1/line 4

(Safety)


(Duration)

23/Levine.N Engl J Med.March.1996/p677/c2/line

18;p678/c1/line 40 (Design)



02977 M4 2009 MVA qxd:Layout 1 4/28/09 10:47 AM Page 5



multiple patient types and indications

5

ARR=absolute riskreduction(the differencebetweena control group’sevent rateand thetreatmentgroup’s eventrate); CI=confidenceinterval;NNT=numberneededto treat(the estimated number of patients whoneed to betreated withLOVENOX® ratherthan a comparator for1 additionalpatientto benefit);NS=not significant; OAD=observed absolutedifference(the observeddifferencebetween 2 groups[NS]); RRR=relative risk reduction.

Please refer to pages 28-35 for full dosing andadministration information.


Please see accompanying full prescribing information,including boxed WARNING, inside pocket.

Major hemorrhage:

2% vs 4%

P =NS

Injection-site

hematoma:

5.1% vs 0.9%

P =NS

Major hemorrhage:

1.7% vs 3.4%

P =NS

Major hemorrhage:

0% vs 2%

P =NS

Overall hemorrhage:

18.7% vs17.1%

P =NS

Major hemorrhage:

4.1% vs 2.9%P =NS

71% RRRARR=30%

in DVTdocumentedbyvenographyor

noninvasivetests

LOVENOX® vsplacebo(12% vs42%)

P =0.0007N=100

NNT=420,a

53% RRRARR=20.9%

in DVT/PE events

LOVENOX® vs placebo(17.9% vs 38.8%)95% CI; P <0.001

N=233NNT=520,a

82% RRRARR=47%

in DVTdocumentedby venographyornoninvasive tests

LOVENOX® vs placebo(10% vs 57%)

95% CI; P <0.0001N=104

NNT=320,a

3.5% OADin DVT/PE incidenceLOVENOX® vsUFH

(14.7% vs 18.2%)

95%CI; P =NS

N=631

Hip-replacementsurgery24

This studywas a double-blind,randomizedtrial comparing

LOVENOX® withplacebo

in patients undergoinghip-replacement surgery

Hip-replacementsurgery (extendedprophylaxis)25

A prospective, randomized,double-blind study conducted

ata single center, withall

patientsreceiving LOVENOX®

duringtheir hospitalization

andblinded drugat theend

of hospitalization

Knee-replacementsurgery26

Thisstudy wasa double-blind,randomized,multicenter trial

comparingLOVENOX® with

placeboin patientsundergoingknee-replacement surgery

Abdominal surgery12

ENOXACANwas a prospective,

double-blind,randomized, multi-

centertrialcomparingLOVENOX®

withUFH inpatientsundergoing

electivecurativesurgeryforabdominalor pelviccancer

Based on trialresults,

LOVENOX® wouldhaveanestimated 300fewer

symptomaticDVT events

during hospitalization per1000 hip-replacement

patientsvs placebo,

with comparable

major bleeding20,a


LOVENOX® wouldhave

anestimated 209fewer

DVTeventsper 1000hip-replacement patients

having extended

prophylaxis vs placebo,with comparable

major bleeding20,a


LOVENOX® wouldhavean estimated470 fewer

DVTevents during

hospitalization per 1000knee-replacement

patientsvs placebo,

with comparablemajor bleeding20,a

Basedon trial results,

LOVENOX® would haveanestimated 35 fewer DVT/PE

eventsper 1000abdominal

surgerypatientsvs UFH,

withcomparablemajorbleeding (NS)20,a

Primary efficacyoutcome


Patient type/study design

Safetyendpoints


Duration oftreatment

Benefit/riskprofile

(ARR x 1000patients)

Therapy initiated

12to 24hourspostoperatively

and continued for

14 days or untildischarge

In-hospital

7 to11days;outpatient

19to23 days

(scheduled: 21 days)

Therapy initiated on

the morning ofthefirstpostoperative

day(day1) and

was continuedfor14 days

or untildischarge

Therapy initiated

2 hourspreoperatively

and continued

for 10± 2 days

F P O


24/Turpie.N Engl J Med.October.1986/p925/c1/line

A3; c2/line A6; p926/c1/line 37; c2/line 25; p927/c1/

line 24, Table 2; p928/Table 3


26/Leclerc.Thromb Haemost.April.1992/p417/c1/line 6;

p418/c1/line 7,11; c2/line 11; p420/c2/line 32, Table 4;

p421/Table 5


12/ENOXACAN Study Group.Br J Surg.August.1997/

p1099/lineA12;p1101/table 2 (Efficacy)


p1101/c1/line 33 (Safety)


p1099/c2/line 24 (Duration)


p1099/c2/line 2 (Design)


25/Bergqvist.N Engl J Med.September.1996/p696/c1/line

A31; 698/c1/table 2 (Efficacy)


11 (Safety)


20 (Duration)


6; line 20 (Design)


02977 M4 2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 6



6


Make aProven Choice

LOVENOX® outperforms UFH in critical areas

a After 1.5mg/kgSC,basedon anti-Xaactivityin healthyvolunteers.28

b Becauseroutine coagulationtests,suchas PTand aPTT, arerelativelyinsensitivemeasures ofLOVENOX® activity, thesetests are unsuitablefor monitoringinpatients withnormal baselinecoagulationparameters.Periodiccompletebloodcounts, including plateletcount, andstooloccult blood testsarerecommendedduringtreatment.28

c HITisdefinedasa ≥50%plateletcountfallfrom thepostoperativepeakvs standarddefinition ofplatelet count <150x 109 /L.31

LOVENOX®—more predictable anticoagulation vs UFH27-31

LOVENOX® quickly achieves and maintains therapeutic anti-Xa levels20

Comparable incidence of HIT (reported as decreased platelet count) in 4 head-to-head trials comparing LOVENOX® with a non-heparin anticoagulant32

F P O

LOVENOX® use is associated with more predictable outcomes27-31

Plasma anti-Xa activity after LOVENOX® 1 mg/kg SC injection20

A

n t i - X a a c t i v i t y ( I U / m L ) After steady-state

level is attained.

Data on file.

2.0

1.6

1.2

0.8

0.4

0.0

Time after administration (hours)

Therapeutic anti-Xa

0 2 4 6 8 10 12

The clinical significance of the comparisons of anti-Xa:IIa ratio,bioavailability, and aPTT monitoring have not been established.

Feature UFH LOVENOX® Potential benefits

Anti-Xa:IIa ratio 1:127 14:128,a Greater inhibition of thrombin

generation and activity29

Bioavailability Widespread binding Minimalbinding Predictable dose response;

(as measuredby toserumproteins toserum proteins near 100% bioavailabilityprotein binding) or endothelium30 or endothelium30 based on factor Xa activity30

aPTTmonitoring IV UFH requires No30 No needfor routinemonitoring and coagulation monitoring30,b

dose adjustment30

HIT 4.8%31 0.6%31 Reduction in the risk of HIT31,c

_ _ q y / / g

27/Fuster.Hurst's the Heart.2001/p1407/c1/line 52 28/LOVENOX PI.June.2008/p6/c2/line 1929/Lee.Expert Rev Cardiovasc

Ther.2007/p388/c2/line 4

30/Weitz.N Engl J Med.September.1997/

p690/c2/line 19; p688/c2/line 55

30/Weitz.N Engl J Med.September.1997/

p690/c2/line 31; c1/table 3

31/Warkentin.Arch Intern Med.

November.2003/p2518/c2/line A8

31/Warkentin/Arch Intern Med.November.2003/

p2518/c2/line A1; c1/line 15

28/LOVENOX PI.July.2008/p6/c2/line 19


20/DOF-Aventis Study 155/p3/figure 5

32/Tran.Ann Pharmacother.November.2003/

p1635/c1/line 30; p1639/c1/line 25

32/Tran.Ann Pharmacother.November.2003/

p1639/c1/line 25, 28, 29

02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 7



Patient/procedure type



LOVENOX®—more predictable and consistentanticoagulation compared with UFH

With UFH, >68% of patients are not in therapeutic range within 12 hoursafter administration20,21,33,34

LOVENOX® is recommended in key national guidelines3,11,35-39

DVT prophylaxis is also recommended as part of quality measures in patient care

National Quality Forum (NQF) Safe Practices 28 and 2940

The Joint Commission 2009 National Patient Safety Goals 03.05.01 (formerly 3E), 8, and 1341

Surgical Care Improvement Project (SCIP) measures to prevent postoperative complications 42

7

d ACC/AHA=AmericanCollege of Cardiology/AmericanHeart Association.e ACCP=American Collegeof ChestPhysicians.f ASCO=American Societyof ClinicalOncology.g ASCRS=AmericanSociety of Colon& RectalSurgeons.h AAOS=American Academyof Orthopaedic Surgeons.i ACOG=TheAmerican Collegeof Obstetricians and Gynecologists.

Hip-

replacementsurgery

ACCP11,e

AAOS38,h

Knee-

replacementsurgery

ACCP11,e

AAOS38,h

Abdominal

surgery

ACCP11,e

ASCO36,f

ASCRS37,g

ACOG39,i

DVT

treatment

ACCP11,e

ASCO36,f

DVT prophylaxis in:

Please refer to pages 36-38 for further information regarding specific classifications in national guidelines.

Anticoagulation with UFH within 12 hours as measured by aPTT 20,21,33,34

P a t i e n t s ( % )

100

80

60

40

20

0

Supratherapeutic

Therapeutic

Subtherapeutic

Results from ESSENCE.

Cohen et al. NEnglJ Med .

1997;337(7):447; INTERACT.

Goodman et al. Circulation.

2003;107(2):238; SYNERGY.JAMA. 2004;292(1):45;

and data on file.

30.3%

17.4%

52.2%

ESSENCE21

n=1564

69.0%

16.7%

14.3%

INTERACT33

n=366

31.6%

32.6%

35.8%

SYNERGY20,34

n=4985

Acutely ill

medicalpatients

ACCP11,e

ASCO36,f

ASCRS37,g

F P O

The clinical significance of these data has not been established.

Cardiology—

STEMI andUA/NSTEMI

ACC/AHA3,35,d

20/DOF - Aventis Study 155/p5/figure 1

21/Cohen.N Engl J Med.August.1997/p449/c2/tables 1 & 2

33/Goodman.Circulation.January.2003/p241/c1/line18;p239/table 1

34/SYNERGY.JAMA.July.2004/p46/figure 1

3/Anderson.J Am Coll Cardiol.

January.2008/p231/table 12

35/Antman.J Am Coll

Cardiol.2008/p231/Table 12

11/Geerts.Chest.

June.2008/p381S/line

A12

36/Lyman.J Clin

Oncol.December.2007/

p5501/table 5

37/Stahl.Dis Colon

Rectum.October.2006/

p1481/c1/line 14; c2/

line 25

39/ACOG.Obstet Gynecol.


38/Johansen.www.aaos.org/p2/line 1

40/NQF Safe Practices.2006/p2941/www.jointcommission.org.

NPSG.Hospital.2008/slides 10,

19, 23

42/Medqic.www.medqic.org.scip project/p1/line 20

21/Cohen.N Engl J Med.January.1997/

p449/c2/tables 1 & 2

33/Goodman.Circulation.January.2003/p241/c1/line18;p239/table 1

20/DOF - ESSENCE_INTERACT_SYNERGY

34/SYNERGY.JAMA.July.2004/p46/figure 1




8

WARNING: SPINAL/EPIDURAL HEMATOMAS

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients

anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins or

heparinoids for prevention of thromboembolic complications are at risk of developing an epidural

or spinal hematoma, which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of indwelling epidural catheters for administration

of analgesia or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-

inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants.The risk also appears

to be increased by traumatic or repeated epidural or spinal puncture.

Monitor patients for signs and symptoms of neurological impairment. If neurologic compromise

is noted, urgent treatment is necessary.

Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated

or to be anticoagulated for thromboprophylaxis (see Warnings and Precautions [5.1] and

Drug Interactions [7 ]).

LOVENOX® (enoxaparin sodium injection) cannot be used interchangeably with other low-

molecular-weight heparins or unfractionated heparin (UFH), as they differ in their manufacturing

process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage

As with other anticoagulants, use with extreme caution in patients with conditions that increasethe risk of hemorrhage. Dosage adjustment is recommended in patients with severe renal

impairment. Unless otherwise indicated, agents that may affect hemostasis should be

discontinued prior to LOVENOX® therapy. Bleeding can occur at any site during LOVENOX®

therapy. An unexplained fall in hematocrit (HCT) or blood pressure should lead to a search

for a bleeding site. (SeeWARNINGS and PRECAUTIONS)

Important safety information

Visit our website, www.LOVENOX.com, for health care professional and patientinformation.

200,000,000 PatientsTreated Worldwide

F P O





In the ST-segment elevation myocardial infarction (STEMI) pivotal trial, the rates of major

hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in

HCT or clinically overt bleeding, including intracranial hemorrhage [ICH]) at 30 days were

2.1% in the LOVENOX® group and 1.4% in the UFH group.The rates of ICH at 30 days were

0.8% in the LOVENOX® group and 0.7% in the UFH group.The 30-day rate of the composite

endpoint of death, myocardial infarction (MI), or ICH (a measure of net clinical benefit) was

significantly lower in the LOVENOX® group (10.1%) as compared to the UFH group (12.2%)

Thrombocytopenia can occur with LOVENOX®. In patients with a history of heparin-induced

thrombocytopenia (HIT), LOVENOX® should be used with extreme caution.Thrombocytopenia

of any degree should be monitored closely. If the platelet count falls below 100,000/mm3,

LOVENOX® should be discontinued. Cases of HIT have been observed in clinical practice.

(SeeWARNINGS and PRECAUTIONS)

The use of LOVENOX® has not been adequately studied for thromboprophylaxis in pregnant

women with mechanical prosthetic heart valves. (SeeWARNINGS and PRECAUTIONS)

LOVENOX® is contraindicated in patients with hypersensitivity to enoxaparin sodium,

heparin, or pork products, and in patients with active major bleeding

9

Important safety information (continued)

I m p or t an t s af e t y

i nf or m a t i on

F P O




Make aProven Choice


10

LOVENOX® saved significantly more livesand reduced reinfarction more than UFH

in acute STEMI patients18

ExTRACT–TIMI 25—landmark study in >20,000 acute STEMI patients18,19,a

Benefit/risk profile

Based on trial results, LOVENOX® would have an estimated 21 fewer deathsor MIs per 1000 STEMI patients vs UFH, with 7 additional major bleeds20

LOVENOX® provided a significant net clinical benefit vs UFH in STEMI patients18

a A randomized,double-blind,double-dummy, parallel-group, multinational, active-controlledclinicaltrial comparingLOVENOX® withUFH in acuteSTEMIpatients.18,19

Safety: the rates of major bleeding (including ICH) at 30 days were 2.1% in theLOVENOX® group and 1.4% in the UFH group.The rates of ICH at 30 days were 0.8%

in the LOVENOX® group and 0.7% in the UFH group 18

F P O

Cumulative incidence of the time to development of the primaryefficacy endpoint (death or nonfatal MI) in the ITT population18,19

E n d p o i n t ( % )

15

12

9

6

3

0

0 5 10 20 2515 30

Days

Day 2

P =0.08

Day 8

P <0.001

P <0.001

RR (95% CI)=0.83 (0.77–0.90)

NNT=48

CI=confidence interval; NNT=number

needed to treat; RR=relative risk;

RRR=relative risk reduction.

