02977_M4_2009 MVA_annot_042809_adj annot 061809
-
Upload
jenkinsjeffrey -
Category
Documents
-
view
223 -
download
0
Transcript of 02977_M4_2009 MVA_annot_042809_adj annot 061809
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 1/52
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 Page 1
1/IMS National Sales Perspectives.
February.2009
2/IMS Patient Projections.March.2008
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 2/52
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 2
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 3/52
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 3
NO ANNOTATIONS REQUIRED FOR
INDICATIONS
02977 M4 2009 MVA d L t 1 4/28/09 10 47 AM P 4
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 4/52
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
Basedon trialresults,
LOVENOX® would have
an estimated32 fewerdeaths, MIs,or recurrent
angina events per1000
UA/NSTEMIpatients vsUFH,with comparable
majorbleeding20,a
Basedon trialresults,
LOVENOX® would havean estimated94 fewer
DVT/PE events per1000acutely ill medicalpatientsvs placebo,
with comparable
majorbleeding20,a
Basedon trialresults,
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
(LOVENOX® vs comparator)
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 4
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)
18/Antman.N Engl J Med.April.2006/p1479/c1/line 38
(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)
20/DOF-ARR.NNT calculations
22/Samama.N Engl J Med.September.
1999/p795/c2/line 11 (Efficacy)
22/Samama.N Engl J Med.September.
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)
20/DOF-ARR.NNT calculations
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)
23/Levine.N Engl J Med.March.1996/p679/c1/line 49
(Duration)
23/Levine.N Engl J Med.March.1996/p677/c2/line
18;p678/c1/line 40 (Design)
20/DOF-ARR.NNT calculations
2/IMS Patient Projections.March.2008
02977 M4 2009 MVA qxd:Layout 1 4/28/09 10:47 AM Page 5
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 5/52
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 important safety information on pages 8 and 9.
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
Based on trialresults,
LOVENOX® wouldhave
anestimated 209fewer
DVTeventsper 1000hip-replacement patients
having extended
prophylaxis vs placebo,with comparable
major bleeding20,a
Based on trialresults,
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
(LOVENOX® vs comparator)
Patient type/study design
Safetyendpoints
(LOVENOX® vs comparator)
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 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
20/DOF-ARR.NNT calculations
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
20/DOF-ARR.NNT calculations
12/ENOXACAN Study Group.Br J Surg.August.1997/
p1099/lineA12;p1101/table 2 (Efficacy)
12/ENOXACAN Study Group.Br J Surg.August.1997/
p1101/c1/line 33 (Safety)
12/ENOXACAN Study Group.Br J Surg.August.1997/
p1099/c2/line 24 (Duration)
12/ENOXACAN Study Group.Br J Surg.August.1997/
p1099/c2/line 2 (Design)
20/DOF-ARR.NNT calculations
25/Bergqvist.N Engl J Med.September.1996/p696/c1/line
A31; 698/c1/table 2 (Efficacy)
25/Bergqvist.N Engl J Med.September.1996/p699/c1/line
11 (Safety)
25/Bergqvist.N Engl J Med.September.1996/p697/c1/line
20 (Duration)
25/Bergqvist.N Engl J Med.September.1996/p697/c1/line
6; line 20 (Design)
20/DOF-ARR.NNT calculations
02977 M4 2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 6
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 6/52
6
with Proven Outcomes
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
28/LOVENOX PI.July.2008/p4/c1/line 7
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 7/52
Patient/procedure type
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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.
August.2007/p430/c1/line 37
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 8
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 8/52
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 9
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 9/52
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 10
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 10/52
Make aProven Choice
with Proven Outcomes
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
18/Antman.N Engl J Med.April.2006/p1486/table 4
18/Antman.N Engl J Med.April.2006/p1479/c2/line 6
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
18/Antman.N Engl J Med.April.2006/p1483/
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 11/52
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 12/52
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
18/Antman.N Engl J Med.
April.2006/p1483/c1/line 18;
p1485/table 3
19/Antman.Am Heart J.
February.2005/p223/table II,
II
18/Antman.N Engl J Med.
April.2006/p1483/c1/
line18;p1485/table 3
18/Antman.N Engl J Med.
April.2006/ p1483/c1/line23,
p1485/table 3
18/Antman.N Engl J Med.
April.2006/p1483/c1/line23;
p1485/table 3
28/LOVENOX PI.
July.2008/p10/c2/line 1
19/Antman.Am Heart J.
