Enoxaparin Drug Information

Generic name: ENOXAPARIN SODIUM

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Uses of Enoxaparin

Prophylaxis of Deep Vein Thrombosis Enoxaparin sodium injection is indicated for the

prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing abdominal surgery who are at risk for thromboembolic complications in patients undergoing hip replacement surgery, during and following hospitalization in patients undergoing knee replacement surgery in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness

Treatment of Acute Deep Vein Thrombosis Enoxaparin sodium injection is indicated for

the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium the outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium

Prophylaxis of Ischemic Complications of Unstable Angina and Non−Q-Wave Myocardial Infarction Enoxaparin

sodium injection is indicated for the prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction, when concurrently administered with aspirin.

Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin sodium injection, when administered

concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).

Dosage & Administration of Enoxaparin

IndicationDosage Regimen
Prophylaxis in abdominal surgery30 mg administered subcutaneously once daily
Prophylaxis in hip or knee replacement surgery30 mg administered subcutaneously once daily
Prophylaxis in medical patients during acute illness30 mg administered subcutaneously once daily
Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium1 mg/kg administered subcutaneously once daily
Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium1 mg/kg administered subcutaneously once daily
Prophylaxis of ischemic complications of unstable angina and non –Q-wave myocardial infarction, when concurrently administered with aspirin1 mg/kg administered subcutaneously once daily
Treatment of acute ST-segment elevation myocardial infarction in patients <75 years of age, when administered in conjunction with aspirin30 mg single intravenous bolus plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg administered subcutaneously once daily.
Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, when administered in conjunction with aspirin1 mg/kg administered subcutaneously once daily (no initial bolus)