UFH (n=10,223)

LOVENOX® (n=10,256)

12.0%

9.9%

17%RRR

ExTRACT–TIMI 25 net clinical benefit at 30 days16

Death, nonfatal MI, or

nonfatal disabling stroke

Death, nonfatal MI, ornonfatal major bleeding

Death, nonfatal MI,or nonfatal ICH

LOVENOX®

(N=10,256)%

10.1

11.0

10.1

UFH(N=10,223)

%

12.3

12.8

12.2

18

14

17

0.8 0.9 1.0

RR

95% CI;P

<0.001

95% CI; P <0.001

95% CI; P <0.001

CI=confidence interval;RR=relative risk;RRR=relative risk reduction.

Prespecified definitions RRR

%

LOVENOX®

better

UFH

better

18/Antman.N Engl J Med.April.2006/p1477/line A27

18/Antman.N Engl J Med.April.2006/p1483/

c1/line33; p1486/table 4; p1483/c1/line 41



19/Antman.Am Heart J.February.2005/p218/c2/line 4

18/Antman.N Engl J Med.

April.2006/p1483/Figure 1A; p1477/

Abstract/line 12

18/Antman.N Engl J Med.April.2006/p1477/line A12; p1482/table 2; p1483/Figure 1A


c1/line 18; p1485/table 3; p1483/c1/line 23

18/Antman.N Eng J Med.April.2006/p1477/line A6

19/Antman.Am Heart J.February.2005/p218/c2/line24

20/DOF--sanofi-aventis calculations

02977_M4 Pullout Pocket pages.qxd:Layout 2 4/28/09 11:25 AM Page 1





LOVENOX® benefits were consistent across keyprespecified subgroups in EXTRACT–TIMI 2518

b Theoveralltreatmenteffectof LOVENOX® ascompared withUFHis shownby thediamond(left andrightedgesrepresent95% CI).

c Fibrin-specificfibrinolyticagents includedalteplase, tenecteplase,and reteplase.18d Time totreatmentindicatesthetime fromtheonsetof symptomsto theadministrationofstudydrug(median,3.2 hours).18

11

LOVENOX® has been shown to reduce the rate of the combined endpoint ofrecurrent MI or death in patients with acute STEMI receiving thrombolysis andbeing managed medically or with PCI

Relative risks of and absolute event rates for the primary efficacy endpoint(death or nonfatal MI) at 30 days in various subgroups18

CI=confidence interval; RR=relativerisk; RRR=relative risk reduction.

LOVENOX® UFHSubgroup Patients 95% CIb RR Endpoints RRR

nSex

Male 15,696Female 4783

Age<75 years 17,947≥75 years 2532

Infarct locationAnterior 8933Other 11,400

DiabetesNo 17,189Yes 3060

Prior MINo 17,745Yes 2659

Fibrinolytic agentStreptokinase 4139Fibrin-specificc 16,283

Time to treatmentd

<Median 9899≥Median 10,394

PCI in 30 DaysNo 15,763Yes 4716

Overall 20,479

0.5 1.0

8.2 10.1 1815.4 18.3 16

7.9 9.9 2024.8 26.3 6

12.5 14.0 117.9 10.2 23

9.2 11.1 1713.6 17.1 21

9.2 11.1 1714.3 17.8 20

10.2 11.8 139.8 12.0 18

8.7 11.3 2311.0 12.5 12

9.7 11.4 1510.8 13.9 23

9.9 12.0 17

These data are drawn from subgroup analyses and should be interpreted with caution.

//

% %%

LOVENOX®

better UFHbetter

F P O

A C S

t a b p ul l s o u t of t h i s p o c k e t p a g e


18/Antman.N Engl J Med.April.2006/

p1482/c2/line 4

28/LOVENOX.PI.July.2008/p10/figure 1

18/Antman.N Eng J Med.April.2006/p1484/figure2 and footnotes

18/Antman.N Eng J Med.April.2006/p1484/figure2 and footnotes



ICH episodes at 30 days in the ExTRACT-TIMI 25 safety population 18

Low incidence of ICH—the most serious type of major bleeding18

No statistically significant difference in ICH between LOVENOX ® and UFH (0.8% vs 0.7%,respectively; P =0.14)18

In the STEMI pivotal trial, the rates of major hemorrhages (defined as requiring 5 or more unitsof blood for transfusion, or 15% drop in HCT or clinically overt bleeding, including ICH) at 30days were 2.1% in the LOVENOX® group and 1.4% in the UFH group.The rates of ICH at 30 dayswere 0.8% in the LOVENOX® group and 0.7% in the UFH group.

TIMI hemorrhagic episodes at 30 days in the ExTRACT-TIMI 25 safety population 18,19

12

In ExTRACT–TIMI 25, overall hemorrhage rates were low18

LOVENOX® was associated with a statistically significant increase in major or minor bleedingvs UFH (4.6% vs 3.1%, respectively; P <0.001)18

Well-documented safety profilein acute STEMI patients

a TIMI major bleeding was defined as intracranial or clinically significant overt signs of hemorrhage (including imaging) associated with a drop in Hgb of ≥5 g/dL(3.1 mmol/L), or when Hgb was not available, an absolute fall in HCT of 15%.19

b TIMI minor bleeding was defined as any clinically significant overt sign of hemorrhage (including imaging) associated with a fall in Hgb of 3 g/dL to <5 g/dL(1.9 mmol/L to <3.1 mmol/L) or an absolute fall in HCT of 9% to <15%.19

Parameter LOVENOX® UFH LOVENOX®

( N=10,176) ( N=10,1 51) vs UFHn (%) n (%) RR (95% CI) P value

ICH at 30 days 84 (0.8) 66 (0.7) 1.27 (0.92–1.75) 0.14

CI=confidence interval; RR=relative risk.

Parameter LOVENOX® UFH LOVENOX®

(N=10,176) (N=10,151) vs UFHn (%) n (%) RR (95% CI) P value

TIMI major hemorrhage19,a 211 (2.1) 138 (1.4) 1.53 (1.23–1.89) <0.001

TIMI minor hemorrhage19,b 260 (2.6) 184 (1.8) 1. 41 (1.17– 1. 70) <0. 001

TIMI major or minor hemorrhage 464 (4.6) 315 (3.1) 1.47 (1.28–1.69) <0.001

CI=confidence interval; RR=relative risk.

200,000,000 PatientsTreated Worldwide F P

O


April.2006/p1483/c1/line 18;

p1485/table 3

19/Antman.Am Heart J.

February.2005/p223/table II,

II


April.2006/p1483/c1/

line18;p1485/table 3


April.2006/ p1483/c1/line23,

p1485/table 3


April.2006/p1483/c1/line23;

p1485/table 3

28/LOVENOX PI.

July.2008/p10/c2/line 1


February.2005/p223/table II


February.2005/p223/table II




Pharmacokinetics of LOVENOX® IV

In the Le Liboux study20,43,c

After an initial 30-mg IV bolus followed by the first 1-mg/kg q12h SC dose:

—LOVENOX® immediately reached therapeutic anti-Xa levels (0.66 ± 0.23 IU/mL) and

maintained a therapeutic level until the SC dose was absorbed

—LOVENOX® provided initial peak anti-Xa levels of 1.16 ± 0.17 IU/mL 2 to 4 hours aftertreatment initiation, with an average exposure corresponding to 84% of steady-state levels

In the PEPCI study44,d

LOVENOX® SC provided anti-Xa levels that were within the target range (0.6 to 1.8 IU/mL)

in 98% of patients 2 to 8 hours after the last SC dose

An additional 0.3-mg/kg IV bolus given 8 to 12 hours after the last SC dose maintains anti-Xalevels within target range for an additional 2 hours



Pharmacokinetics of LOVENOX® IV boluswith an SC dosing regimen

13

c Sixteenhealthyelderlyvolunteers (age57± 1.4years)weregivenLOVENOX® 30mgas asingleIVbolusin period1. Inperiod2, theyreceivedthe samesingleIV bolus andsimultaneousLOVENOX®

1.0mg/kgq12hSC for4 days. Theplasmapharmacokineticsof anti-Xa,anti-IIa, andaPTTwereevaluated onday 1 ofbothperiodsandday 4 ofperiod2.20,43

d Fifty-fivepatientsreceived a LOVENOX® 30-mg IVbolusfollowed byat least 1 LOVENOX®

1-mg/kgSC injection,or a minimumof five1-mg/kgq12h SCinjections(bothallowingsteady-stateexposurepriortoPCI).44

Pharmacokinetics of LOVENOX® IV bolus and SC dosing20,43

17%

A n t i - X

a a c t i v i t y ( I U / m L )

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

Hours

Therapeutic level

0 3 6 9 12

30 mg IV + 1.0 mg/kg SC

(day 1)

1.0 mg/kg SC (no bolus)

(day 1)

30 mg IV + 1.0 mg/kg SC

(steady state)

N=16

Results from Le Liboux

et al. J Am Coll Cardiol .2000;35(suppl 1):373A,

and data on file.

F P O

The clinical significance of these data has not been established.

20/DOF - LeLiboux Poster/Figure 2

43/LeLiboux.J Am Coll Cardiol.

February.2000/p373A/c2/line 31

44/Martin.Cath Cardio Interv.2004/p166/c1/line

8; p163/c1/line 21

44/Martin.Cath Cardio Interv.2004/p163/line A8

20/DOF - LeLiboux Poster/Figure 2; c3/line 4



20/DOF - LeLiboux Poster/Figure 2; c3/line 4



44/Martin.Cath Cardio Interv.2004/p164/c1/line 35

20/DOF - LeLiboux Poster/Figure

2; c3/line 4






14


Make aProven Choice

In ESSENCE, LOVENOX® provided early and long-term superiority vs UFHin ischemic events21

ESSENCE was a prospective, randomized, double-blind, parallel-group, multicenter,

multinational trial21


Based on trial results, LOVENOX® would have an estimated 32 fewer deaths,MIs, or recurrent angina events per 1000 UA/NSTEMI patients vs UFH, withcomparable major bleeding20

LOVENOX® saved more lives and reduced MIsand ischemia vs UFH in UA/NSTEMI patients

In ESSENCE

At 30 days, major bleeds were comparable (6.5% LOVENOX® vs 7.0% UFH; P =NS)—overallbleeding for LOVENOX® was higher vs UFH (18.4% vs 14.2%, respectively; P =0.001)21

At 1-year follow-up, the need for diagnostic catheterization (55.8% vs 59.4%; P =0.036)and coronary revascularization (35.9% vs 41.2%; P =0.002) was lower for LOVENOX®

vs UFH, respectively45

LOVENOX® is indicated for the prophylaxis of ischemic complications of UAand non–Q-wave MI when concurrently administered with aspirin

F P O

Proven efficacy in reducing death, MI, and recurrent angina vs UFH21,45

95% CI; P =0.019

N=3171; NNT=32


Cohen et al. N Engl J Med .

1997;337( 7):447.

95% CI; P =0.016

N=3171; NNT=29


Cohen et al. N Engl J Med .

1997;337( 7):447.

95% CI; P =0.022

N=2915; NNT=27


Goodman et al. J Am Coll

Cardiol . 2000;36(3)693.

Early Long-term

CI=confidence interval;

NNT=number needed

to treat; RRR=relative

risk reduction.

16%RRR

15% 10%RRR RRR

21/Cohen.N Engl J Med.August.1997/p448/c1/line A19; c2/

line 27; p448/C1/line 19

21/Cohen.N Engl J Med.August.1997/p447/

Abstract/line 19; p450/table 321/Cohen.N Engl J Med.August.1997/p447/

Abstract/line 23; p450/table 3

45/Goodman.J Am Coll Cardiol.September.2000/

p693/Abstract/line A13; p695/c2/line12/c2/line12

21/Cohen.N Engl J Med.August.1997/p447/

Abstract/line 29; p450/c1/line 1; p451/c2/

table 5

20/DOF--sanofi-aventis

calculations

45/Goodman.J Am Coll Cardiol.January.2000/

p693/Abstract/line A16




15



INTERACT and SYNERGY confirmedresults of ESSENCE in UA/NSTEMI patients

In INTERACT, LOVENOX® significantly reduced ischemia and saved lives33

INTERACT was a prospective, randomized, open-label, multicenter trial designed to evaluate thesafety and efficacy of LOVENOX® compared with UFH in high-risk patients33

a Detected by continuous ECG monitoring.33

b GUSTO severe was defined as ICH, or bleeding resulting in hemodynamic compromise. 34

c A prespecified protocol analysis of a subpopulation of 6138 patients with no prerandomization therapy, or similar prerandomization and postrandomization therapy; patients did not switchantithrombin therapy at time of randomization.34

In INTERACT 33

All major hemorrhage, including CABG-related bleeding, was lower in the LOVENOX®

group compared with the UFH group at 96 hours (2.1% vs 5.5%, respectively; P =0.016)

Major non–CABG-related bleeding at 96 hours was significantly lower among

LOVENOX®-treated patients than UFH-treated patients (1.8% vs 4.6%, respectively; P =0.03)

At 30 days, major non–CABG-related bleeding was lower in the LOVENOX ® group comparedwith the UFH group (2.9% vs 5.7%, respectively; P =0.055)

In SYNERGY34

SYNERGY was a prospective, randomized, open-label, multicenter, international trial designedto study clinical outcomes of high-risk UA/NSTEMI patients treated with LOVENOX® or UFH

No significant difference between LOVENOX® and UFH in major bleeding (GUSTO severeb

[2.7% vs 2.2%, respectively; P =NS])

In a prespecified patient population of 6138,c bleeding outcomes were not significantlyincreased in the LOVENOX® group vs the UFH group (16.9% vs 17.0%, respectively; P =NS)

Ischemic event rates and composite endpoints of death and nonfatal MI 33

40

30

20

10

0

P a t i e

n t s ( % )


NNT=number needed

to treat.

Allpatientsdosed with

eptifibatideand aspirin.

Results from INTERACT.

Goodman et al. Circulation.

2003;107(2):238.12.7%

LOVENOX®

(n=322)

95% CI; P <0.001

48 to 96 hoursfollowing randomization

Endpoint: ischemic eventsa

N=624; NNT=8

25.4%

UFH(n=357)

14.3%LOVENOX®

(n=357)

95% CI; P <0.001

First 48 hoursof treatment

Endpoint: ischemic eventsa

N=714; NNT=10

5.0%LOVENOX®

(n=380)

95% CI; P =0.031

30 daysEndpoint: death

or nonfatal [re]MI

N=746; NNT=25

9.0%UFH

(n=366)

25.9%

UFH(n=302)

F P O

33/Goodman.Circulation.January.2003/

p238/line A3; p239/c2/line 8; p239/c2/

line 21; p242/c2/line 33

33/Goodman.Circulation.January.