February.2005/p223/table II
19/Antman.Am Heart J.
February.2005/p223/table II
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 13
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 13/52
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
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
43/LeLiboux.J Am Coll Cardiol.
February.2000/p373A/c2/line 31
20/DOF - LeLiboux Poster/Figure 2; c3/line 4
43/LeLiboux.J Am Coll Cardiol.
February.2000/p373A/c2/line 8
44/Martin.Cath Cardio Interv.2004/p164/c1/line 35
20/DOF - LeLiboux Poster/Figure
2; c3/line 4
43/LeLiboux.J Am Coll Cardiol.
February.2000/p373A/c2/line 31
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 14
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 14/52
14
with Proven Outcomes
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
Benefit/risk profile
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
Results from ESSENCE.
Cohen et al. N Engl J Med .
1997;337( 7):447.
95% CI; P =0.016
N=3171; NNT=29
Results from ESSENCE.
Cohen et al. N Engl J Med .
1997;337( 7):447.
95% CI; P =0.022
N=2915; NNT=27
Results from ESSENCE.
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 15
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 15/52
15
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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 ( % )
CI=confidence interval;
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
33/Goodman.Circulation.
January.2003/p240/c2/table 3,
line7; p240/c2/line 7
33/Goodman.Circulation.
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
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 16
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 16/52
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
200,000,000 PatientsTreated Worldwide F P
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
46/Amin.J Thromb Haemost.August.
2007/p1610/c1/line20; p1614/table 3
46/Amin.J Thromb Haemost.August.
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
02977_M4 Pullout Pocket pages.qxd:Layout 2 4/28/09 11:25 AM Page 2
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 17/52
Average hospital LOS vs recommended duration of prophylaxis28,48–50
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
47/Spencer.Arch Intern Med.
July.2007/pp1474/c2/line 7
41/www.jointcommission.
org.NPSG.Hospital.2008/
slides 19, 23
47/Spencer.Arch Intern Med.
July.2007/p1474/c2/line 12, 20
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 18/52
MakeaProven Choice
with Proven Outcomes
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
Benefit/risk profile
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.
CI=confidence interval;
NNT=number needed to treat;
RRR=relative risk reduction.
14.9%Placebo(n=288)
63%RRR
20
15
10
5
0
LOVENOX®
40 mg SC once daily(n=291)
5.5%
20/DOF--sanofi-aventis
calculations
22/Samama.N Engl J Med.September.1999/
p793/c1/line A7; p795/c1/line 8
22/Samama.N Engl J Med.September.
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
22/Samama.N Engl J Med.
September.1999/p798/c1/table 5
28/LOVENOX PI.July.2008/p4/c1/table 4
22/Samama.N Engl J Med.
September.1999/p798/c1/table 5
28/LOVENOX PI.July.2008/p4/c1/table 4
22/Samama.N Engl J Med.
September.1999/p794/c2/line 8
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 19
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 19/52
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 important safety information on pages 8 and 9.
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
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p343/table1;table 2
51/Alikhan.Blood Coagul Fibrinolysis.June.2003/
p342/c1/line 11; c2/line 21; p341/c1/line A6
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 20
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 20/52
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
Results from subgroup analyses of MEDENOX trial
In a MEDENOX subanalysis, LOVENOX® demonstrated consistent efficacy andsafety in a wide range of patients28,51,a
200,000,000 PatientsTreated Worldwide F P
O
Relative reduction in the incidence of DVT/PE inpatients with acute respiratory disease51
20
15
10
5
0
3.3%LOVENOX®
40 mg SC once daily(n=153)
95% CI; P =0.003
I n c i d e n c e o f D
V T / P E ( % )
CI=confidence interval;
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®
40 mg SC once daily(n=99)
95% CI; P =0.02
I n c i d
e n c e o f D V T / P E ( % )
CI=confidence interval;
NNT=number needed
to treat.
N=195; NNT=10
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.
14.6%Placebo(n=96)
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p342/c2/line28;p343/table 1
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p342/c2/line28;p343/table 1
51/Alikhan.Blood Coagul Fibrinolysis.
