LOVENOX® clinical outcomes summary

WARNING: SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

Use of indwelling epidural catheters
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
A history of traumatic or repeated epidural or spinal punctures
A history of spinal deformity or spinal surgery

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

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Continued below

Patient Type	Primary Efficacy Outcome	Safety Endpoints	Duration of Treatment/NNS	Study Design
STEMI 18,19	LOVENOX® vs. comparator 17% RRR in death or MI LOVENOX® vs. UFH (9.9% Vs. 12%) 95% Cl; P<.001 N=20,479	LOVENOX® vs. comparator Major hemorrhage; 21% vs. 1.4% P<.001 ICH: .8% vs. .7% P=0.14	8 days or until hospital discharge; whichever came first NNT=48a	ExTRACT TIMI 25 was randomized, double-blind, double- dummy, parallel group, multi-national, active- controlled, clinical trial Comparing LOVENOX® With UFH in acute STEMI patients
UA/NSTEMI 20	16% RRR in death, MI And recurrent angina LOVENOX® vs. UFH (16.6% vs. 19.8%) 95% Cl; P=.019 N=3171	Overall hemorrhage: 18.4% vs. 14.2% P=.001 Major hemorrhage: 6.5% vs. 7% P=NS	48 hours to 8 days; median: 2.6 days NNT= 32a	ESSENCE was a prospective, randomized, double-blind, parallel- group, multi-center, multi-national trial comparing LOVENOX® and UFH in UA/STEMI patients
Acutely ill Medical Patients 11	63% RRR in DVT/PE events LOVENOX® vs. placebo (5.5% vs. 14.9%) 95% Cl; P<.001 N=579	Major hemorrhage: 1.7% vs. 1.1% P=NS Thrombocytopenia: 2.2% vs. 3.6% P=NS	In hospital treatment for 6-14 days median: 7 days NNT=11a	MEDONOX was a multi- center, multi-national, double-blind study of hospitalized acutely ill medical patients Randomized to LOVENOX® or placebo
DVT Outpatient Treatment 16	1.4% ARR in recurrent symptomatic thromboembolism LOVENOX® vs. UFH (5.3% vs. 6.7%) 95% Cl; P=NS N=500	Major hemorrhage: 2.0% vs. 1.2% P=NS	Mean duration of LOVENOX®: 5.8 +- 1.8 days; UFH 5.5 +- 1.2 days	This study was randomized, open-label trial comparing LOVENOX® outpatient treatment of DVT with inpatient IV UFH, each In conjunction with warfarin
Hip- Replacement Surgery 13	LOVENOX® vs. comparator 77% RRR in symptomatic DVT during hospitalization LOVENOX® vs. warfarin (.3% vs. 1.1%) 95% Cl; P=.008 N=3011	LOVENOX® vs. comparator Major hemorrhage: .6% vs. .3% P=NS	Therapy initiated within 24 hours postoperatively; mean duration: 7.3 days NNT=125a	This study was randomized, open-label trial comparing LOVENOX® with warfarin in patients undergoing ip-replacement surgery
Hip- Replacement Surgery (extended prophylaxis) 26	53% RRR in DVT/PE events LOVENOX vs. placebo (17.9% vs. 38.8%) 95% Cl; P<.001 N=233	Injection-site hematoma: 5.2% vs. 1.0% P=NS	In-hospital 7 to 11 days; outpatient 19- 23 days (average 21 days) NNT= 5a	A prospective, randomized, double- blind study conducted at a single center with all patients receiving LOVENOX® during their hospitalization and blinded drug at the end of hospitalization