2003/p238/abstract/line A7, A11;

p239/c2/line 6; p241/figure 1, table 4

33/Goodman.Circulation.

January.2003/p240/c2/table 3,c2/line 2

34/SYNERGY.JAMA.

July.2004/p45/abstract/line

A4, c1/line 30; p46/c1/line 8

33/Goodman.Circulation.January.2003/p238/abstract/

line A11; p239/c2/line 6; p241/figure 1, c1/line 26

33/Goodman.Circulation.January.2003/

p238/abstract/line A11; p239/c2/line 6;

p241/figure 1, c1/line 26

33/Goodman.Circulation.January.2003/p238/abstract/

line A13; p241/table 4,c2/line7; p239/c2/line 4


January.2003/p240/c2/table 3,

line7; p240/c2/line 7


January.2003/p240/c2/table 3

34/SYNERGY.JAMA.

July.2004/p52/table 6

34/SYNERGY.JAMA.

July.2004/p52/c1/table 7

33/Goodman.Circulation.January.2003/p238/abstract/line A11; p241/c1/line 25

34/SYNERGY.JAMA.July.2004/p52/table 6 footnote

34/SYNERGY.JAMA.July.2004/p52/table 7

33/Goodman.Circulation.January.

2003/p238/abstract/line A7, A11;

p239/c2/line 6; p241/figure 1, table 4




16

2007 analysis of the Premier Perspective™ database of 5.5 million patientsdischarged from hospitals46

196,104 patients discharged from 227 US hospitals met the inclusion criteria—defined as acutely ill patients ≥40 years of age with a hospital stay ≥6 daysand no anticoagulation contraindication

Only 33.9% of eligible patients received appropriate prophylaxis

Hospitalized medical patients at high risk forDVT/PE were not appropriately prophylaxed

Nearly 7 out of 10 patients did not receive appropriate prophylaxis46

a Appropriatedrugdosages (perhospitalserviceday) wereatleast10,000U forUFHand 40mg forenoxaparin. Appropriatemechanicalprophylaxiswasdefinedas useof guideline-recommendedIPC orelasticatedstockings duringthe hospitalstay. Patientsdischarged withacutespinalcord injurywererequiredtoreceiveIPCor elasticatedstockingsin additiontopharmacologicprophylaxisforthe durationoftheirhospital stayminus2 days. Durationof

therapyrequiredforUFH, enoxaparin,dalteparin, andtinzaparinwaslengthof patient’sstay minus 2 daystoaccommodatethepossibilitiesof partialdaysofstay oran invasiveprocedureduring hospitalizationforwhichanticoagulationwasnot recommendedon thedayof theprocedure.46


O

Appropriate prophylaxis dose and duration were low across all hospital types46,a

60

40

20

0

36.6%32.3% 29.4%

34.6% 31.2%35.3%

29.7%33.7%

37.8%

28.1% 28.5%

Teaching Non- teaching

Rural U rban ED 0–99 100–199 200–299 300–499 500+Physicianreferral

Hospital type Bed numbersAdmission source

N=227

A p p r o p r i a t e p r o p h y l a x i s r

a t e ( % )

Results from Amin et al. J Thromb Haemost. 2007;5(8):1610.

Treatment of the 66.1% of discharged patientswho did not receive appropriate prophylaxis46

40

30

20

10

0

I n a p p r o p r i a t e p r o p h y l a x i s r a t e ( % )

38.4%Received NOprophylaxis

N=196,104

All medical patients at high risk for DVT/PE

16.7%Received

insufficientduration 4.7%

Receivedonly mechanical

prophylaxis

6.3%Received

inappropriatedosage

Results from

Amin et al.

JThromb Haemost.

2007;5(8):1610.

LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE,in medical patients who are at risk for thromboembolic complications dueto severely restricted mobility during acute illness

46/Amin.J Thromb

Haemost.

August..2007/p1610/

c1/line 10; line 17

46/Amin.J Thromb

Haemost.

August..2007/

p1610/c1/line 20

46/Amin.J Thromb Haemost.August.

2007/p1610/c1/line25;p1615/table 4


2007/p1610/c1/line20; p1614/table 3


2007/p1612/c1/line 34; p1611/c2/

line 51; p1612/c1/line 38,25

46/Amin.J Thromb

Haemost.

August..2007/p1611/

c1/line 29




Average hospital LOS vs recommended duration of prophylaxis28,48–50



Appropriate length of DVT prophylaxis begins in thehospital and may continue with outpatient therapy

Many hospitalized acutely ill medical patients developed DVT/PE as outpatients47

Hospital stays are often shorter than recommended prophylaxis duration28,48–50

Approximately 50% of outpatients who experiencedVTE following hospit alization hada length of stay≤4 days (analysis of Worcester, MA, residents’ medical records)47

Better postdischarge care is a national quality imperative—The Joint Commission’sNPSGs 8 and 13 call for better management of medication records upon dischargeand better preparation of patients for discharge41

17

To assure the best outcome, patients should receive DVT/PE prophylaxis for the fullrecommended length of therapy47

Thrombosis prophylaxisindications for LOVENOX®

Acute medical illness

Abdominal surgery

Total hip-replacement surgery

Total knee-replacement surgery

Average hospital LOS

5–6 days

2–10 days

4–5 days

4–5 days

Approved length of DVTprophylaxis with LOVENOX®

6–11 days

7–10 days

7–10 days or 3 weeks(extended therapy)

7–10 days

Timing of VTE diagnosis among those who developedVTE as outpatients47

70

60

50

40

30

20

10

0

Within 1

1–2

2–3

66.4%(n=166)

18.3%(n=46) 15.2%(n=38)

66.9%(n=177)

19.9%(n=52) 13.2%(n=35)

Results from

Spencer et al.

Arch Intern Med .

2007;167(14):1471.

Months after

hospital discharge

Medical hospitalization only(n=264)

Hospitalization with surgery(n=250)

O u

t p a t i e n t s w i t h V T E ( % )

F P O

A c u t el y i l l t a b

p ul l s o u t of t h i s p o c k e t p a g e

47/Spencer.Arch Intern Med.

July.2007/p1471/c1/A16, c2/A1 47/Spencer.Arch Intern Med.

July.2007/p1473/c2/Figure; p1474/

Table 2

28/LovenoxPI.July.2008/

p2/c1/line 1

48/deJong.Health

ServRes.Apr.2006/

p374/line A10-A11;

p379/Table 2; p383/

Table 3

49/Basse.DisColon

Rectum.March.2004/ p272/c2/line 11;

p273/c1/line 1

50/Anderson.Chest.

Dec.2003/p350S/c1/

line 46-48; p351/Table 1;

c1/line 17


July.2007/pp1474/c2/line 7

41/www.jointcommission.

org.NPSG.Hospital.2008/

slides 19, 23


July.2007/p1474/c2/line 12, 20



MakeaProven Choice


18

Significantly fewer DVT/PE events with LOVENOX® vs placebo22

In MEDENOX, a multicenter, multinational, double-blind study, 1102 acutely ill medical patientswere randomized to either LOVENOX® (20 mg or 40 mg) SC once daily or placebo for a planned6 to 14 days22


Based on trial results, LOVENOX® would have an estimated 94 fewer DVT/PEevents per 1000 acutely ill medical patients vs placebo, with comparablemajor bleeding20

LOVENOX® demonstrated consistent safety outcomes in a wide rangeof patients22,28

No statistically significant difference in major bleeding events comparing LOVENOX®

40 mg SC once daily with placebo (1.7% vs 1.1%, respectively)22,28,a,b

No statistically significant difference in thrombocytopenia comparing LOVENOX®

40 mg SC once daily with placebo (2.2% vs 3.6%, respectively)22

Proven outcomes in acutely ill medical patientsfrom landmark MEDENOX trial22

aBased onthe rateofmajorbleedingon LOVENOX® upto 24hoursafterthelast dose.28bHemorrhagewasclassifiedas majorif bleedingwasovertandwasassociatedwiththe needfortransfusionof 2or moreunitsof packedred bloodcellsorwholeblood,orwitha decreaseintheHgbconcentrationof2.0 g/dLormorefrombaseline,or ifbleedingwas retroperitoneal,intracranial,orfatal.22

LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE, inmedical patients who are at risk for thromboembolic complications due toseverely restricted mobility during acute illness

F P O

DVT/PE events in MEDENOX—results from total population22

D

V T / P E e v e n t s ( % )

95% CI; P <0.001

N=579; NNT=11

Results from Samama et al.

N Engl J Med . 1999;341(11):793.


NNT=number needed to treat;


14.9%Placebo(n=288)

63%RRR

20

15

10

5

0

LOVENOX®

40 mg SC once daily(n=291)

5.5%


calculations

22/Samama.N Engl J Med.September.1999/

p793/c1/line A7; p795/c1/line 8


1999/p797/c1/table3/p795/c2/line 11

22/Samama.N Engl J Med.

September.1999/p797/c1/tables 3 &

4; p795/c2/line 11


September.1999/p798/c1/table 5

28/LOVENOX PI.July.2008/p4/c1/table 4


September.1999/p798/c1/table 5



September.1999/p794/c2/line 8




Incidence of DVT/PE (days 1 to 14) by patient characteristic 22,51

In MEDENOX subgroup analyses, LOVENOX® demonstrated significantreductions in DVT/PE events across all patient characteristics51


Please see accompanying full prescribing information,including boxedWARNING, inside pocket. 19

LOVENOX® consistently reduced DVT/PE inhigh-risk patients across characteristics22,51,c

c Resultsfroma posthocanalysis inpredefinedsubgroupsof theMEDENOX study.Patientsincludedwerehospitalizedforacuteheartfailure(NYHAClass III[moderate]orClassIV [severe]CHF)oracuterespiratoryfailurethat didnotrequireimmediateventilatorysupport.Otherpatientshad1 of3 medicalconditions(acute infectiousdisease withoutsepticshock, anacuterheumaticdisorder, oran activeinflammatory bowel disease)andat least 1 morepredefined DVT/PEriskfactor. Overall,therewasa 63%RRRin DVT/PE.51

Patient characteristic Placebo LOVENOX® 40 mgPatients with DVT/PE Patients with DVT/PE

% %

Acute illness

— Heart failure 14.6 4.0

— Respiratory disease 13.1 3.3

— Infectious disease 15.5 6.3

Cancer(active or previous) 19.5 9.7

Age(>75 years) 18.5 4.1

Walking at end of treatment(<10 m) 20.3 9.0

Obesity 15.2 7.5

Chronic respiratory failure 12.8 3.4

Chronic heart failure 12.1 2.2

Varicose veins 21.3 5.1

These data are drawn from subgroup analyses and should be interpreted with caution.

F P O

Results from subgroup analyses of MEDENOX trial

22/Samama.N Engl J Med.September.1999/p793/

line A18

51/Alikhan.Blood Coagul Fibrinolysis.June.2003/

p343/table 1

22/Samama.N Engl J Med.September.1999/

p796/table 2

51/Alikhan.Blood Coagul Fibrinolysis.

June.2003/p343/table1; table 2; p343/c2/

line 17


June.2003/p343/table1;table 2


p342/c1/line 11; c2/line 21; p341/c1/line A6




20

LOVENOX® reduced DVT/PE in at-risk patientswith comorbidities

In MEDENOX, the incidence of major bleeding with LOVENOX ® 40 mg SC once daily wascomparable to placebo (<1% [3/360] vs <1% [2/362], respectively)28,b,c

THE-PRINCE study reaffirmed efficacy in patients with CHF 52

In patients with heart failure, LOVENOX® SC once daily was associated with a significantlylower rate of DVT/PE vs UFH SC 3 times daily (9.7% vs 16.1%, respectively; P =0.014; RRR=40%)

Patients treated with LOVENOX® had significantly fewer injection-site hematomasd

vs UFH (7.2% vs 12.6%, respectively; P =0.027)

a Resultsfroma posthocanalysis inpredefinedsubgroupsof theMEDENOXstudy.Patientsincludedwerehospitalized foracuteheartfailure(NYHAClassIII[moderate]or Class IV[severe]CHF) oracuterespiratory failurethatdid notrequire immediate ventilatorysupport.Otherpatientshad 1 of3 medicalconditions(acuteinfectiousdiseasewithoutseptic shock,an acute rheumaticdisorder,or anactiveinflammatoryboweldisease)andat least1 morepredefinedDVT/PEriskfactor. Overall, there wasa 63%RRRin DVT/PE.51

b Based onthe rateof major bleedingonLOVENOX® upto 24hoursafterthe lastdose.28

c Bleedingcomplicationswereconsideredmajorifthe hemorrhagecauseda significantclinicalevent,or ifaccompaniedbyan Hgbdecreaseof ≥2 g/dLortransfusionof2 ormore units ofbloodproducts.Retroperitonealandintracranial hemorrhageswerealwaysconsidered major.28

d Diameter>5 cmat injection site.52


In a MEDENOX subanalysis, LOVENOX® demonstrated consistent efficacy andsafety in a wide range of patients28,51,a


O

Relative reduction in the incidence of DVT/PE inpatients with acute respiratory disease51

20

15

10

5

0

3.3%LOVENOX®


95% CI; P =0.003

I n c i d e n c e o f D

V T / P E ( % )


NNT=number needed

to treat.

N=306; NNT=11

Results from Alikhan et al.

Blood Coagul Fibrinolysis .

2003;14(4):341.

These data are drawn from a subgroup analysis and should be interpreted with caution.

13.1%Placebo(n=153)

Incidence of DVT/PE at day 14 in patients with CHF 51

20

15

10

5

0

4.0%LOVENOX®


95% CI; P =0.02

I n c i d

e n c e o f D V T / P E ( % )


NNT=number needed

to treat.

N=195; NNT=10



2003;14(4):341.


14.6%Placebo(n=96)


June.2003/p342/c2/line28;p343/table 1


June.2003/p342/c2/line28;p343/table 1


June.2003/p343/table 1

28/LOVENOX PI.July.2008/p4/table 4

52/Kleber.Am Heart J April.2003/p617/tableIII; p618/figure 2; p615/c1/line 36

52/Kleber.Am Heart J April.2003/p

619/table IV


June.2003/p342/c1/line 11; c2/line 21;

p341/c1/line A6


28/LOVENOX PI.July.2008/p4/

c1/table 4

52/Kleber.Am Heart J.April.2003/

p615/c2/line 26; p619/table IV






In a MEDENOX subanalysis, LOVENOX® reduced the risk of DVT/PE inhospitalized patients with infectious disease, rheumatic disorder, orinflammatory bowel disease in addition to cancer51

LOVENOX®—proven outcomes acrossmultiple patient types

In a MEDENOX subanalysis, LOVENOX® reduced the incidence of DVT/PE inpatients with acute infectious disease28,51

21

In MEDENOX, the incidence of major bleeding with LOVENOX ® 40 mg SC once daily wascomparable to placebo (<1% [3/360] vs <1% [2/362], respectively)28,b,c


Incidence of DVT/PE at day 14 in patients with cancer 51

20

15

10

5

0

9.7%LOVENOX®


95% CI; P =0.4

I n c i d e n c e

o f D V T / P E ( % )


NNT=number needed

to treat.