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
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p342/c1/line 11; c2/line 21;
p341/c1/line A6
28/LOVENOX PI.July.2008/p4/c1/table 4
28/LOVENOX PI.July.2008/p4/
c1/table 4
52/Kleber.Am Heart J.April.2003/
p615/c2/line 26; p619/table IV
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 21
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 21/52
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
Results from subgroup analyses of MEDENOX trial
Incidence of DVT/PE at day 14 in patients with cancer 51
20
15
10
5
0
9.7%LOVENOX®
40 mg SC once daily(n=31)
95% CI; P =0.4
I n c i d e n c e
o f D V T / P E ( % )
CI=confidence interval;
NNT=number needed
to treat.
N=72; 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.
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®
40 mg SC once daily(n=159)
95% CI; P =0.01
I n c i d e n c e o f D V T / P E ( % )
CI=confidence interval;
NNT=number needed
to treat.
N=314; 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.
15.5%Placebo(n=155)
F P O
51/Alikhan.Blood Coagul Fibrinolysis.June.2003/
p343/table 2
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p343/table 1
28/LOVENOX PI.July.2008/p4/table 5
51/Alikhan.Blood Coagul Fibrinolysis.June.2003/
p343/table 1; p342/c1/line 18
28/LOVENOX PI.July.2008/p4/table 5
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p343/tables 1 & 2
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 22
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 22/52
22
with Proven Outcomes
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 ( % )
CI=confidence interval;
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
02977_M4 Pullout Pocket pages.qxd:Layout 2 4/28/09 11:25 AM Page 3
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 23/52
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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 ( % )
CI=confidence interval;
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 ( % )
CI=confidence interval;
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
23/Levine.N Engl J Med.March.1996/p680/c1/line 4
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
23/Levine.N Engl J Med.March.1996/p677/
c2/line18;p680/c1/line 27
56/Merli.Ann Intern Med.February.2001/p192/c1/line 23; p195/table 2
23/Levine.N Engl J Med.March.1996/p677/
c2/line A14
56/Merli.Ann Intern Med.February.2001/p191/
c2/line A1
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 24/52
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
200,000,000 PatientsTreated Worldwide F P
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
02977_M4 Pullout Pocket pages.qxd:Layout 2 4/28/09 11:25 AM Page 4
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 25/52
25
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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
Benefit/risk profile
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
Benefit/risk profile
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
Benefit/risk profile
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
CI=confidence interval;
NNT=number needed to treat;
RRR=relative risk reduction.
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
20/DOF--sanofi-aventis
calculations
20/DOF--sanofi-aventis
calculations
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 26/52
Make aProven Choice
with Proven Outcomes
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
02977_M4 Pullout Pocket pages.qxd:Layout 2 4/28/09 11:25 AM Page 5
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 27/52
27
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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 ( % )
CI=confidence interval;
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
CI=confidence interval;
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.
August.1997/p1102/c1/line 62
12/ENOXACAN Study Gp.Br J Surg.
August.1997/p1102/c1/line 59
12/ENOXACAN Study Gp.Br J Surg.August.1997/
p1101/c1/line33/p1101/c2/table 3
12/ENOXACAN Study Gp.Br J Surg.
August.1997/p1101/c1/line 26
12/ENOXACAN Study Gp.Br J Surg.
August.1997/p1102/c1/line 60
12/ENOXACAN Study Group. Br J Surg.
August.1997/p1099/line A10; c2/line 2; c2/line 22
12/ENOXACAN Study Gp.Br J Surg.
August.1997/p1101/c1/line 33
12/ENOXACAN Study Gp.Br J Surg.
August.1997/ p1101/C1/line 26
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 28/52
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
200,000,000 PatientsTreated Worldwide F P
O
28/LOVENOX PI.July.2008/
p2/c2/line 18
28/LOVENOX PI.
July.2008/p2/c2/line 18
28/LOVENOX PI.
July.2008/p2/c2/line 18
28/LOVENOX PI.
July.2008/p2/c2/line 18
28/LOVENOX PI.July.2008/p1/c1/table:
line 17; p2/c2/line 8
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
28/LOVENOX PI.July.2008/p2/c2/line 14
28/LOVENOX PI.July.2008/p2/c2/line 21
28/LOVENOX PI.July.2008/p2/c1/line 16
FPO
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 29
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 29/52
Prophylaxis of ischemic complications in UA/NSTEMI patients28
29
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
LOVENOX®—practical dosingwith proven outcomes
Patient type Dosing Duration of therapy
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.
July.2008/p2/c2/line 16
28/LOVENOX PI.
July.2008/p1/c1/table/
line 15; p2/c2/line 1
28/LOVENOX PI.