Side Effects of Enoxaparin

  • The following serious adverse reactions are also discussed in other sections of the labeling:
  • Spinal/epidural hematomas [see Boxed Warning and Warnings and Precautions ( 5.1 )]
  • Increased Risk of Hemorrhage [see Warnings and Precautions ( 5.1 )]
  • Thrombocytopenia [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, nausea, ecchymosis, fever, edema, peripheral edema, dyspnea, confusion, and injection site pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosis following abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non – Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosis with or without pulmonary embolism. Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg subcutaneously once daily to 30 mg subcutaneously twice daily. In the clinical studies for prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg intravenous bolus followed by 1 mg/kg every 12 hours subcutaneously. Hemorrhage The following rates of major bleeding events have been reported during clinical trials with enoxaparin sodium (see Tables 2 to 7). Table 2: Major Bleeding Episodes following Abdominal and Colorectal Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg -daily subcutaneously Heparin 5000 U q8h subcutaneously Abdominal Surgery n=555 23 (4%) n=560 16 (3%) Colorectal Surgery n=673 28 (4%) n=674 21 (3%) *Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. Table 3: Major Bleeding Episodes Following Hip or Knee Replacement Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Hip Replacement Surgery without Extended Prophylaxis † – n=786 31 (4%) n=541 32 (6%) Hip Replacement Surgery with Extended Prophylaxis Peri-operative Period ‡ Extended Prophylaxis Period § – – – n=288 4 (2%) – – n=221 0 (0%) – – Knee Replacement Surgery without Extended Prophylaxis † – n=294 3 (1%) n=225 3 (1%) * Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages. † Enoxaparin sodium 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery ‡ Enoxaparin sodium 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery § Enoxaparin sodium 40 mg subcutaneously once a day for up to 21 days after discharge NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours postoperative hip replacement surgery prophylactic regimens compared in clinical trials. Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the enoxaparin sodium patients versus 1.8% of the placebo patients. Table 4: Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility during Acute Illness* Indication Dosing Regimen Enoxaparin Sodium † 20 mg daily subcutaneously Enoxaparin Sodium † 40 mg daily subcutaneously Placebo † Medical Patients during Acute Illness n=351 1 (<1%) n=360 3 (<1%) n=362 2 (<1%) * Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial. † The rates represent major bleeding on study medication up to 24 hours after last dose. Table 5: Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism Treatment* Indication Dosing Regimen † Enoxaparin Sodium 1.5 mg/kg daily subcutaneously Enoxaparin Sodium 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy Treatment of DVT and PE n=298 5 (2%) n=559 9 (2%) n=554 9 (2%) *Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. † All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing within 72 hours of enoxaparin sodium or standard heparin therapy and continuing for up to 90 days. Table 6: Major Bleeding Episodes in Unstable Angina and Non−Q-Wave Myocardial Infarction Indication Dosing Regimen Enoxaparin Sodium * 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Unstable Angina and Non−Q-Wave MI †,‡ n=1578 17 (1%) n=1529 18 (1%) * The rates represent major bleeding on study medication up to 12 hours after dose. † Aspirin therapy was administered concurrently (100 to 325 mg per day). ‡ Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease by ≥3 g/dL or transfusion of 2 or more units of blood products. Intraocular , retroperitoneal, and intracranial hemorrhages were always considered major. Table 7: Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction Indication Dosing Regimen Enoxaparin Sodium * Initial 30 mg intravenous bolus followed by 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Acute ST-Segment Elevation Myocardial Infarction Major bleeding (including ICH) † Intracranial hemorrhages (ICH) n=10176 n (%) 211 (2.1) 84 (0.8) n=10151 n (%) 138 (1.4) 66 (0.7) * The rates represent major bleeding (including ICH) up to 30 days † Bleedings were considered major if the hemorrhage caused a significant clinical event associated with a hemoglobin decrease by ≥5 g/dL. ICH were always considered major. Elevations of Serum Aminotransferases Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during treatment with enoxaparin sodium. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like enoxaparin sodium should be interpreted with caution. Local Reactions Local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection of enoxaparin sodium. Adverse Reactions in Patients Receiving Enoxaparin Sodium for Prophylaxis or Treatment of DVT, PE Other adverse reactions that were thought to be possibly or probably related to treatment with enoxaparin sodium, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the enoxaparin sodium group, are provided below (see Tables 8 to 11). Table 8: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Patients Undergoing Abdominal or Colorectal Surgery Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n=1228 % Heparin 5000 U q8h subcutaneously n=1234 % Severe Total Severe Total Hemorrhage <1 7 <1 6 Anemia <1 3 <1 3 Ecchymosis 0 3 0 3 Table 9: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Patients Undergoing Hip or Knee Replacement Surgery Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Placebo q12h subcutaneously Peri-operative Period n=288* % Extended Prophylaxis Period n=131 † % n=1080 % n=766 % n=115 % Severe Total Severe Total Severe Total Severe Total Severe Total Fever 0 8 0 0 <1 5 <1 4 0 3 Hemorrhage <1 13 0 5 <1 4 1 4 0 3 Nausea – – – – <1 3 <1 2 0 2 Anemia 0 16 0 <2 <1 2 2 5 <1 7 Edema – – – – <1 2 <1 2 0 2 Peripheral edema 0 6 0 0 <1 3 <1 4 0 3 *Data represent enoxaparin sodium 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received enoxaparin sodium peri-operatively in an unblinded fashion in one clinical trial. † Data represent enoxaparin sodium 40 mg subcutaneously once a day given in a blinded fashion as extended prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical trial. Table 10: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium-Treated Medical Patients with Severely Restricted Mobility During Acute Illness Adverse Reaction Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n=360 % Placebo daily subcutaneously n=362 % Dyspnea 3.3 5.2 Thrombocytopenia 2.8 2.8 Confusion 2.2 1.1 Diarrhea 2.2 1.7 Nausea 2.5 1.7 Table 11: Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium- Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism Adverse Reaction Dosing Regimen Enoxaparin Sodium 1.5 mg/kg daily subcutaneously n=298 % Enoxaparin Sodium 1 mg/kg q12h subcutaneously n=559 % Heparin aPTT Adjusted Intravenous Therapy n=544 % Severe Total Severe Total Severe Total Injection Site Hemorrhage 0 5 0 3 <1 <1 Injection Site Pain 0 2 0 2 0 0 Hematuria 0 2 0 <1 <1 2 Adverse Events in Enoxaparin Sodium-Treated Patients with Unstable Angina or Non − Q-Wave Myocardial Infarction Non-hemorrhagic clinical events reported to be related to enoxaparin sodium therapy occurred at an incidence of ≤1%. Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more frequently reported in patients treated with subcutaneous enoxaparin sodium than in patients treated with intravenous heparin. Serious adverse events with enoxaparin sodium or heparin in a clinical trial in patients with unstable angina or non − Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the enoxaparin sodium group are provided below (see Table 12). Table 12: Serious Adverse Events Occurring at ≥0.5% Incidence in Enoxaparin Sodium-Treated Patients with Unstable Angina or Non−Q-Wave Myocardial Infarction Adverse Event Dosing Regimen Enoxaparin Sodium 1 mg/kg q12h subcutaneously n=1578 n (%) Heparin aPTT Adjusted Intravenous Therapy n=1529 n (%) Atrial fibrillation 11 (0.70) 3 (0.20) Heart failure 15 (0.95) 11 (0.72) Lung edema 11 (0.70) 11 (0.72) Pneumonia 13 (0.82) 9 (0.59) Adverse Reactions in Enoxaparin Sodium-Treated Patients with Acute ST-Segment Elevation Myocardial Infarction In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of enoxaparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been reports of epidural or spinal hematoma formation with concurrent use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had a postoperative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria , anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis [see Warnings and Precautions (5.5) ] have been reported. Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined. Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported Osteoporosis has also been reported following long-term therapy.