N=72; NNT=11



2003;14(4):341.


19.5%Placebo(n=41)

Relative reduction in the incidence of DVT/PE in at-riskpatients with acute infectious disease51

20

15

10

5

0

6.3%LOVENOX®


95% CI; P =0.01

I n c i d e n c e o f D V T / P E ( % )


NNT=number needed

to treat.

N=314; NNT=11



2003;14(4):341.


15.5%Placebo(n=155)

F P O


p343/table 2


June.2003/p343/table 1



p343/table 1; p342/c1/line 18



June.2003/p343/tables 1 & 2




22


Make aProven Choice

LOVENOX® outperforms UFHin critical areas

UFH requires monitoring and constant dose adjustments53

The top 5 medication errors consistently include the use of UFH 54

The #1 drug error due to improper dosage or quantity

The #1 reported emergency department medication error

One of the top 5 medication errors 4 years in a row

VTE recurrence linked to subtherapeutic aPTT level at 24 hours 55

A pooled analysis of 3 randomized trials demonstrated that out-of-range aPTT within 24 hoursmay lead to DVT recurrence55

LOVENOX® is indicated for:— The inpatient treatment of acute DVT, with or without PE, when

administered in conjunction with warfarin sodium

— The outpatient treatment of acute DVT, without PE, when administeredin conjunction with warfarin sodium

F P O

Inpatients with thrombosis who received at least 3 days of UFH53

N=311

Results from Hylek et al.

Arch Intern Med . 2003;163(5):621.

Therapeutic rangemaintained on each

of 4 sequential days in

7%Subtherapeutic

or supratherapeutic

levels occurred on

at least 1 of 4

sequential days in

93%

25

20

15

10

5

0

23.3%

up to

6%

95% CI; P =0.02

I n c i d e n c e o f D V T / P E ( % )


NNT=number needed

to treat.

N=746; NNT=6

Results from Hull et al.

Arch Intern Med.

1997;157(22):2562.

Subtherapeutic aPTTat 24 hours (n=30)

aPTT within therapeuticrange at 24 hours (n=87)

Rate of VTE recurrence was related to aPTT level at 24 hours55

53/Hylek.Arch Intern Med.

March.2003/p621/c2/line A4

54/Niccolai.Pharmacotherapy.2004/p147S/c2/line

20; p147S/table 1

54/Niccolai.Pharmacotherapy.2004/p147S/c2/line 22

54/Niccolai.Pharmacotherapy.2004/p148S/c1/line1

54/Niccolai.Pharmacotherapy.2004/p148S/c1/line

7;p148S/Table 2

55/Hull.Arch Intern Med.December.1997/

p2565/c2/line19

55/Hull.Arch Intern Med.December.1997/

p2565/c1/line 8

53/Hylek.Arch Intern Med.

March.2003/p621/c2/line 7






LOVENOX®—proven for inpatient andoutpatient treatment of acute DVT

LOVENOX® is an appropriate choice for outpatient DVT treatment vs inpatientIV with UFH23

Incidence of major hemorrhage for all patients was comparable (1.2% UFH vs 2.0%LOVENOX®; P =NS)23

LOVENOX® 1.5 mg/kg SC once daily is a clear choice in the hospital56

No statistical difference in patients with DVT, with or without PE, among treatment groups

in the incidence of hemorrhagic complications or transfusion requirements 56

23

aInthis study, a randomized, open-labeltrialcomparingUFHto LOVENOX®, themeantimespentinthe hospitalafter randomizationfor LOVENOX® patientswas 1.1± 2.9days.23

bInthis trial,a randomized, controlled, partiallyblinded,equivalencetrial,patientsup to155 kgwere studied.56

Incidence of recurrent symptomatic thromboembolism

within 3 months after the start of therapy23,a

7

6

5

4

3

2

1

0

6.7%

5.3%

95% CI; P =NS

I n c i d e n c

e o f D V T / P E ( % )


NS=not significant.

N=500

Results from

Levine et al.

N Engl J Med .

1996;334(11):677.

UFH(n=253)

LOVENOX®

(n=247)

All patients receivedwarfarin starting on the second day.

Incidence of recurrent symptomatic thromboembolism

within 3 months after the start of therapy56,b

5

4

3

2

1

0

4.1%4.4%

95% CI; P =NS

A l l t r e a t e d p a t i e n t s ( % )


NS=not significant.

N=900

At baseline, 32% had

DVT with PE.

Results from Merli et al.

Ann Intern Med .

2001;134(3):191.

UFH(n=290)

LOVENOX®

1.5 mg/kgSC once daily

(n=298) 2.9%LOVENOX®

1.0 mg/kgq12h SC(n=312)

All patients receivedwarfarin starting on the second day.

F P O

DV T t r e a t m en t t a b p ul l s o u t of t h i s p o c k e t p a g e

23/Levine.N Engl J Med.March.1996/p679/

c2/line27; p680/c1/table 2


56/Merli.Ann Intern Med.February.2001/p196/

table 3; p195/table 2; p191/line A15; line A20

56/Merli.Ann Intern Med.February.2001/

p197/c1/line 19


c2/line18;p680/c1/line 27

56/Merli.Ann Intern Med.February.2001/p192/c1/line 23; p195/table 2


c2/line A14

56/Merli.Ann Intern Med.February.2001/p191/

c2/line A1



24

Without prophylaxis, many patients undergoing hip-replacement surgerywill develop DVT57

The incidence of DVT in untreated total hip-replacement patients exceeded 77% during thefirst week57

The high risk of DVT/PE persists after surgery and hospital discharge58

DVT/PE risk is elevated and requiresprophylaxis early on inTHR andTKR surgery

LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE:

— In patients undergoing hip-replacement surgery, during and followinghospitalization

— In patients undergoing knee-replacement surgery

a As determined by leg scanning.57


O

Occurrence of DVT after hip-replacement surgery

among patients with no prophylaxis57,a

30

25

20

15

10

5

0 H i p - r e p l a c e m e n t p a t i e n t s ( n )

1 2 3 4 5 6 7 11 12 13 14 15 168 9 10

DVT femoral

DVT total

N=107(untreated patients)

Results from Sikorski

et al. J Bone JointSurgBr .

1981;63-B(2):171.

Postoperative day (no DVT prophylaxis)

DVT/PE cases diagnosed after total hip or total knee arthroplasty 58

80

60

40

20

0 I n

c i d e n c e o f D V T / P E ( % )

76%After hospital

discharge24%

95% CI; P <0.001

N=556Total hip arthroplasty

53%Before hospital

discharge

47%After hospital

discharge

95% CI; P <0.001

N=508Total knee arthroplasty

Before hospitaldischarge

CI=confidence interval.

Results fromWhiteet al. Arch Intern Med .1998;158(14):1525.

57/Sikorski.Br J Bone Joint Surg.1981/p172/

c2/line33; p171/c2/line 21; line 4

57/Sikorski.Br J Bone Joint Surg.1981/

p172/c1/figure 1; p171/c2/line 21

57/Sikorski.Br J Bone Joint Surg.1981/

p172/c2/line33; p171/c2/line21

[NOTE:82÷107=77%]

58/White.Arch Intern Med.

July.1998/p1525/c1/line 17; c2/

line A1

57/Sikorski.Br J Bone Joint Surg.1981/p172/c1/line 26




25



LOVENOX® significantly reduced DVT risk vs warfarin24,26,b

Hip-replacement surgery—in symptomatic DVT during hospitalization,LOVENOX® 30 mg q12h SC significantly reduced DVT risk vs warfarin(0.3% vs 1.1%, respectively; P =0.008)59,c


Based on trial results, LOVENOX® would have an estimated 8 fewer symptomaticDVT events during hospitalization per 1000 hip-replacement patients vs warfarin,with comparable major bleeding20

The incidence of major bleeding episodes was comparable between thegroups (0.6% LOVENOX® vs 0.3% warfarin; P =NS)59

Knee-replacement surgery—in VTE documented by venography,LOVENOX® 30 mg SC twice daily significantly reduced VTE risk vs warfarin

(25.4% vs 45.5%, respectively; P <0.001)60,d


Based on trial results, LOVENOX® would have an estimated 201 fewer DVT eventsper 1000 knee-replacement patients vs warfarin,with comparable major bleeding20

No statistically significant difference in the incidence of major bleedingbetween the 2 groups (5.2% LOVENOX® vs 2.3% warfarin, respectively; P =NS)60

LOVENOX® is proven through 21 days of continued DVTprophylaxis in total hip-replacement surgery25,e


Based on trial results, LOVENOX® would have an estimated 210 fewer DVT events per 1000hip-replacement patients having extended prophylaxis vs placebo, with comparable major bleeding20

Transfusions and blood loss were similar between the groups25

Proven outcomes in orthopedicsurgery patients

b Warfarin initiated at 7.5 mg daily and adjusted to target INR 2.0–3.0. 59,60

c This study was a randomized, multicenter, open-label, parallel-group clinical trial. 59

d This study was a prospective, randomized, multicenter, open-label, parallel-group clinical trial. 60

eThiswasa prospective,randomized,double-blindstudyconductedat asinglecenterwithallpatientsreceivingLOVENOX® 40 mg once daily during their hospitalization and blinded drug at the end of hospitalization. 25

77%RRRin DVT

95% CI; P =0.008

N=3011; NNT=114

44%RRR

inVTE

95% CI; P <0.001

N=349; NNT=5

Results fromFitzgerald et al.

J Bone Joint SurgAm.2001;83-A(6):900.

Results fromColwell et al.

J Bone Joint SurgAm.1999;81-A(7):932.

DVT/PE cases diagnosed after total hip arthroplasty25

D V T / P E ( % )

40

30

20

10

07 14 21 28

39%

18%

Postoperative days

LOVENOX®

Placebo


NNT=number needed to treat;


N=233 (evaluable patients);NNT=5

All 288 patients received

LOVENOX® for 7 to 11 (average 9)

days in-hospital, and 262patients were randomized post

hospital discharge to receive

LOVENOX® or placebo (range,

19 to 23 days; average, 21 days).

Results from Bergqvist et al.

N Engl J Med . 1996;335(10):696.

40 mg SC once daily

53%RRR

95% CI; P <0.001

F P O

Hi p / K n e e t a b

p ul l s o u t of t h i s p o c k e t p a g e

59/Colwell.J Bone Joint Surg

Am.July.1999/p936/table IV

60/Fitzgerald.J Bone Joint Surg

Am.June.2001/p903/table II

59/Colwell.J Bone

Joint Surg.July.1999/

p936/table IV; p933/

c2/line 9

59/Colwell.J Bone Joint Surg.

July.1999/p937/table VI

60/Fitzgerald.J Bone Joint Surg.June.2001/p903/table II; p900/line A5

60/Fitzgerald.J

Bone Joint Surg.

June.2001/p904/

c2/line 28

25/Bergqvist.N Engl J

Med.Sep.1996/p697/

c1/line 20; p698/table

2; c2/line 7, 26

25/Bergqvist.N Engl J Med.

September.1996/p698/c1/line 16

59/Colwell.J

Bone Joint Surg

Am.1999/p933/

c2/line 18

60/Fitzgerald.J

Bone Joint

Surg.June.2001/

p901/c2/line 46

59/Colwell.J Bone Joint Surg.July.1999/p933/c1/line 46

60/Fitzgerald.J Bone Joint Surg.June.2001/p900/line A4

25/Bergqvist.N

Engl J Med.

September.1996/

p697/c1/line 6

20/DOF--sanofi-aventis calculations


calculations


calculations



Make aProven Choice


26

DVT/PE is the second leading cause of deathin hospitalized patients with cancer16

LOVENOX® dosing offers practical advantages28,62

a In thefirst fewmonthsfollowingthe interruption of anticoagulanttreatment.61

LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE,in patients undergoing abdominal surgery who are at risk for thromboemboliccomplications

The risk of DVT/PE in patients with cancer undergoing surgery is 3- to 5-fold higher than

in those without cancer16

Patients with cancer exhibit a risk of recurrent DVT/PE that is approximately twice as highas that observed in patients without cancer61,a

Cancer is one of the major risk factors for developing DVT/PE afterabdominal surgery15

F P O

Incidence of DVT/PE events after cancer surgery17

2.5

2.0

1.5

1.0

0.5

0

C u m u l a t i v e i n c i d e n c e o f D V T / P E ( % )

Mean time toVTE=17 days postop

60% of events

Surgery

N=2360

Adapted from

Agnelli. Ann Surg .2006;243(1):89.

1-5 days

n=12

6-10 days

n=9

11-15 days

n=8

16-20 days

n=1

21-25 days

n=5

26-30 days

n=8

>30 days

n=7

LOVENOX® vs 3 UFH62

ONE SHOT, ONCE A DAY 5000 IU q8h

16/Donati.Haemostasis.1994/p128/lineA1

15/Kakkar.Hematol J.2004/pS20/c1/line 25

17/Agnelli.Ann Surg.January.2006/

p89/c2/lineA9;p93/c1/line 27

16/Donati.Haemostasis.1994/p129/c2/line 15

61/Prandoni.Can Treat Rev.2002/p134/c2/line 11

28/LOVENOX PI.July.2008

62/Heparin PI.December.2000/p1/line 25

61/Prandoni.Can Treat Rev.2002/p133/line A2

PO




27



LOVENOX® is a successfulreplacement for UFH

bA prospective, double-blind,randomized, multicentertrialin 1115patientsundergoingplannedelectivecurativesurgeryfor abdominalor pelviccancer.Patientsreceived eitherLOVENOX® 40mgSConcedailybeginning2 hoursbeforeoperationandcontinuingfor10± 2daysor UFH5000IUSCbeginning2 hoursbeforeoperationand then3 timesdailyfor10± 2days.12

In patients with cancer, LOVENOX® 40 mg SC once daily was as effective asUFH 5000 IU SC 3 times daily12

Incidence of hemorrhage was comparable between the groups (P =NS)12

No intracranial or intraocular hemorrhages12

No cases of thrombocytopenia occurred in the LOVENOX® group12

In patients with colorectal cancer, LOVENOX® 40 mg SC once daily was aseffective as UFH 5000 IU SC 3 times daily12

The incidence of hemorrhage was comparable and not statistically significant

between the groups12

Incidence of DVT/PE in patients undergoing cancer surgery12,b

20

15

10

5

0

18.2%UFH

5000 IU SC3 times daily

(n=319)

14.7%

95% CI; P =NS

D V T / P E ( % )


NS=not significant.