July.2008/p1/c1/table:
line 15; p2/c2/table 1:
line 11; p2/c2/line 1
28/LOVENOX PI.July.2008/p2/c2/line 26
28/LOVENOX PI.July.2008/p6/
c1/line 53
28/LOVENOX PI.July.2008/p2/
c1/line 14
Make aProven ChoiceO
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 30
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 30/52
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
Patient type Dosing Duration of therapy
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
Patient type Dosing Duration of therapy
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®—practical dosingwith proven outcomes
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
28/LOVENOX PI.July.2008/p1/c1/
table: line 7; p2/c1/line 41
28/LOVENOX PI.July.2008/p1/c1/
table: line 7; p2/c2/table 1: line 3; c1/
line 41
28/LOVENOX PI.July.2008/p1/
c1/table: line 9; p2/c1/line 49,53
28/LOVENOX PI.July.2008/p1/c1/
table: line 12; p2/c1/line 46,53
28/LOVENOX PI.July.2008/p1/c1/
table: line 9,12; p2/c2/table 1/line 4,7;
c1/line 55
28/LOVENOX PI.July.2008/p2/c1/
line 7,41
28/LOVENOX PI.July.2008/p2/c1/
line 1,7
28/LOVENOX PI.July.2008/p2/c1/
line 9
FP O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 31
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 31/52
Prophylaxis of DVT in hip- or knee-replacement surgery patients28
31
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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® may be largely neutralized (up to 60%) by the slow IV injection of protamine sulfate(1% solution)
LOVENOX®—practical dosingwith proven outcomes
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
Patient type Dosing Duration of therapy
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
F P
28/LOVENOX PI.July.2008/p1/
c1/table: line 5; p2/c1/line 32,39
28/LOVENOX PI.July.2008/p2/
c1/line 35
28/LOVENOX PI.July.2008/p1/c1/
table: line 3; p2/c1/line 32,39
28/LOVENOX PI.July.2008/p1/c1/
table/line 3,5; p2/c2/table 1/line 2;
c1/line 39
28/LOVENOX PI.July.2008/p2/
c2/line 26
28/LOVENOX PI.July.2008/p6/c1/line 53
28/LOVENOX PI.July.2008/p2/c1/
line 5,6
200,000,000 PatientsPO
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 32
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 32/52
Prophylaxis of DVT in abdominal surgery patients28
32
LOVENOX®—practical dosingwith proven outcomes
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)
Patient type Dosing Duration of therapy
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
28/LOVENOX PI.July.2008/p1/
c1/table/line 1; p2/c1/line 27
28/LOVENOX PI.July.2008/p1/c1/
table: line 1; p2/c2/table 1/line 1;
c1/line 27
28/LOVENOX PI.July.2008/p2/
c2/line 26
28/LOVENOX PI.July.2008/p6/
c1/line 53,65
28/LOVENOX PI.July.2008/p2/c1/
line 1, 3
28/LOVENOX PI.July.2008/p2/
c1/boxed warning: line 1
F P O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 33
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 33/52
Dosage for patients with severe renal impairment (CrCI <30 mL/min)28
33
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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® may be largely neutralized (up to 60%) by the slow IV injection of protamine sulfate(1% solution)
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
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 15
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 18
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 11
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 3
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 4,7
28/LOVENOX PI.July.2008/p2/c2/
table 1/line 2
28/LOVENOX PI.July.2008/p1/c1/
table: line 1; p2/c2/table 1: line 1
28/LOVENOX PI.July.2008/p6/
c1/line 37
28/LOVENOX PI.July.2008/p2/
c2/line 26
28/LOVENOX PI.July.2008/p6/
c1/line 53
28/LOVENOX PI.July.2008/p2/c1/
line 7,41
P O
Make aProven Choice
O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 34
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 34/52
34
with Proven Outcomes F P
O
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.
July.2008/p1/c1/line 4
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)
28/LOVENOX PI.July.2008/p6/c1/line 5
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
28/LOVENOX PI.July.2008/p6/c1/line 17
28/LOVENOX PI.July.2008/p6/c1/line 49
28/LOVENOX PI.July.2008/p6/c1/line 41
28/LOVENOX PI.July.2008/p2/c2/line 29, Table 1; p6/c1/line 38
28/LOVENOX PI.July.2008/p5/c2/line 32
28/LOVENOX PI.July.2008/p5/c2/line 41
28/LOVENOX PI.July.2008/p5/c2/line 50
28/LOVENOX PI.July.2008/p6/c1/
line 1
28/LOVENOX PI.July.2008/p6/c1/
line 1
28/LOVENOX PI.July.2008/p6/c1/
line 4
F P O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 35
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 35/52
35
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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)
28/LOVENOX PI.July.2008/p6/c1/
line 5
28/LOVENOX PI.