Warnings & Cautions for Enoxaparin

Increased Risk of Hemorrhage Cases of epidural or spinal hemorrhage and subsequent

hematomas have been reported with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of postoperative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity . To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (30 mg once or twice daily or 40 mg once daily) of enoxaparin sodium and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin sodium.

Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided. Patients receiving the 0.75 mg/kg twice-daily dose or the 1 mg/kg twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin sodium dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

For patients with creatinine clearance <30 mL/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin sodium (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day) . Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use enoxaparin sodium with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal.

Bleeding can occur at any site during therapy with enoxaparin sodium. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

Increased Risk of Bleeding following Percutaneous Coronary Revascularization Procedures To minimize the

risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non – Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium doses. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last intravenous/subcutaneous enoxaparin sodium injection.

If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation .

Increased Risk of Bleeding in Patients with

Concomitant Medical Conditions Enoxaparin sodium should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.

Risk of Heparin-Induced Thrombocytopenia with or Without Thrombosis Enoxaparin sodium may cause

heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia (HIT) with thrombosis (HITTS). HITTS may lead to organ infarction, limb ischemia, or death. Monitor thrombocytopenia of any degree closely. Use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated . Circulating antibodies may persist for several years.

Only use enoxaparin sodium in patients with a history of HIT if more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present. Because HIT may still occur in these circumstances, the decision to use enoxaparin sodium in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.

Thrombocytopenia Thrombocytopenia can occur with the administration of enoxaparin sodium. Moderate thrombocytopenia

(platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given enoxaparin sodium, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm 3 occurred at a rate of 0.1% in patients given enoxaparin sodium, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of any degree should be monitored closely.

If the platelet count falls below 100,000/mm 3, enoxaparin sodium should be discontinued.

Interchangeability with Other Heparins Enoxaparin sodium cannot be used interchangeably (unit for

unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.

Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves

Use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves may result in value thrombosis. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. No patients in the heparin/warfarin group (0 of 4 women) died.

There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion, and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed .

Drug Interactions with Enoxaparin

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If coadministration is essential, conduct close clinical and laboratory monitoring . Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium or conduct close clinical and laboratory monitoring

Pregnancy Safety for Enoxaparin

Pregnancy Risk Summary Placental transfer of enoxaparin was observed in the animal studies. Human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin sodium does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis . Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.

Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches . Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy.

It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of enoxaparin sodium affect the safety and the efficacy of the drug during pregnancy. Data Human Data There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy.

A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage.

Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. There have been postmarketing reports of fetal death when pregnant women received enoxaparin sodium. Causality for these cases has not been determined.

Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted . Animal Data Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use of Enoxaparin

Pediatric Use Safety and effectiveness of enoxaparin sodium in pediatric patients have not been established. Enoxaparin sodium is not approved for use in neonates or infants.

Contraindications for Enoxaparin

  • Enoxaparin sodium injection is contraindicated in patients with:
  • Active major bleeding
  • History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies [see Warnings and Precautions (5.4) ]
  • Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/ anaphylactoid reactions) [see Adverse Reactions (6.2) ]
  • Known hypersensitivity to heparin or pork products Active major bleeding ( 4 ) History of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies ( 4 ) Hypersensitivity to enoxaparin sodium ( 4 ) Hypersensitivity to heparin or pork products ( 4 )

Overdosage Information for Enoxaparin

Accidental overdosage following administration of enoxaparin sodium may lead to hemorrhagic complications. Injected enoxaparin sodium may be largely neutralized by the slow intravenous injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of enoxaparin sodium injected: 1 mg protamine sulfate should be administered to neutralize 1 mg enoxaparin sodium, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required.