N=631

Results from the

ENOXACANStudy

Group. Br J Surg .1997;84(8):1099.

LOVENOX®

40 mg SConce daily

(n=312)

Incidence of DVT in patients undergoing colorectal cancer surgery 12,b

20

15

10

5

0

D V T ( % )

16.6%LOVENOX®

40 mg SConce daily

(n=102)

95% CI; P =NS


NS=not significant.

N=217

Results from the

ENOXACANStudyGroup. Br J Surg .

1997;84(8):1099.

18.8%UFH

5000 IU SC3 times daily

(n=115)

F P O

A b d omi n al t a b p ul l s o u t of t h i s p o c k e t p a g e

12/ENOXACAN Study Gp. Br J.August.1997/

p1099/A17; p1102/c1/line 62

12/ENOXACAN Study Gp.Br J Surg.




12/ENOXACAN Study Gp.Br J Surg.August.1997/

p1101/c1/line33/p1101/c2/table 3





12/ENOXACAN Study Group. Br J Surg.

August.1997/p1099/line A10; c2/line 2; c2/line 22




August.1997/ p1101/C1/line 26



Patients transitioned to PCI28

Thrombolytic therapy (fibrin-specific or non–fibrin-specific)28

Treatment of acute STEMI patients28

Acute coronary syndrome

LOVENOX®—practical dosingwith proven outcomes

Patient type Dosing Duration of therapy

<7 5 years of age 3 0 mg single IV bolus plus LOVENOX® treatment duration1 mg/kg SC followed by 1 mg/kg SC in the pivotal clinical trial wasevery 12 hours (maximum 100 mg for 8 days or until hospital discharge,

each of the first 2 SC doses only, whichever came first. An optimalfollowed by 1 mg/kg dosing for the duration of treatment is not known,remaining doses). In pivotal trial, first but it is likely to be longer thanSC dose given within 15 minutes 8 daysof IV bolus

<75 years of age with 30 mg single IV bolus plus 1 mg/kg SC LOVENOX® treatment durationsevere renal impairment followed by 1 mg/kg SConcedaily in the pivotal clinical trial was(CrCl <30 mL/min); does not 8 days or until hospital discharge,apply to hemodialysis patients whichever came first

≥75 years of age No initial IV bolus; 0.75 mg /kg SC LOVENOX® treatment durationevery 12 hours (maximum 75 mg for in the pivotal clinical trial waseach of the first 2 SC doses only, 8 days or until hospital discharge,followed by 0.75 mg/kg dosing for the whichever came first. An optimalremaining d oses) d urat io n o f trea tme nt is n ot known,

but it is likely to be longer than8 days

≥75 yea rs o f a ge wit h No i ni ti al IV b ol us; LOVENOX® treatment durationsevere renal impairment 1 mg/kg SConcedaily in the pivotal clinical trial was(CrCl <30 mL/min); does not 8 days or until hospital discharge,apply to hemodialysis patients whichever came first

28

LOVENOX® has been shown to reduce the rate of the combined endpoint ofrecurrent MI or death in patients with acute STEMI receiving thrombolysisand being managed medically or with PCI

When LOVENOX® is administered LOVENOX® should be given between 15 minutes before andin conjunction with a thrombolytic 30 minutes after the start of fibrinolytic therapy

If the last LOVENOX® SCadministration was given:<8 hours before balloon inflation No additional dosing needed>8 hours before balloon inflation Administer LOVENOX® 0.3 mg/kg IV bolus


O

28/LOVENOX PI.July.2008/

p2/c2/line 18

28/LOVENOX PI.


28/LOVENOX PI.


28/LOVENOX PI.


28/LOVENOX PI.July.2008/p1/c1/table:


18/Antman.N Engl J Med.April.2006/

p1479/c1/line 20

28/LOVENOX PI.July.2008/ p1/c1/table:

line 17; p2/c2/table 1/line 15

28/LOVENOX PI.July.2008/p1/c2/

table/ line 1; p2/c2/line 32

28/LOVENOX PI.July.2008/ p1/c2/table/

line 1; p2/c2/table 1: line 18




FPO




Prophylaxis of ischemic complications in UA/NSTEMI patients28

29





UA/NSTEMI 1 mg/kg SC every 12 hours • Minimum: 2 daysand continued(non–Q-waveMI) (inconjunctionwithoralaspirin therapy until clinical stabilization

100mgto 325mgoncedaily) • Usual:2 to8 days• Administeredup to12.5 days

in clinical trials

Severerenalimpairment 1 mg/kgSC oncedaily • Minimum: 2 daysand continued(CrCl <30mL/min);doesnot (inconjunctionwithoralaspirin therapy until clinical stabilizationapplyto hemodialysis patients 100mgto 325mgoncedaily) • Usual:2 to8 days

LOVENOX® requires no dose adjustments with moderate (CrCl=30 to 50 mL/min) and mild(CrCl=50 to 80 mL/min) renal impairment; all such patients should be observed carefully forsigns and symptoms of bleeding28

LOVENOX® may be largely neutralized (up to 60%) by the slow IV injection of protamine sulfate(1% solution)

IV dosage proven effective in acute STEMI patients20,63

Mean anti-Xa levels increased from 0 to 1.25 U/mL within 5 minutes after IV dosingof LOVENOX®, and then decreased to 0.63 U/mL at 8 hours63

After an initial 30-mg IV bolus of LOVENOX ®, followed by the first 1-mg/kg q12h SC dose,adequate anti-Xa levels (0.66 ± 0.23 IU/mL) were reached immediately and maintaineduntil the SC dose was absorbed20

UA/NSTEMI dosing

All patients should receiveASA as soon as they are identified as having STEMI, and maintainedwith 75 mg to 325 mg once daily, unless contraindicated

LOVENOX® is indicated for the prophylaxis of ischemic complications of UAand non–Q-wave MI when concurrently administered with aspirin

F P O

D o s i n g an d

a d mi ni s t r a t i on

63/Bijsterveld.J Am Coll

Cardiol.2003/p425/c2/line

11; p425/figure 1

20/DOF - Le Liboux Poster/

c3/line 4

28/LOVENOX PI.


28/LOVENOX PI.

July.2008/p1/c1/table/


28/LOVENOX PI.

July.2008/p1/c1/table:

line 15; p2/c2/table 1:




c1/line 53


c1/line 14

Make aProven ChoiceO




Inpatient and outpatient treatment of acute DVT28

Prophylaxis of DVT in acutely ill medical patients 28

30

with Proven OutcomesProven Choice

DVT treatment

Acutely ill medical patients


Severelyrestrictedmobility 40mgSConcedaily • Usual:6 to11 daysduringacute illnessa • Administeredup to14 days

in the controlled clinical trial

Severe rena l impa irme nt 30mg SCo nc e da ily • Usual:6 to11 days(CrCl <30mL/min);doesnot • Administeredup to14 daysapplyto hemodialysis patients in the controlled clinical trial


I npa ti ent swit h acu te DVT, 1.5mg/ kg SCo nc e da ily • Average: 7 days

with orwithout PE (atthesame time every day) • Continuefor a minimum ofor 5 days anduntilINR=2.0–3.01 mg/kgSC every 12 hours • Administeredup to17 days

in controlledclinical trials(bothin conjunctionwithwarfarin sodiumtherapy)

Outpatients w ith a cute 1 m g/kg S C e very 1 2 h ours • Average: 7 daysDVT, without PE (in conjunctionwith • Continuefor a minimum of

warfarinsodiumtherapy) 5 daysanduntilINR=2.0–3.0• Administeredup to17 days

in controlledclinical trials

Inpatients(with acute DVT, withor 1 mg/kg SConcedaily • Average: 7 dayswithout PE) or outpatients (withacute (in conjunctionwith • Continuefor a minimum of5 daysDVT, without PE)withsevere renal warfarinsodiumtherapy) anduntilINR=2.0–3.0impairment(CrCl <30 mL/min); does

not applyto hemodialysis patients


LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE, inmedical patients who are at risk for thromboembolic complications due toseverely restricted mobility during acute illness

a Medicalpatientswho areat riskforthromboemboliccomplicationsdueto severelyrestrictedmobility duringacuteillness.28

LOVENOX® is indicated for:— The inpatient treatment of acute DVT, with or without PE, when

administered in conjunction with warfarin sodium— The outpatient treatment of acute DVT, without PE, when administered

in conjunction with warfarin sodium

F P O


table: line 7; p2/c1/line 41


table: line 7; p2/c2/table 1: line 3; c1/

line 41


c1/table: line 9; p2/c1/line 49,53


table: line 12; p2/c1/line 46,53


table: line 9,12; p2/c2/table 1/line 4,7;

c1/line 55


line 7,41


line 1,7


line 9

FP O




Prophylaxis of DVT in hip- or knee-replacement surgery patients28

31



Surgery

LOVENOX® requires no dose adjustments with moderate (CrCl=30 to 50 mL/min) and mild(CrCl=50 to 80 mL/min) renal impairment; all such patients should be observed carefullyfor signs and symptoms of bleeding28



LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE:— In patients undergoing hip-replacement surgery, during and following

hospitalization— In patients undergoing knee-replacement surgery


Hip-r eplacement s urgery, 30 m g S C every 1 2 h ours • Usual:7 to10 daysduring and following (initiated 12to 24 hours • Administeredup to14 dayshospitalization postoperatively)provided inclinicaltrials

hemostasishas beenestablishedat thewound siteor40mg SConcedailymay be considered

(initiated 12± 3hours preoperatively)

Continued p rophylaxis i n 40 m g S C once d aily • 3 weeksrecommendedhip-replacement surgery (followinginitial phase

of thromboprophylaxis)

Kne e-re pl ac eme nt surge ry 30mg SCe ve ry12h ou rs • Usual:7 to10 days(initiated 12to 24 hours • Administeredup to14 days inpos toperatively) cli ni cal t rial sprovided hemostasishas beenestablishedatthe woundsite

Severe r enal i mpairment 30 m g SC o nce daily • Usual:7 to10 days(CrCl <30mL/min);doesnot • Administeredup to14 days inapplyto hemodialysis patients clinical trials

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Prophylaxis of DVT in abdominal surgery patients28

32


LOVENOX® requires no dose adjustments with moderate (CrCl=30 to 50 mL/min) and mild(CrCl=50 to 80 mL/min) renal impairment; all such patients should be observed carefullyfor signs and symptoms of bleeding28

LOVENOX® may be largely neutralized (up to 60%) by the slow IV injection of protamine sulfate

(1% solution)


Abdominal surgery 40 mg SC once daily • Usual:7 to10 days(initiated2 hours • Administeredup to12 daysprior to surgery) in clinical trials

Severe r enal i mpairment 30 m g S C once d aily • Usual:7 to10 days(CrCl<30 mL/min); • Administeredup to12 daysdoes notapply to in clinical trialshemodialysis patients

WARNING: SPINAL/EPIDURAL HEMATOMAS

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patientsanticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins orheparinoids for prevention of thromboembolic complications are at risk of developing an epiduralor spinal hematoma, which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of indwelling epidural catheters for administrationof analgesia or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants.The risk also appearsto be increased by traumatic or repeated epidural or spinal puncture.

Monitor patients for signs and symptoms of neurological impairment. If neurologic compromiseis noted, urgent treatment is necessary.

Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulatedor to be anticoagulated for thromboprophylaxis (see Warnings and Precautions [5.1] andDrug Interactions [7 ]).

Surgery

LOVENOX® is indicated for the prophylaxis of DVT, which may lead to PE, inpatients undergoing abdominal surgery who are at risk for thromboemboliccomplications

, ,Treated Worldwide F P

O


c1/table/line 1; p2/c1/line 27


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Dosage for patients with severe renal impairment (CrCI <30 mL/min)28

33



In patients with renal impairment, there is an increased exposure to LOVENOX ®. All such

patients should be observed carefully for signs and symptoms of bleeding. Becauseexposure to LOVENOX® is significantly increased in patients with severe renal impairment(CrCl <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylacticdosage ranges28

LOVENOX® requires no dose adjustments with moderate (CrCl=30 to 50 mL/min) and mild

(CrCl=50 to 80 mL/min) renal impairment; all such patients should be observed carefullyfor signs and symptoms of bleeding28


LOVENOX®—dosage and usein special populations

a Medicalpatientswho areat riskforthromboemboliccomplicationsdue toseverely restrictedmobilityduringacute illness.28

Patient type

Treatment of acuteSTEMI in patients<75yearsof age

Treatment of acuteSTEMI in patients≥75yearsof age

Prophylaxisof ischemic complicationsofUA andnon–Q-waveMI patients

Prophylaxisin acutely ill medical patientsa

Inpatient treatment (withacute DVT, withorwithout PE) or outpatienttreatment(withacute DVT, without PE)

Prophylaxisin hip-or knee-replacementsurgery patients

Prophylaxisin abdominalsurgery patients

Dosingin patients with CrCl <30mL/min;does notapply to hemodialysis patients

30 mgsingle IV bolusplus 1 mg/kgSC followedby1 mg/kg SConce daily

NoinitialIV bolus;1 mg/kgSC once daily

1 mg/kgSC once daily (in conjunctionwith oralaspirintherapy)

30mg SConce daily

1 mg/kgSC once daily (in conjunctionwith warfarinsodiumtherapy)

30mg SConce daily

30mg SConce daily

F


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table 1/line 18


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Patient characteristics28

Pregnancy • LOVENOX® is notpredictedto increase the risk of developmental abnormalities

• Pregnancy aloneconfersan increased risk for thromboembolismthatis evenhigher for womenwith thromboembolic disease and certain

high-risk pregnancy conditions (see Warnings andPrecautions in full

prescribing information)• Pregnant womenreceivinganticoagulants suchas LOVENOX® are atriskfor

bleeding andshould be carefully monitoredfor evidence of bleeding or excessive

anticoagulation (see BoxedWarning in fullprescribinginformation)

Nursingmothers • Itis notknownwhetherthisdrugis excretedin humanmilk• Because many drugsare excretedin humanmilk,cautionshouldbe exercised

whenLOVENOX® is administered to nursing women

Pediatric use • Safetyand effectiveness of LOVENOX® in pediatric patients havenot

beenestablished

LOVENOX®—16 years of real-world experiencein the US across multiple patient types28

Well-documented in clinical practice with:

Acutely ill medical patients with comorbidities, such as cancer, heart disease, COPD,and acute infection22,28,51

Hip or knee replacements in elderly patients (≥65 years of age)25,28,59,60

ACS patients (≥65 years of age)18,21,28

DVT inpatient and outpatient treatment in patients with or without comorbidities

Well-documented safety profile in special populations28

Elderly patients

Low-weight patients

No dose adjustments recommended for patients with mild (CrCl 50–80 mL/min)or moderate (CrCl 30–50 mL/min) renal impairment

Modify dosing for patients with severe renal impairment (CrCl <30 mL/min)

across all indications

Refer to page 33 for full dosing and administration information for patients with severerenal impairment (CrCl <30 mL/min)

LOVENOX®—use in special populations

28/LOVENOX PI.