July.2008/p6/c1/line 22
28/LOVENOX PI.
July.2008/p6/c1/line 26
28/LOVENOX PI.
July.2008/p6/c1/line 28
28/LOVENOX PI.
July.2008/p6/c1/line 35
28/LOVENOX PI.
July.2008/p6/c1/line 46
28/LOVENOX PI.July.2008/p6/c1/line 49
200,000,000 PatientsTreated WorldwideFP
O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:47 AM Page 36
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 36/52
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)
Treated Worldwide F P
35/Antman.J Am Coll Cardiol.August.2007/p224/table 8
35/Antman.J Am Coll
Cardiol.January.2008/
p213/table 1
35/Antman.J Am Coll
Cardiol.January 2008/
p224/table 8/1b
35/Antman.J Am Coll
Cardiol.January 2008/
p224/table 8/1b; line 11
35/Antman.J Am Coll
Cardiol.January 2008/
p224/table 8/1b
3/Anderson.J Am Coll
Cardiol.August.2007/
p661/c1/line 7
3/Anderson.J Am Coll Cardiol.
August.2007p661/c1/line 7
3/Anderson.J Am Coll Cardiol.
August.2007/p661/c1/line 13
3/Anderson.J Am Coll Cardiol.
August.2007/p661/c1/line 17
64/Guyatt.Chest.June.2008/
p125S/Table 1
11/Geerts.Chest.June.2008/
p387S/c1/line 18
35/Antman.J Am Coll Cardiol.January.2008/
p224/table 8
3/Anderson.J Am Coll Cardiol.August.2007
11/Geerts.Chest.June.2008/p387S/c1/line 18
F P O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:48 AM Page 37
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 37/52
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
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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)
11/Geerts.Chest.June.2008/p388S/c2/line 29
64/Guyatt.Chest.June.2008/
p125S/Table 1
65/Kearon.Chest.June.2008/
p455S/c1/line 1
65/Kearon.Chest.June.2008/
p455S/c1/line 15
65/Kearon.Chest.June.2008/
p455S/c2/line 15
65/Kearon.Chest.June.2008/
p457S/c2/line 11
65/Kearon.Chest.June.2008/
p458S/c1/line 11
65/Kearon.Chest.June.2008/p455/
c2/line 20; p458S/c1/line 19
11/Geerts.Chest.
June.2008/p385S/c2/
line 5; p384S/c2/line
8,34
11/Geerts.Chest.
June.2008/p385S/
c2/line 9
11/Geerts.Chest.June.2008/
p382S/c2/line 32
11/Geerts.Chest.June.2008/p382S/
c2/line 37; p383S/c1/line 1
11/Geerts.Chest.June.2008/
p383S/c1/line 5
64/Guyatt.Chest.June.2008/
p125S/Table 1
64/Guyatt.Chest.June.2008/
p125S/Table 1
65/Kearon.Chest.June.2008/p455S/c1/line 1.15;
c2/line 15,20; p457S/c2/line 11; p458S/c1/line 11,19
11/Geerts.Chest.June.2008/p384S/c2/line 8,34; p385S/c2/line 5,9
11/Geerts.Chest.June.2008/p382S/c2/line 32,37; p383S/c1/line 5
Make aProven Choice
with Proven OutcomesFP
O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:48 AM Page 38
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 38/52
with Proven Outcomes
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
37/Stahl.DisColonRectum.October.2006/
p1478/table
37/Stahl.DisColonRectum.October.2006/
p1478/c1/line 19
37/Stahl.DisColonRectum.October.2006/
p1481/c1/line 21
36/Lyman.J Clin Oncol.December.2007/
p5490/line A12
36/Lyman.J Clin Oncol.December.2007/
p5490/line A17
38/Johansen.www.aaos.org/p11/line 7, 19
38/Johansen.www.aaos.org/p2/line 7; p2/line 26
38/Johansen.www.aaos.org/p2/line 7
38/Johansen.www.aaos.org/p2/line 5, 26
39/ACOG Practice Bulletin.Obstet
Gynecol.2007/p437/c1/line 8
39/ACOG Practice Bulletin.Obstet
Gynecol.2007/p437/c1/line 10
39/ACOG Practice Bulletin.Obstet
Gynecol.2007/p437/c1/line 25
66/ASRA.www.asra.com/p5/line 10
66/ASRA.www.asra.com/p5/line 12
66/ASRA.www.asra.com/p5/line 10
11/Geerts.Chest.June.2008/p388S/c2/line 29
F P O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:48 AM Page 39
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 39/52
39
Please see important safety information on pages 8 and 9.