Knee- Replacement Surgery 14	44% RRR in total VTE documented by venography LOVENOX® vs. warfarin (25.4% vs. 45.5%) 95% Cl; P<.001 N=349	Major hemorrhage: 5.2% vs. 2.3% P=NS	Therapy initiated within 8 hours postoperatively and continued for 4 to 14 days NNT=5a	This study was prospective, randomized, multicenter, open label parallel-group trial comparing LOVENOX® with warfarin in patients undergoing knee-replacement surgery
Abdominal Surgery 15	3.5% ARR in DVT/PE incidence LOVENOX® vs. UFH (14.7% vs. 18.2%) 95% Cl; P=NS N=631	Overall hemorrhage: 18.7% vs. 17.1% P=NS Major hemorrhage: 4.1% vs. 2.9% P=NS	Therapy initiated 2 hours preoperatively and continued for 10 +- 2 days	ENOXACAN was a prospective, double- blind, randomized, multicenter trial comparing LOVENOX® with UFH patients undergoing elective urative surgery for abdominal or pelvic cancer

ARR=absolute risk reduction; DVT=deep vein thrombosis; DVT/PE=deep vein thrombosis/pulmonary embolism; ENOXACAN=Enoxaparin and Cancer; ESSENCE=Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events; ExTRACT–TIMI 25=Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction 25; ICH=intracranial hemorrhage; MEDENOX=Prophylaxis in Medical Patients With Enoxaparin; MI=myocardial infarction; NNT=number needed to treat (as observed difference—the estimated number of patients who need to be treated with LOVENOX® rather than a comparator for 1 additional patient to benefit); NS=not significant; OAD=observed absolute difference (the observed difference between 2 groups [NS]); RRR=relative risk reduction; STEMI=ST-segment elevation MI; UA/NSTEMI=unstable angina/non–ST-segment elevation MI; UFH=unfractionated heparin; VTE=venous thromboembolism=DVT and/or PE.

^a The NNT and the benefit/risk profile were not prespecified analyses in the trials and were calculated using the reported ARR results. ¹⁰

^bP value calculated based on Chi-Square test. ⁶

^cSafety data reflect prescribing information (PI) data for the treatment of DVT, with or without PE. ⁶

^dSafety data reflect PI data from the LOVENOX® vs heparin trial. ⁶

^eSafety data reflect PI data from the extended prophylaxis period (does not include a comparator). ⁶

Important Safety Information for LOVENOX^®

WARNING: SPINAL/EPIDURAL HEMATOMA

Use of indwelling epidural catheters
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
A history of traumatic or repeated epidural or spinal punctures
A history of spinal deformity or spinal surgery

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

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS

LOVENOX® (enoxaparin sodium injection) is contraindicated in patients with active major bleeding; thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium; known hypersensitivity to enoxaparin sodium, heparin, pork products, or benzyl alcohol (multi-dose formulation only)

WARNINGS AND PRECAUTIONS

LOVENOX® should be used with extreme caution in conditions with increased risk of hemorrhage. Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal. 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
For percutaneous coronary revascularization procedures, obtain hemostasis at the puncture site before sheath removal and observe the site for signs of bleeding or hematoma formation
In the STEMI population, 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 unfractionated heparin (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, or ICH (a measure of net clinical benefit) was significantly lower in the LOVENOX® group (10.1%) compared to the UFH group (12.2%)
LOVENOX® should be used with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage
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
LOVENOX® cannot be used interchangeably with other branded LMWH or UFH, as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosages
Pregnant women with mechanical prosthetic heart valves and their fetuses may be at increased risk for thromboembolism. Frequent monitoring of anti-Factor Xa levels and adjusting of dosage may be needed
LOVENOX® multiple-dose vials contain benzyl alcohol and should be used with caution in pregnant women and only if clearly needed due to the risk of fatal "gasping syndrome" in premature neonates
Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with LOVENOX®

ADVERSE REACTIONS

Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea

For more information, contact your local sanofi-aventis U.S. Representative or call sanofi-aventis U.S. Medical Information Services at 1-800-633-1610.

Please see full Prescribing Information, including boxed WARNING.

Prescription LOVENOX® is available in pharmacies.

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