28/LOVENOX PI.July.2008/p7/c2/line 1; p8/c12/line 6

22/Samama.N Engl J Med.September.1999/p796/table 2

51/Alikhan.Blood Coagul Fibrinolysis.June.2003/p343/

table1; table 2; p343/c2/line 1725/Bergqvist.N Engl J Med.September.1996/p698/Table 1; mean age: 70 (44-87)


59/Colwell.J Bone Joint Surg Am.July.1999/p935/Table II; mean age: 64

60/Fitzgerald.J Bone Joint Surg Am.June.2001/p903/c2/line 14; Appendix: Figure 1;

available at: www.jbjs.org; mean age: 6828/LOVENOX PI.July.2008/p6/c1/line 5

18/Antman.N Engl J Med.April.2006/p1480/table 1; 12% were >75 years of age

21/Cohen.N Engl J Med.August.1997/p449/c1/line 14; mean age: 65

23/Levine.N Engl J Med.March.1996/p679/c2/Table 1

28/LOVENOX PI.July.2008/p6/c2/line 19,35,41,52; p7/c2/line 25, 33; p8/c1/line 19




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35



Patient characteristics28

LOVENOX®—use in special populations

• Inthe clinicalstudyfor treatmentof acuteSTEMI, there wasno evidenceofdifferencein efficacy between patients ≥75 yearsof age(n=1241)and patients

<75yearsof age(n=9015). Patients≥75years ofagedidnotreceivea 30mg IVbolus

prior tothe normalregimenand hadtheir SC dose adjustedto 0.75mg/kg every12 hours (see Dosage andAdministration in full prescribinginformation)

• The incidenceof bleeding complications was higherin patients≥65yearsof age

ascomparedto younger patients (<65 years ofage)

• Useof LOVENOX® in patients withmechanicalprosthetic heartvalves has not beenadequatelystudied.Isolated casesof prostheticheart valvethrombosishave been

reported in patients withmechanical prostheticheart valveswho havereceived

LOVENOX® for thromboprophylaxis. Someof thesecases werepregnantwomen inwhomthrombosisled to maternal and fetaldeaths. Insufficient data,the underlying

disease, andthe possibility of inadequateanticoagulation complicatethe evaluation

ofthesecases

• Pregnantwomenwithmechanical prosthetic heartvalvesmay beat higherrisk for thromboembolism (see Warnings and Precautions in full prescribinginformation)

• The impact of hepatic impairmenton LOVENOX® exposure and antithrombotic

effect has not beeninvestigated. Caution shouldbe exercised whenadministering

LOVENOX® to patients withhepatic impairment

• Anincreasein exposureof LOVENOX® withprophylactic dosages (non–weight-

adjusted)has been observedin low-weight women(<45 kg)andlow-weight men(<57 kg). Allsuchpatientsshould beobservedcarefullyfor signs andsymptoms

of bleeding (see Clinical Pharmacology in fullprescribinginformation)

Geriatricuse— treatmentof

acuteSTEMI

Patients withmechanicalprostheticheartvalves

Hepatic impairment

Low-weight patients

Geriatric use— • More than 2800patients, 65 years andolder, have received LOVENOX® in pivotalD VT in h ip-o r c linica ltr ia ls.T he e ff ica cyo f LOVENOX® inthe geriatric(≥65 years)was similar

knee-replacement tothat seenin younger patients(<65 years). The incidence ofbleeding

and abdominal complicationswassimilar between geriatricandyoungerpatients whensurgery;treatment of 30mg q12hor 40mg oncedailydoses ofLOVENOX® wereemployed.The incidence

DVT; preventionof ofbleeding complications was higherin geriatricpatientsas comparedto younger

ischemiccomplications patients when LOVENOX® wasadministered atdosesof 1.5mg/kgoncedailyof U A and or 1 m g/kg q 12h. T he r isk o f LOVENOX® -associatedbleedingincreasedwith age.

non–Q-waveMI Seriousadverse eventsincreased withageforpatients receivingLOVENOX®.

Otherclinicalexperience(includingpostmarketingsurveillance and literaturereports) has not revealed additionaldifferences in thesafety of LOVENOX®

between geriatric and younger patients. Careful attentionto dosingintervalsandconcomitant medications(especiallyantiplatelet medications) is advised.

LOVENOX® shouldbe used with care ingeriatricpatientswho mayshowdelayedeliminationof enoxaparin.Monitoring of geriatric patients withlow bodyweight

(<45kg) andthose predisposedto decreasedrenal function should be considered

(see Warnings and Precautions in full prescribinginformation)


line 5

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28/LOVENOX PI.


28/LOVENOX PI.


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ACCP guidelines: prophylaxis of DVT in medical patientswith restricted mobility during acute illness11,64,c

ACC/AHA guidelines: management of patients with UA/STEMI3,b

ACC/AHA guidelines: management of patients with STEMI35,a

36

LOVENOX® is the only LMWH recommended by name as Class 1in ACC/AHA guidelines35

LOVENOX®—recommended in keynational guidelines

a Excerpted from2007focusedupdateof theACC/AHA 2004guidelines forthemanagementof patientswithSTEMI(table 8).35

b Excerptedfrom ACC/AHA2007 guidelinesfor managementof patientswith UA/NSTEMI.3c Excerpted fromtheACCPevidence-basedclinicalpractice guidelinesfor preventionof VTE(8thedition) (Section6.0.1).11

Class 1—procedure/treatment SHOULD be performed/administered

Administerenoxaparin (providedthe serumcreatinine is <2.5mg/dL inmen and<2.0mg/dLin women):

• Forpatients<75 years ofage, aninitial 30-mg IVbolusis given,followed15 minutes later bySC injectionsof1.0 mg/kgevery12 hours

• For patients≥75 yearsof age, theinitialIV bolus is eliminated andtheSC dose is reduced to0.75 mg/kgevery12 hours

• Regardlessof age, if theCrCl(usingtheCockroft-Gault formula)duringthecourseof treatmentis estimatedto be<30mL/min,the SC regimen is 1.0mg/kgevery24 hours

Class 1—procedure/treatment SHOULD be performed/administered

Anticoagulant therapy shouldbe addedto antiplatelettherapyin UA/NSTEMIpatients as soonas possibleafterpresentation

• Forpatientsin whom aninvasive strategy is selected,regimenswithestablishedefficacyat a:

—Level ofEvidence:A LOVENOX® andUFH

—Level ofEvidence:B Bivalirudin

• For patients in whoma conservativestrategyis selected, regimens withestablishedefficacyuse either:

—LOVENOX® orUFH( Level ofEvidence:A)

Grade1A—strong recommendationbased on consistentevidencefrom RCTs without importantlimitations,or exceptionally strong evidence fromobservational studies

• Acutely illmedicalpatientswho have been admittedto thehospital with CHFor severerespiratorydisease,or whoareconfinedto bedandhave 1 ormore additionalriskfactors,includingactive cancer, previous VTE, sepsis,acuteneurologicdisease, or inflammatory boweldisease:ACCP recommendsthromboprophylaxis withLMWH or LDUHor fondaparinux (eachGrade1A)

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64/Guyatt.Chest.June.2008/

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ACCP guidelines: prophylaxis of DVT following hip- or knee-replacement surgery11,64,e

ACCP guidelines: treatment of DVT with or without PE 64,65,d

37

Leading authorities recommend DVTprophylaxis with LMWH



Appropriate use of DVT prophylaxis is the number one strategy to improvepatient safety in hospitals11

G ui d el i n e s

Grade1A—strong recommendationbasedon consistentevidence fromRCTswithoutimportantlimitations,orexceptionally strong evidencefrom observational studies; Grade1B—strong recommendationbasedon evidencefromRCTs withimportant limitations (inconsistent results, methodologic flaws, indirector imprecise), or verystrong evidencefromobservationalstudies;Grade1C—strong recommendationbasedon evidencefor at least1 critical outcomefromobservationalstudies,case series, or RCTs withseriousflaws or indirectevidence

• PatientsundergoingTHR orTKR surgery:VTE prophylaxisfor atleast10 days with LMWH (attheusualhigh-riskdose),fondaparinux,or adjusted-doseVKA (INRtarget,2.5; INR range, 2.0–3.0) (each Grade1A)

• Patientsundergoing THR:extendedthromboprophylaxisbeyond10 daysand up to 35 daysafter surgery; therecommended options forextendedthromboprophylaxisin THR include LMWH(Grade1A) ,a VKA (Grade1B),or fondaparinux( Grade1C)

d Excerptedfrom the ACCPevidence-basedclinical practiceguidelinesfor antithrombotic therapyfor venous thromboembolicdisease (8thedition) (Sections1.1.1, 1.1.4,1.4.1, 1.4.2,4.1.1, 4.1.8,4.1.9).65

e Excerpted fromtheACCPevidence-basedclinicalpractice guidelinesfor preventionof VTE(8thedition)(Sections3.1.1, 3.2.1,3.5.3.1, 3.5.3.2).11

f Excerpted fromtheACCPevidence-basedclinicalpractice guidelinesfor preventionof VTE(8thedition)(Sections2.1.2, 2.1.3,2.1.4).11

Grade1A—strong recommendationbasedon consistentevidence fromRCTswithoutimportantlimitations,orexceptionally strong evidencefrom observational studies; Grade1C—strong recommendationbased on evidenceforat least1 critical outcomefrom observationalstudies,case series, or RCTs withseriousflaws or indirect evidence

• Patientswith objectively confirmedDVT:short-term treatmentwith SC LMWH,IV UFH,monitored SC UFH,fixed-doseSCUFH, orSC fondaparinux(each Grade1A) rather thanno suchshort-term treatment

• PatientswithacuteDVT: initiation ofVKA togetherwithLMWHor UFHon thefirst treatmentdayrather than delayedinitiation ofVKA (Grade1A)

• PatientswithacuteDVT: initial treatmentwithLMWHSC once ortwicedaily,as anoutpatientif possible( Grade 1C),oras aninpatient ifnecessary (Grade1A),rather than treatmentwithIV UFH

• Patientswith objectivelyconfirmed PE:short-termtreatmentwith SC LMWH,IV UFH,monitored SC UFH,fixed-doseSCUFH,or SCfondaparinux (each Grade1A) ratherthanno such acutetreatment

• Patientswith acute nonmassivePE: initial treatmentwith LMWHover IV UFH( Grade1A)

• Patientswith acute DVTor acutePE treated withLMWH: recommendagainstroutinemonitoring withanti-factorXalevelmeasurements (Grade1A)

ACCP guidelines: prophylaxis of DVT following abdominal surgery11,64,f

Grade1A—strong recommendationbasedon consistentevidence fromRCTswithoutimportantlimitations,orexceptionally strong evidencefrom observational studies; Grade1C—strong recommendationbased on evidenceforat least1 critical outcomefrom observationalstudies,case series, or RCTs withseriousflaws or indirect evidence

• Moderate-riskgeneral surgery patients undergoing a majorprocedure for benign disease: thromboprophylaxis withLMWH,LDUH, or fondaparinux(each Grade 1A)

• Higher-risk general surgery patientsundergoing a majorprocedure for cancer: thromboprophylaxis withLMWH,LDUH3 timesdaily,or fondaparinux(each Grade 1A)

• General surgery patientswith multiplerisk factors forVTE whoare thoughtto be at particularly highrisk: pharmacologic

method (ie,LMWH, LDUH3 timesdaily,or fondaparinux) combinedwith theoptimaluse of a mechanicalmethod(ie, GCSand/orIPC)( Grade1C)



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38

DVT prophylaxis with LMWH recommendedin key national guidelines

ASCRS guidelines37,a

GradeA—recommendationsbased on meta-analysis of multiple well-designed, controlled,randomized trialswithlow-false positive and low-false negative errors(high power)

• The vastmajority of patients undergoingcolon resectionsor laparotomyfor bowel-related diseases will fallinto amoderate-risk to high-risk category and require someform of VTE prophylaxis

• Patients in the moderate-riskto high-risk categoriesfor VTE undergoingabdominalsurgery shouldreceive prophylaxiswith LDUH orLMWH. Levelof Evidence:I ; GradeA recommendation

ASCO guidelines36,b

• All hospitalizedcancer patients shouldbe consideredfor VTE prophylaxiswith anticoagulants in the absenceof bleeding or othercontraindications

• Low-molecular-weight heparin represents thepreferredagent for boththe initial and continuingtreatment of cancerpatients withestablished VTE

AAOS guidelines38,c

GradeB—fairevidence(Level II or III studies withconsistentfindings)for recommending intervention

• AAOS issuedno GradeA recommendations

• Patients atelevated(abovestandard)riskof PEand atstandardriskof major bleeding shouldbe considered foroneof thechemoprophylactic agents evaluated in this guideline,including,in alphabeticalorder: LMWH,synthetic

pentasaccharides, andwarfarin (LevelIII, GradeB)• Allpatientsshould beassessedpreoperativelyfor elevatedrisk (greaterthanstandardrisk)of PE (LevelIII, GradeB

[choice of prophylacticagent],GradeC [dosage and timing])

ACOG guidelines39,d

Level A—recommendationsbased on goodand consistentscientificevidence

• Thromboprophylaxisfor moderate-risk patients: LMWH (enoxaparin40 mg) SC administered12 hoursbefore surgeryand oncedaily postoperatively untildischarge(LevelA )

• Prophylaxisfor high-risk patients undergoinggynecologic surgery: LMWH(enoxaparin40 mg)SC administered12 hours beforesurgery andoncedailypostoperativelyuntil discharge(Level A)

ASRA guidelines66,e

• For postoperative use in patients receiving neuraxial anesthesia

—Thefirst doseof LMWHshould be administered no earlierthan 24 hourspostoperativelyafter establishmentof adequate hemostasis

—Indwellingcatheters shouldbe removed priorto initiation of LMWHthromboprophylaxis

—Acontinuousepidural catheter maybe left indwelling overnightand removed thefollowing day, with thefirstdose ofLMWH administeredat least2 hours after catheterremoval

Primary thromboprophylaxis reduces DVT/PE and fatal PE11

F P

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38/Johansen.www.aaos.org/p11/line 7, 19

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Leading authorities support DVT risk assessmentand prophylaxis as part of quality measures

DVT-related PE is the most common cause of preventable hospital death11

NQF safe practices40,f

• SafePractice 28—evaluateeach patient uponadmission,and regularly thereafter, for the risk of developingvenous thromboembolism/deepvein thrombosis(VTE/DVT).Utilize clinically appropriate, evidence-based methodsof thromboprophylaxis

• SafePractice 29—every patient on long-term oral anticoagulants shouldbe monitoredby a qualified healthprofessional usinga careful strategy to ensurethe appropriateintensityof supervision

The Joint Commission 2009 National Patient Safety Goals 41,g

• NPSG.03.05.01(formerly 3E)—reducethe likelihood of patient harmassociatedwith the use of anticoagulant therapy

• NPSG 8—accurately andcompletelyreconcilemedications acrossthe continuumof care

• NPSG 13—encourage patients’ activeinvolvement in theirown careas a patient safetystrategy

SCIP measures42,h

SCIP measures to prevent postoperative complications:

• VTE Measure 1—surgery patients withrecommended VTE prophylaxisordered

• VTE Measure 2—surgery patients who received appropriateVTE prophylaxisreceived within24 hoursprior to surgery

and24 hoursaftersurgery

CMS HACs67,i

• DVT/PE following total kneereplacement or hipreplacementis 1 of 11 HACsdesignatedby theCMS

• Effective October 1,2008,CMSno longer will payfora DVT/PEHACif itwas not present onadmissionto thehospital

• Thissurgerysubpopulationwas chosenby CMS(in collaborationwith expertsat theCDC) becauseDVT/PEcouldreasonably be prevented in these patientsthrough theuse of evidence-based prophylaxis

a Excerpted fromASCRS practiceparameters forthepreventionof venousthrombosis.37

b Excerptedfrom ASCOguideline: recommendationsfor venousthromboembolismprophylaxisand treatmentin patientswith cancer.36

c Excerptedfrom theAAOSpracticebulletin:clinical guidelineson preventionof symptomaticpulmonaryembolismin patientsundergoing total hipor knee arthroplasty.38

d Excerptedfrom ACOGclinical managementguidelinesfor obstetrician-gynecologists.39

e Excerptedfrom ASRAconsensus statements–regionalanesthesiain theanticoagulatedpatient: definingthe risks.66

f Excerpted fromtheNational QualityForumsafepracticesforbetterhealthcare2006update.40

g Excerptedfrom TheJoint CommissionNationalPatient SafetyGoals.41

h Excerpted fromtheSCIPprocessandoutcome measures.42

i Excerptedfrom the FederalRegister , August19, 2008.67

40/NQF Safe Practices.2006/

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40/NQF Safe Practices.2006/

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41/www.jointcommission.org.