Please see accompanying full prescribing information,including boxedWARNING, inside pocket.
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/
p29/table 1
40/NQF Safe Practices.2006/
p29/table 1
41/www.jointcommission.org.
NPSG.Hospital.2008/
slides 10, 19, 23
42/Medqic.www.medqic.
org/p2/line 21
42/Medqic.www.medqic.
org/p2/line 23
42/Medqic.www.medqic.
org/p2/line 25
42/Medqic.www.medqic.
org/p3/line 1
67/FedReg.Aug19.2008/
p48471/c3/lines 37-53;
p48473/Table; p48474/
c3/line 50
67/FedReg.Aug19.2008/
p48481/c3/lines 28-32;
48472/c1/lines 16-21
67/FedReg.Aug19.2008/
p48472/c2/line 20; c3/
line 18; p48481/c3/lines
20-32
11/Geerts.Chest.June.2008/p388S/c2/line 29
200,000,000 PatientsTreated Worldwide
FP O
02977_M4_2009 MVA.qxd:Layout 1 4/28/09 10:48 AM Page 40
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 40/52
40
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 41/52
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 important safety information on pages 8 and 9.
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 42/52
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 important safety information on pages 8 and 9.
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
28/LOVENOX PI.July.2008/p1/c1/line 4
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
28/LOVENOX PI.July.2008/p6/c2/line 26
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
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
12/ENOXACAN Study Gp. Br J.August.1997/p1101/c1/line33;
c2/table 3; p1102/c1/line 59
18/Antman.N Engl J Med.April.2006/p1485/table 3
21/Cohen.N Engl J Med.August.1997/p451/table 5
22/Samama.N Engl J Med.September.1999/p798/c1/table 5
23/Levine.N Engl J Med.March.1996/p680/c1/line 4
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
28/LOVENOX PI.July.2008/p1/c1/line 4
51/Alikhan.Blood Coagul Fibrinolysis.
June.2003/p343/table1; table 2; p343/c2/line 17
2/IMS Patient Projections.March.2008
28/LOVENOX PI.July.2008/p4/c1/line 7
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
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 43/52
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 2
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 44/52
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®—proven acrossmultiple patient types28
Please refer to pages 28–35 for full dosing and administration information.
LOVENOX® is indicated for the prophylaxis of ischemiccomplications of UA and non–Q-wave MI when concurrentlyadministered with aspirin
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 3
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 45/52
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®—proven acrossmultiple patient types28
Please refer to pages 28–35 for full dosing and administration information.
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
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 4
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 46/52
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 5
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 47/52
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
Please refer to pages 28–35 for full dosing and administration information.
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
Hypothetical patient profile
LOVENOX®—proven acrossmultiple patient types28
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 6
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 48/52
D V T t r e a t m e n t
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:50 AM Page 7
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 49/52
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®—proven acrossmultiple patient types28
Please refer to pages 328–35 for full dosing and administration information.
LOVENOX® is indicated for the prophylaxis of DVT, which maylead to PE in patients undergoing hip-replacement surgery, duringand following hospitalization
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:51 AM Page 8
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 50/52
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®—proven acrossmultiple patient types28
Please refer to pages 28–35 for full dosing and administration information.
LOVENOX® is indicated for the prophylaxis of DVT, which may leadto PE in patients undergoing knee-replacement surgery
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:51 AM Page 9
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 51/52
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®—proven acrossmultiple patient types28
Please refer to pages 28–35 for full dosing and administration information.
LOVENOX® is indicated for the prophylaxis of DVT, which maylead to PE, in patients undergoing abdominal surgery who areat risk for thromboembolic complications
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
02977_M4_ 2009 MVA Pullout tabs.qxd:Layout 1 4/28/09 10:51 AM Page 10
8/9/2019 02977_M4_2009 MVA_annot_042809_adj annot 061809
http://slidepdf.com/reader/full/02977m42009-mvaannot042809adj-annot-061809 52/52
A b d o m i n a l s u r g e r y