The second infusion of 0.5 mg protamine sulfate per 1 mg of enoxaparin sodium may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate.

Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.

Clinical Studies of Enoxaparin

Prophylaxis of Deep Vein Thrombosis following Abdominal Surgery in Patients at Risk

for Thromboembolic Complications Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE). In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others.

Enoxaparin sodium 40 mg subcutaneously, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours subcutaneously in reducing the risk of DVT. The efficacy data are provided below (see Table 14). Table 14: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery * VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin † CI = Confidence Interval Indication Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%) All Treated Abdominal Surgery Patients 555 560 Treatment Failures Total VTE * (%) DVT Only (%) 56 (95% CI†: 8 to 13) 63 (95% CI: 9 to 14) 54 (95% CI: 7 to 12) 61 (95% CI: 8 to 13) In a second double-blind, parallel group study, enoxaparin sodium 40 mg subcutaneously once a day was compared to heparin 5000 U every 8 hours subcutaneously in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery.

The efficacy data are provided below (see Table 15). Table 15: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis following Colorectal Surgery * VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin † CI = Confidence Interval Indication Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%) All Treated Colorectal Surgery Patients 673 674 Treatment Failures Total VTE * (%) DVT Only (%) 48 (95% CI†: 5 to 9) 45 (95% CI: 5 to 9) 47 (95% CI: 5 to 9) 44 (95% CI: 5 to 8)

Prophylaxis of Deep Vein Thrombosis following Hip or Knee Replacement Surgery Enoxaparin

sodium has been shown to reduce the risk of postoperative deep vein thrombosis (DVT) following hip or knee replacement surgery. In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated.

Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below (see Table 16). Table 16: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis following Hip Replacement Surgery * p value versus placebo = 0.0002 † p value versus placebo = 0.0134 Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h subcutaneously n (%) Placebo q12h subcutaneously n (%) All Treated Hip Replacement Patients 50 50 Treatment Failures Total DVT (%) Proximal DVT (%) 5 * 23 1 † 11 A double-blind, multicenter study compared three dosing regimens of enoxaparin sodium in patients with hip replacement.

A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others.

Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below (see Table 17). Table 17: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis following Hip Replacement Surgery * p value versus enoxaparin sodium 10 mg once a day = 0.0008 † p value versus enoxaparin sodium 10 mg once a day = 0.0168 Indication Dosing Regimen 10 mg daily subcutaneously n (%) 30 mg q12h subcutaneously n (%) 40 mg daily subcutaneously n (%) All Treated Hip Replacement Patients 161 208 199 Treatment Failures Total DVT (%) Proximal DVT (%) 40 22 * 27 17 8 † 9 There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously was compared to placebo in patients undergoing knee replacement surgery.

A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery.

The incidence of proximal and total DVT after surgery was significantly lower for enoxaparin sodium compared to placebo. The efficacy data are provided below (see Table 18). Table 18: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis following Total Knee Replacement Surgery * p value versus placebo = 0.0001 † CI = Confidence Interval ‡ p value versus placebo = 0.013 § CL = Confidence Limit Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h subcutaneously n (%) Placebo q12h subcutaneously n (%) All Treated Total Knee Replacement Patients 47 52 Treatment Failures Total DVT (%) Proximal DVT (%) 5 * (95% CI†: 1 to 21) 32 (95% CI: 47 to 76) 0 ‡ (95% Upper CL§: 5) 7 (95% CI: 3 to 24) Additionally, in an open-label, parallel group, randomized clinical study, enoxaparin sodium 30 mg every 12 hours subcutaneously in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours subcutaneously. A total of 453 patients were randomized in the study and all were treated.

Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days.

The incidence of deep vein thrombosis was lower for enoxaparin sodium compared to heparin. Extended Prophylaxis of Deep Vein Thrombosis following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin sodium 40 mg subcutaneously, initiated up to 12 hours prior to surgery for the prophylaxis of postoperative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks.

A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo.

The efficacy data are provided below (see Table 19). Table 19: Efficacy of Enoxaparin Sodium in the Extended Prophylaxis of Deep Vein Thrombosis following Hip Replacement Surgery * p value versus placebo = 0.008 † CI= Confidence Interval ‡ p value versus placebo = 0.537 Indication (Post Discharge) Post-discharge Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n (%) Placebo daily subcutaneously n (%) All Treated Extended Prophylaxis Patients 90 89 Treatment Failures Total DVT (%) Proximal DVT (%) 6 * (95% CI†: 3 to 14) 18 (95% CI: 12 to 30) 5 ‡ (95% CI: 2 to 13) 7 (95% CI: 3 to 16) In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with enoxaparin sodium 40 mg subcutaneously, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n=131) once a day subcutaneously or to placebo (n=131) for 3 weeks.