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References

1. IMS National Sales Perspective, February 2009.2. IMS Patient Perspectives, March 2008.3. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction—

executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction): developed in collaboration with the AmericanCollege of Emergency Physicians, American College of Physicians, Society of Academic Emergency Medicine, Society for Cardiovascular Angiography andInterventions, and Society of Thoracic Surgeons. J Am Coll Cardiol . 2007;50(7):652-726.

4. American Public Health Association. Deep-vein thrombosis: advancing awareness to protect patient lives: white paper. Paper presented at: Public HealthLeadership Conference on Deep-Vein Thrombosis; February 26, 2003; Washington, DC.

5. Rosamond W, Flegal K, Friday G, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115(5):e69-e171.

6. Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, López-Sendón J; GRACE Investigators. Practice variation and missed opportunities for reperfusion inST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet. 2002;359(9304):373-377.

7. Armstrong PW, Fu Y, Chang W-C, et al; GUSTO-IIb Investigators. Acute coronary syndromes in the GUSTO-IIb trial: prognostic insights and impact of recurrentischemia. Circulation . 1998;98(18):1860-1868.

8. Gerotziafas GT, Samama MM. Prophylaxis of venous thromboembolism in medical patients. Curr Opin Pulm Med . 2004;10(5):356-365.9. Heit JA, Cohen AT, Anderson FA Jr; VTE Impact Assessment Group. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism

(VTE) events in the US. Presented at: American Society of Hematology, 47th Annual Meeting and Exposition; December 10-13, 2005; Atlanta, GA. Poster 68.10. Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost .

2002;88(3):407-414.11. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines

(8th edition). Chest . 2008;133(6 suppl):381S-453S.12. ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery:

a double-blind randomized multicentre trial with venographic assessment. Br J Surg . 1997;84(8):1099-1103.13. Bergqvist D. Low molecular weight heparin for the prevention of venous thromboembolism after abdominal surgery. Br J Surg . 2004;91(8):965-974.14. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost .

2003;90(3):446-455.15. Kakkar AK. Thrombosis and cancer. Hematol J . 2004;5(suppl 3):S20-S23.16. Donati MB. Cancer and thrombosis. Haemostasis . 1994;24(2):128-131.17. Agnelli G, Bolis G, Capussotti L, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS Project.

Ann Surg . 2006;243(1):89-95.18. Antman EM, Morrow DA, McCabe CH, et al; ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial

infarction. N Engl J Med. 2006;354(14):1477-1488.19. Antman EM, Morrow DA, McCabe CH, et al; ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving

fibrinolysis for ST-elevation myocardial infarction: design and rationale for the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25). Am Heart J. 2005;149(2):217-226.

20. Data on file, sanofi-aventis, Bridgewater, NJ.21. Cohen M, Demers C, Gurfinkel EP, et al; Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group. A comparison of low-

molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med . 1997;337(7):447-452.22. Samama MM, Cohen AT, Darmon J-Y, et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the

prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med . 1999;341(11):793-800.23. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the

hospital for proximal deep-vein thrombosis. N Engl J Med . 1996;334(11):677-681.

24. Turpie AGG, Levin MN, Hirsh J, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patientsundergoing elective hip surgery. N Engl J Med . 1986;315(15):925-929.25. Bergqvist D, Benoni G, Björgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement.

N Engl J Med . 1996;335(10):696-700.26. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of deep vein thrombosis after major knee surgery—a randomized, double-blind trial comparing a low

molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost . 1992;67(4):417-423.27. Fuster V, Alexander RW, O’Rourke RA, eds. Hurst’s The Heart. 10th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2001.28. LOVENOX® (enoxaparin sodium injection) Prescribing Information. sanofi-aventis, Bridgewater, NJ.29. Lee S, Gibson CM. Enoxaparin in acute coronary syndromes. Expert Rev Cardiovasc Ther . 2007;5(3):387-399.30. Weitz JI. Low-molecular-weight heparins. N Engl J Med . 1997;337(10):688-698.31. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.

Arch Intern Med. 2003;163(20):2518-2524.32. Tran AH, Lee G. Fondaparinux for prevention of venous thromboembolism in major orthopedic surgery. Ann Pharmacother . 2003;37(11):1632-1643.33. Goodman SG, Fitchett D, Armstrong PW, Tan M, Langer A; Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT)

Trial Investigators. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non–ST-segmentelevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation . 2003;107(2):238-244.

34. The SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndromes managedwith an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292(1):45-54.

35. Antman EM, Hand M, Armstrong PW, et al; 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of PatientsWith ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. 2007 focused update of the ACC/AHA 2004 guidelines for the managementof patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2008;117(2):296-329.

36. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505.

37. Stahl TJ, Gregorcyk SG, Hyman NH, Buie WD; Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for theprevention of venous thrombosis. Dis Colon Rectum. 2006;49(10):1477-1483.

38. Johanson NA, Lachiewicz PF, Lieberman JR, et al; AAOS Physician Volunteer Work Group. American Academy of Orthopaedic Surgeons clinical guideline onprevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty: summary of recommendations.http://www.aaos.org/Research/guidelines/PE_guideline.pdf. Accessed April, 1 2008.

39. ACOG Committee on Practice Bulletins—Gynecology, American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 84: prevention of deepvein thrombosis and pulmonary embolism. Obstet Gynecol. 2007;110(2, pt 1):429-440.

40. The National Quality Forum (NQF). Safe practices for better healthcare 2006 update: a consensus report. Washington, DC: National Quality Forum; 2006.41. The Joint Commission. National patient safety goals: 2008 national patient safety goals hospital program. The Joint Commission website.

http://www.jointcommission.org/NR/rdonlyres/31666E86-E7F4-423E-9BE8-F05BD1CB0AA8/0/HAP_NPSG.pdf. Accessed May 14, 2008.42. Surgical Care Improvement Project. SCIP process and outcome measures. QualityNet website.

http://www.qualitynet.org/dcs/ContentServer?cid=1136495755695&pagename=Medqic%2FOtherResource%2FOtherResourcesTemplate&c=OtherResource.Accessed December 8, 2008.

43. Le Liboux A, Sanderink G-J, Grosjean P, et al. Enoxaparin pharmacokinetics and pharmacodynamics after intravenous bolus administration alone and at initiation of asubcutaneous dosing regimen [abstract 1106-129]. J Am Coll Cardiol. 2000;35(suppl 1):373A-374A.

F P



41

44. Martin JL, Fry ETA, Sanderink G-J CM, et al. Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: thePharmacokinetics of Enoxaparin in PCI (PEPCI) study. Catheter Cardiovasc Interv. 2004;61(2):163-170.

45. Goodman SG, Cohen M, Bigonzi F, et al; Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q Wave Coronary Events (ESSENCE) Study Group. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE study.J Am Coll Cardiol . 2000;36(3):693-698.

46. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost . 2007;5(8):1610-1616.47. Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med . 2007;167(14):1471-147548. de Jong JD, Westert GP, Lagoe R, Groenewegen PP. Variation in hospital length of stay: do physicians adapt their length of stay decisions to what is usual in the

hospital where they work? Health Serv Res . 2006;41(2):374-394.49. Basse L, Thorbøl JE, Løssl K, Kehlet H . Colonic surgery with accelerated rehabilitation or conventional care.Dis Colon Rectum . 2004;47(3):271-277.50. Anderson FA Jr, Hirsch J, White K, Fitzgerald RH Jr. Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty

1996–2001: findings from the hip and knee registry. Chest . 2003;124(6 suppl):349S-356S.51. Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study.

Blood Coagul Fibrinolysis . 2003;14(4):341-346.52. Kleber F-X, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW; THE-PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated

heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease.Am Heart J . 2003;145(4):614-621.53. Hylek EM, Regan S, Henault LE, et al. Challenges to the effective use of unfractionated heparin in the hospitalized management of acute thrombosis.

Arch Intern Med . 2003;163(5):621-627.54. Niccolai CS, Hicks RW, Oertel L, Francis JL; Heparin Consensus Group. Unfractionated heparin: focus on a high-alert drug.Pharmacotherapy.

2004;24(8, pt 2):146S-155S.55. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous

thromboembolism during heparin treatment for deep vein thrombosis.Arch Intern Med . 1997;157(22):2562-2568.56. Merli G, Spiro TE, Olsson C-G, et al; Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated

heparin for treatment of venous thromboembolic disease. Ann Intern Med . 2001;134(3):191-202.57. Sikorski JM, Hampson WG, Staddon GE. The natural history and aetiology of deep vein thrombosis after total hip replacement. J Bone Joint Surg Br .

1981;63-B(2):171-177.58. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty.

Arch Intern Med . 1998;158(14):1525-1531.59. Colwell CW Jr, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip

arthroplasty: evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am . 1999;81-A(7):932-940.60. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al; Enoxaparin Clinical Trial Group. Prevention of venous thromboembolic disease following primary total knee

arthroplasty: a randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin.J Bone Joint Surg Am . 2001;83-A(6):900-906.61. Prandoni P. Cancer and thromboembolic disease: how important is the risk of thrombosis?Cancer Treat Rev . 2002;28(3):133-136.62. Heparin Sodium Injection, USP Prescribing Information. Kalamazoo, MI: Pharmacia & Upjohn Company; 2008.63. Bijsterveld NR, Moons AH, Meijers JCM, Levi M, Büller HR, Peters RJG. The impact on coagulation of an intravenous loading dose in addition to a subcutaneous

regimen of low-molecular weight heparin in the initial treatment of acute coronary syndromes.J Am Coll Cardiol . 2003;42(3):424-427.64. Guyatt G, Schünemann HJ, Cook D, Jaeschke R, Pauker S. Applying the grades of recommendation for antithrombotic and thrombolytic therapy: the Seventh

ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest . 2004;126(3 suppl):179S-187S.65. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest

Physicians evidence-based clinical practice guidelines (8th edition). Chest . 2003;133(6 suppl):454S-545S.66. American Society of Regional Anesthesia and Pain Medicine. Consensus statements: regional anesthesia in the anticoagulated patient: defining the risks.

http://www.asra.com/publications/consensus-statements-2.html. Accessed September 26, 2006.67. Centers for Medicare & Medicaid Services. Medicare programs; changes to the hospital inpatient prospective payment systems and fiscal year 2009 rates.

Fed Regist. 2008;73(161):48433-49084.

AbbreviationsAAOS=AmericanAcademy ofOrthopaedic Surgeons;ACC/AHA=AmericanCollege of Cardiology/AmericanHeart Association;ACCP=AmericanCollegeof ChestPhysicians;ACE=angiotensin-convertingenzyme;ACOG=AmericanCollege ofObstetricians and Gynecologists;ACS=acutecoronary syndrome;AIDS=autoimmunedeficiencysyndrome; aPTT=activatedpartial thromboplastintime; ARR=absoluterisk reduction;ASA=acetylsalicylicacid; ASCO=AmericanSociety of ClinicalOncology;ASCRS=AmericanSocietyof Colon&RectalSurgeons;ASRA=AmericanSocietyof RegionalAnesthesiaandPainMedicine;BP=bloodpressure; bpm=beatsper minute;BUN=bloodurea nitrogen;CABG=coronaryartery bypassgraft;CDC=CentersforDiseaseControland Prevention;CHF=congestiveheart failure;CI=confidenceinterval;cm=centimeter;CMS=CentersforMedicare&MedicaidServices;CrCl=creatinineclearance; DVT=deepvein thrombosis;DVT/PE=deepvein thrombosis/pulmonaryembolism;ECG=electrocardiographic;ED=emergencydepartment;ENOXACAN=Enoxaparinand Cancer;ESSENCE=EfficacyandSafetyofSubcutaneousEnoxaparininNon–Q-waveCoronary Events;ExTRACT–TIMI25=Enoxaparinand ThrombolysisReperfusionfor AcuteMyocardial InfarctionTreatment–Thrombolysis InMyocardialInfarction25; g/dL=gramsper deciliter;GCS=graduatedcompression stocking;GRACE=GlobalRegistryofAcuteCoronaryEvents;GUSTO=GlobalUseof Strategiesto OpenOccludedCoronary Arteries;HAC=hospital-acquiredcondition; HCT=hematocrit;Hgb=hemoglobin;HIT=heparin-inducedthrombocytopenia;ICH=intracranialhemorrhage;INR=internationalnormalized ratio;INTERACT=Integrilinand EnoxaparinRandomized Assessmentof AcuteCoronary SyndromeTreatment;IPC=intermittentpneumaticcompression;ITT=intentto treat; IU=internationalunit; IU/mL=internationalunits per milliliter;IV=intravenous;kg=kilogram;L=liter; lbs=pounds;LDUH=low-doseunfractionatedheparin;LMWH=low-molecular-weightheparin;LOS=lengthof stay;LVEF=leftventricular ejectionfraction;m=meter;MEDENOX=ProphylaxisinMedicalPatientsWith Enoxaparin;mg=milligram;mg/dL=milligramsper deciliter;mg/kg=milligramsper kilogram;MI=myocardialinfarction; mL/min=millilitersper minute;mm3=cubicmillimeter;mmHg=millimetersof mercury;mmol/L=millimolesper liter;NNT=numberneededtotreat;NQF=NationalQuality Forum;NS=notsignificant; NSAIDs=nonsteroidalanti-inflammatorydrugs;NSTEMI=non–ST-segmentelevation (non–Q-wave)myocardialinfarction; NYHA=NewYork HeartAssociation; OAD=observedabsolutedifference;PCI=percutaneouscoronaryintervention;PE=pulmonaryembolism;PEPCI=Pharmacokineticsof Enoxaparinin PCI;PT=prothrombintime; q8h=every8 hours; q12h=every12hours; RCT=randomizedclinical trial; [re]MI=recurrentmyocardial infarction;RR=relativerisk; RRR=relativerisk reduction;SC=subcutaneous;SCIP=SurgicalCareImprovementProject; STEMI=ST-segmentelevationmyocardial infarction;SYNERGY=TheSuperiorYieldof theNewStrategyof Enoxaparin,RevascularizationandGlycoproteinIIb/IIIa Inhibitors;THE-PRINCE=ThromboembolismPreventionin Cardiacor RespiratoryDisease WithEnoxaparin;THR=totalhip replacement;TIMI=ThrombolysisIn MyocardialInfarction;TKR=totalknee replacement;U=unit; UA=unstableangina; UA/NSTEMI=unstableangina/non–ST-segmentelevation(non–Q-wave)myocardialinfarction; UFH=unfractionatedheparin; U/mL=unitsper milliliter;VKA=vitaminK antagonist;VTE=venousthromboembolism=DVTand/or PE;VTE/DVT=venous thromboembolism/deep vein thrombosis.


Please see accompanying full prescribing information,

including boxed WARNING, inside pocket.

F P O

200,000,000 PatientsTreated Worldwide2 F P

O

02977_M4 2009 MVA Bk_Cvr.qxd:Layout 1 4/28/09 11:19 AM Page 1



Proven

Confidence built on over 16 years of experience in the United States28

Over 200 million patients treated worldwide2

Proven benefit/risk profilesacross multipleindicationsand patient types28,51

Extensive clinical data support evidence-based practice of medicine

LOVENOX® is the only LMWH recommended by name as Class 1 in ACC/AHA guidelines3,35

Predictable

LOVENOX® outperforms UFH in critical areas—quickly achieves and maintains therapeuticanti-Xa levels20,27–31

Predictable and consistent anticoagulation29,a

Unique mechanism of action29,30

Protection

A broad range of indications and proven efficacy across patient types 12,18,21–26,59,60

LOVENOX® saved lives and reduced MIs vs UFH in STEMI and UA/NSTEMI patients 18,21

Consistent, well-documented safety outcomes12,18,21–26,59,60

Widespread presence in hospitals

Confident use across a broad range of indications in multiple specialties

On 91% of managed care formularies20

Comprehensive programs provided to help support hospital staff with thrombosis management

Information provided to help hospitals comply with guidelines and quality measures

LOVENOX®—make a proven choicewith proven outcomes1

US.ENO.09.04.018

©2009 sanofi-aventis U.S. LLC


Please see accompanying full prescribing information, including boxedWARNING, inside pocket.

Visit our website, www.LOVENOX.com , for health care professional and patient information.

For use by sales representatives only. Do not leave with physician.Furnish full prescribing information.

The LOVENOX® Reimbursement Servicesand PatientAssistance Program Hotline

Phone:1-888-632-8607 Fax: 1-888-875-9951Monday through Friday 7:30 AM to 9:00 PM (ET)

On-call service Saturday and Sunday (except on holidays and holiday weekends)

aBecauseroutinecoagulationtests,such asPT andaPTT,are relativelyinsensitivemeasuresof LOVENOX® activity,thesetestsareunsuitableformonitoringin patientswithnormalbaselinecoagulationparameters.Periodiccompleteblood counts,includingplateletcount,andstooloccultbloodtestsare recommendedduringtreatment.28

41


3/Anderson.JAmCollCardiol.Aug.2007/p661/c1/line 6

35/Antman.J Am Coll Cardiol.January.2008/p224/table 8; p231/table 12

20/DOF-Aventis Study 155/p3

20/DOF-Managed Care Claim


27/Fuster.Hurst's the Heart.2001/p1407/c1/line 52

29/Lee.Expert Rev Cardiovasc

Ther.2007/p388/c2/line 4

30/Weitz.N Engl J Med.

September.1997/p690/c2/

line19; p688/c2/line 55; p690/

c2/line31/c1/table 3

31/Warkentin.Arch Intern Med.

November.2003/p2518/c2/line A8

29/Lee.Expert Rev Cardiovasc Thor.2007/p388/c1/line 50; c2/line 1

30/Weitz.N Engl J Med.September.1997/p690/c2/line19, 31, 50

12/ENOXACAN Study Gp. Br J.August.1997/p1099/A17; p1101/c1/line 26; p1102/c1/line 62

18/Antman.N Engl J Med.April.2006/p1482/table2;p1483/figure 1A

21/Cohen.N Engl J Med.August.1997/p449/c1/line 20

22/Samama.N Engl J Med.September.1999/p797/c1/table3; p795/c2/line 11

23/Levine.N Engl J Med.March.1996/p679/c2/line27;p680/c1/table 2

24/Turpie.N Engl J Med.October.1986/p925/c1/line A3; c2/line A6; p926/c1/

line 37; c2/line 25; p927/c1/line 24, Table 2; p928/Table 3

25/Bergqvist.N Engl J Med.September.1996/p696/c1/line A31; 698/c1/table 2

26/Leclerc.Thromb Haemost.April.1992/p417/c1/line 6; p418/c1/line 7,11; c2/

line 11; p420/c2/line 32, Table 4; p421/Table 5

59/Colwell.J Bone Joint Surg Am.July.1999/p936/tableIV; p936/c2/line 6

60/Fitzgerald.J Bone Joint Surg Am.June.2001/p903/table II


table2;p1483/figure 1A

21/Cohen.N Engl J Med.August.1997/p449/c1/

line 20

12/ENOXACAN Study Gp. Br J.August.1997/p1101/c1/line33;

c2/table 3; p1102/c1/line 59


21/Cohen.N Engl J Med.August.1997/p451/table 5

22/Samama.N Engl J Med.September.1999/p798/c1/table 5


24/Turpie.N Engl J Med.October.1986/p925/c1/line A3; c2/line

A6; p926/c1/line 37; c2/line 25; p927/c1/line 24, Table 2; p928/

Table 3

25/Bergqvist.N Engl J Med.September.1996/p699/c1/line 11

26/Leclerc.Thromb Haemost.April.1992/p417/c1/line 6; p418/c1/

line 7,11; c2/line 11; p420/c2/line 32, Table 4; p421/Table 5

59/Colwell.J Bone Joint Surg Am.July.1999/p937/table VI

60/Fitzgerald.J Bone Joint Surg Am.June.2001/p904/table III

1/IMS National Sales Perspectives.

February.2009



June.2003/p343/table1; table 2; p343/c2/line 17



29/Lee.Expert Rev Cardiovasc Thor.2007/p388/c1/line 50; c2/line 1,4

02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 1



LOVENOX®—proven acrossmultiple patient types28

Please refer to pages 28–35 for full dosing and administration information.

F P O

A C S

DianeFemale, 64 years old

Vitals:

Height: 5’ 4”

Weight: 189 lbs

Heart rate: 102 bpm

BP: 140/85 mm Hg

Diagnostics:Three hours after onset of chestpain, Diane was admitted to the hospital from the ED after ECGshowed evidence of an anterior wall acute STEMI. ImmediateSTEMI protocol was activated.

Additional risk factors:

Family history of coronary artery disease

Other risks include smoking, hypertension, and obesity

Treatment plan: Prep for immediate reperfusion therapy. Becausedoor-to-balloon time was 3 hours, and no cardiac catheterizationlaboratory was available, she received fibrinolytic reperfusiontherapy with a fibrin-specific agent, in combination with aspirin andLOVENOX® 30-mg IV bolus, plus 1 mg/kg SC injection followed by1 mg/kg SC every 12 hours until hospital discharge or 8 days

(whichever came first).

Acute STEMI

LOVENOX® has been shown to reduce the rate of the combinedendpoint of recurrent MI or death in patients with acute STEMIreceiving thrombolysis and being managed medically or with PCI

Hypothetical patient profile

28/LOVENOX PI.

July.2008/p6/c1/line 5,

37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




MariaFemale, 68 years old

Vitals:

Height: 5’ 5”

Weight: 165 lbs

Heart rate: 90 bpm

BP: 150/85 mm Hg

Diagnostics: Based on symptoms and ECG results, Maria wasdiagnosed with NSTEMI and admitted to the hospital for furtherevaluation and observation.

Additional risk factors:Mother died of CHF

Hypertension (controlled), dyslipidemia, and overweight

Smoker

Prophylaxis plan: Maria receives acute anti-ischemic therapy(ie, nitroglycerin, ACE inhibitor, and current beta-blocker). Shealso receives 325 mg oral aspirin and LOVENOX® 1 mg/kg every12 hours SC until stabilized (usually 2–8 days).

F P O

A C S

UA/NSTEMI



LOVENOX® is indicated for the prophylaxis of ischemiccomplications of UA and non–Q-wave MI when concurrentlyadministered with aspirin


28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




TedMale, 76 years old

Vitals:

Height: 6’ 0”

Weight: 205 lbs

Heart rate: 105 bpm

BP: 170/90 mm Hg

Diagnostics:Ted was admitted to the hospital from the ED withNYHA Class III CHF.

DVT risk factors:LVEF <20% Hospitalization for acute medical illness

Age >40 years Nursing home residence

DVT prophylaxis plan:Ted received LOVENOX® 40 mg SC once dailyas prophylaxis for prevention of DVT/PE. He was stabilized anddischarged back to the nursing home after 4 days.Ted’s physicianwas concerned about the ongoing risk of DVT/PE after hospitaldischarge. Approved duration of prophylaxis with LOVENOX®

is 6–11 days, administered up to 14 days in the controlledclinical trial.

F P OA c u t el yi l l

m e

d i c al p a t i en t s

Acutely ill medical patient



LOVENOX® is indicated for the prophylaxis of DVT, whichmay lead to PE, in medical patients who are at risk forthromboembolic complications due to severely restrictedmobility during acute illness


28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




A c u t e l y i l l

m e d i c a l p a t i e n t s




PaulMale, 39 years old

Vitals:

Height: 5’ 10”

Weight: 165 lbs

Heart rate: 65 bpm

BP: 120/80 mm Hg

Diagnostics: Former professional soccer player sustained a rightlower extremity injury and was hospitalized. Clinically diagnosedwith a DVT, which was confirmed by Doppler ultrasound.

DVT risk factors:

No overt risk factors in medical history

DVT treatment plan: Paul remained hospitalized for 4 days torecover from his injury. During and following hospitalization, hereceived LOVENOX® 1 mg/kg SC every 12 hours in conjunctionwith warfarin sodium therapy.Treatment continued for 7 daysuntil INR=2.0–3.0.

F P O

DVT t r e a

t m en t

DVT treatment


LOVENOX® is indicated for:— The inpatient treatment of acute DVT, with or withoutPE, when administered in conjunction with warfarin sodium

— The outpatient treatment of acute DVT, without PE,when administered in conjunction with warfarin sodium



28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




D V T t r e a t m e n t




SallyFemale, 60 years old

Vitals:

Height: 5’ 4”

Weight: 115 lbs

Heart rate: 71 bpm

BP: 135/85 mm Hg

Diagnostics: Following normal diagnostic results, Sally wasscheduled for total hip arthroplasty of the left hip using standardsurgical techniques.

DVT risk factors:Major orthopedic surgery Immobility

Age >40 years Hormone-replacement therapy

DVT prophylaxis plan: Sally remained hospitalized for 4 days torecover from surgery and begin physical therapy. Sally continuedrecovery at home, scheduled outpatient physical therapy, andrequested a comprehensive plan to minimizeVTE risk. During andfollowing hospitalization, she received LOVENOX® 30 mg SC every12 hours for 7 to 10 days, followed by extended prophylaxis withLOVENOX® 40 mg SC once daily for 3 weeks.

F P O

Hi p- or k n e e-

r e pl a c em en t s ur g e

r y

Hip-replacement surgery



LOVENOX® is indicated for the prophylaxis of DVT, which maylead to PE in patients undergoing hip-replacement surgery, duringand following hospitalization


28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




LindaFemale, 55 years old

Vitals:Height: 5’ 5”

Weight: 172 lbs

Heart rate: 91 bpm

BP: 115/73 mm Hg

Diagnostics: Routine blood work, including a complete bloodcount, electrolytes, BUN, and serum creatinine were normal. ECG,chest X-ray, and coagulation panel were also normal.

DVT risk factors:

Immobility Major orthopedic surgeryObesity Hormone-replacement therapy

DVT prophylaxis plan: Prior to surgery, Linda’s physician noted thathemostasis had been established. LOVENOX® 30 mg SC wasinitiated 12 hours postoperatively and every 12 hours for 4 daysas Linda recovered. Her doctor was concerned about the risk of VTEfollowing her surgery, and ordered continuation of DVT prophylaxiswhile convalescing.

F P O

H i p - o r k n e e -

r e p l a c e m e n t s u r g e r y

Knee-replacement surgery



LOVENOX® is indicated for the prophylaxis of DVT, which may leadto PE in patients undergoing knee-replacement surgery


28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




MichaelMale, 68 years old

Vitals:

Height: 5’ 10”

Weight: 155 lbs

Heart rate: 70 bpm

BP: 120/85 mm Hg

Diagnostics: Based on imaging, pathology, and results of surgicalexploration, Michael was diagnosed with stage IIIA colon cancer. Hewas referred to a surgical oncologist and was scheduled for surgery.

DVT risk factors:

Malignancy Surgery Age >40 years

DVT prophylaxis plan: Michael received LOVENOX® 40 mg SC2 hours prior to surgery. He underwent exploratory laparotomywith successful hemicolectomy. He received LOVENOX® 40 mg SConce daily for his 4-day hospital stay. On discharge, the surgeonprescribed LOVENOX® 40 mg SC once daily for 6 more days.

F P O

A b d omi n al s ur g er y

Abdominal surgery



LOVENOX® is indicated for the prophylaxis of DVT, which maylead to PE, in patients undergoing abdominal surgery who areat risk for thromboembolic complications


28/LOVENOX PI.


37; c2/line 19,35,41,52;

p7/c2/line 1,25, 33; p8/c1/

line 19; c2/line 6




A b d o m i n a l s u r g e r y

02977_m4_2009 mva_annot_042809_adj annot 061809

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