A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, with a statistically significant difference in both total DVT (enoxaparin sodium 21 versus placebo 45 ; p=0.001) and proximal DVT (enoxaparin sodium 8 versus placebo 28 ; p=<0.001).

Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility

during Acute Illness In a double blind multicenter, parallel group study, enoxaparin sodium 20 mg or 40 mg once a day subcutaneously was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder (acute lumbar or sciatic pain, vertebral compression, acute arthritic episodes of the lower extremities). A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a day subcutaneously, enoxaparin sodium significantly reduced the incidence of DVT as compared to placebo.

The efficacy data are provided below (see Table 20). Table 20: Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility during Acute Illness * Treatment failures during therapy, between Days 1 and 14 † VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin ‡ CI = Confidence Interval Indication Dosing Regimen Enoxaparin Sodium 20 mg daily subcutaneously n (%) Enoxaparin Sodium 40 mg daily subcutaneously n (%) Placebo n (%) All Treated Medical Patients during Acute Illness 351 360 362 Treatment Failure * Total VTE† (%) Total DVT (%) Proximal DVT (%) 43 16 43 43 (95% CI‡: 8.8 to 15.7) 16 (95% CI‡: 2.3 to 6.6) 41 (95% CI‡: 8.1 to 14.6) 13 5 14 At approximately 3 months following enrollment, the incidence of venous thromboembolism remained lower in the enoxaparin sodium 40 mg treatment group versus the placebo treatment group.

Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism

In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium 1.5 mg/kg once a day subcutaneously, (ii) enoxaparin sodium 1 mg/kg every 12 hours subcutaneously, or (iii) heparin intravenous bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.

Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below (see Table 21). Table 21: Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism * All patients were also treated with warfarin sodium commencing within 72 hours of enoxaparin sodium or standard heparin therapy. † VTE = venous thromboembolic event (DVT and/or PE) ‡ The 95% Confidence Intervals for the treatment differences for total VTE were: Enoxaparin sodium once a day versus heparin (-3.0 to 3.5) Enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7) Indication Dosing Regimen * Enoxaparin Sodium 1.5 mg/kg daily subcutaneously n (%) Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated DVT Patients with or without PE 298 312 290 Patient Outcome Total VTE† (%) DVT Only (%) Proximal DVT (%) PE (%) 13 ‡ 9 ‡ 12 11 7 8 9 6 7 2 2 4 Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to enoxaparin sodium or heparin. Patients who could not receive outpatient therapy were excluded from entering the study.

Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated comorbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY enoxaparin sodium patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women.

Patients were randomized to either enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days. Enoxaparin sodium was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism.

The efficacy data are provided below (see Table 22). Table 22: Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis * All patients were also treated with warfarin sodium commencing on the evening of the second day of enoxaparin sodium or standard heparin therapy. † VTE = venous thromboembolic event (deep vein thrombosis and/or pulmonary embolism ). ‡ The 95% Confidence Intervals for the treatment difference for total VTE was: Enoxaparin sodium versus heparin (-5.6 to 2.7). Indication Dosing Regimen * Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated DVT Patients 247 254 Patient Outcome Total VTE† (%) DVT Only (%) Proximal DVT (%) PE (%) 13 ‡ 17 11 14 10 12 2 3

Prophylaxis of Ischemic Complications in Unstable Angina and Non−Q-Wave Myocardial Infarction

In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non − Q-wave myocardial infarction were randomized to either enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25 to 94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other.

All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for enoxaparin sodium compared with heparin therapy at 14 days after initiation of treatment.

The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below (see Table 23). Table 23: Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non−Q-Wave Myocardial Infarction (combined endpoint of death, myocardial infarction, or recurrent angina) * All patients were also treated with aspirin 100 to 325 mg per day. † Evaluation time points are after initiation of treatment.

Therapy continued for up to 8 days (median duration of 2.6 days). Indication Dosing Regimen * Reduction (%) p Value Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated Unstable Angina and Non−Q-Wave MI Patients 1578 1529 – – Time point† 48 Hours 14 Days 30 Days 96 112 1.2 0.120 261 303 3.3 0.017 313 358 3.6 0.014 The combined incidence of death or myocardial infarction at all time points was lower for enoxaparin sodium compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below (see Table 24). Table 24: Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non−Q-Wave Myocardial Infarction (Combined endpoint of death or myocardial infarction) * All patients were also treated with aspirin 100 to 325 mg per day. † Evaluation time points are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days). Indication Dosing Regimen * Reduction (%) p Value Enoxaparin Sodium 1 mg/kg q12h subcutaneously n (%) Heparin aPTT Adjusted Intravenous Therapy n (%) All Treated Unstable Angina and Non−Q-Wave MI Patients 1578 1529 – – Time point† 48 Hours 14 Days 30 Days 16 20 0.3 0.126 76 93 1.3 0.115 96 118 1.6 0.069 In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for enoxaparin sodium versus heparin (32.0% vs 35.7%). Urgent revascularization procedures were performed less frequently in the enoxaparin sodium group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p=0.047).

Treatment of Acute ST-Segment Elevation Myocardial Infarction

In a multicenter, double-blind, double-dummy, parallel-group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either enoxaparin sodium or unfractionated heparin. Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an intravenous bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value.

The intravenous infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient’s age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg subcutaneous dose followed by a subcutaneous injection of 1 mg/kg every 12 hours.

For patients at least 75 years of age, the intravenous bolus was not given and the subcutaneous dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The subcutaneous injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days.

The mean treatment duration of unfractionated heparin was 54 hours. When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last subcutaneous administration was less than 8 hours before balloon inflation, intravenous bolus of 0.3 mg/kg enoxaparin if the last subcutaneous administration was more than 8 hours before balloon inflation.

All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase. Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male.

Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%. The primary efficacy endpoint was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.

The rate of the primary efficacy endpoint (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) (see Table 25). Table 25: Efficacy of Enoxaparin Sodium in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals. Enoxaparin (N=10,256) UFH (N=10,223) Relative Risk (95% CI) P Value Outcome at 48 hours n (%) n (%) Death or Myocardial Re-infarction 478 531 0.90 (0.80 to 1.01) 0.08 Death 383 390 0.98 (0.85 to 1.12) 0.76 Myocardial Re-infarction 102 156 0.65 (0.51 to 0.84) <0.001 Urgent Revascularization 74 96 0.77 (0.57 to 1.04) 0.09 Death or Myocardial Re-infarction or Urgent Revascularization 548 622 0.88 (0.79 to 0.98) 0.02 Outcome at 8 Days Death or Myocardial Re-infarction 740 954 0.77 (0.71 to 0.85) <0.001 Death 559 605 0.92 (0.82 to 1.03) 0.15 Myocardial Re-infarction 204 379 0.54 (0.45 to 0.63) <0.001 Urgent Revascularization 145 247 0.59 (0.48 to 0.72) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 874 1181 0.74 (0.68 to 0.80) <0.001 Outcome at 30 Days Primary efficacy endpoint (Death or Myocardial Re-infarction) 1017 1223 0.83 (0.77 to 0.90) 0.000003 Death 708 765 0.92 (0.84 to 1.02) 0.11 Myocardial Re-infarction 352 508 0.69 (0.60 to 0.79) <0.001 Urgent Revascularization 213 286 0.74 (0.62 to 0.88) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 1199 1479 0.81 (0.75 to 0.87) <0.001 The beneficial effect of enoxaparin on the primary endpoint was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution.

Figure 1: Relative Risks of and Absolute Event Rates for the Primary Endpoint at 30 Days in Various Subgroups* * The primary efficacy endpoint was the composite of death from any cause or myocardial re-infarction in the first 30 days. The overall treatment effect of enoxaparin as compared to the unfractionated heparin (UFH) is shown at the bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of the treatment effect and the horizontal lines represent the 95% confidence intervals.

Fibrin-specific fibrinolytic agents included alteplase, tenecteplase, and reteplase. Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median: 3.2 hours). The beneficial effect of enoxaparin on the primary endpoint observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2). Figure 2: Kaplan-Meier Plot−Death or Myocardial Re-infarction at 30 Days−ITT Population There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in Figure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation. These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours.

There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study. The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group and 0.7% in the unfractionated heparin group.

The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin group (10.1%) as compared to the heparin group (12.2%). enoxaparin-fig6 enoxaparin-fig7

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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