FDA label 24697dc4-9dbd-4587-ae69-e34d38b27d80

WARNING: SPINAL/EPIDURAL HEMATOMAS 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 [see Warnings and Precautions (5.1) and Drug Interactions (7) ]. 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 [see Warnings and Precautions (5.1) and Drug Interactions (7) ].

5 WARNINGS AND PRECAUTIONS • Increased risk of hemorrhage: Use with caution in patients at risk ( 5.1 ) • Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal ( 5.2 ) • Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage ( 5.3 ) • History of heparin-induced thrombocytopenia: Use with caution ( 5.4 ) • Thrombocytopenia: Monitor thrombocytopenia closely ( 5.5 ) • Interchangeability with other heparins: Do not exchange with heparin or other LMWHs ( 5.6 ) • Pregnant women with mechanical prosthetic heart valves and their fetuses, may be at increased risk and may need more frequent monitoring and dosage adjustment ( 5.7 ) 5.1 Increased Risk of Hemorrhage Cases of epidural or spinal hematomas have been reported with the associated use of enoxaparin sodium injection and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative 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 [see Boxed Warning , Adverse Reactions (6.2) and Drug Interactions (7) ]. Enoxaparin sodium injection should be used 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 injection. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. 5.2 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 injection 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 IV/SC 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 [see Dosage and Administration (2.1) ]. 5.3 Use of Enoxaparin Sodium Injection with Concomitant Medical Conditions Enoxaparin sodium injection 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. 5.4 History of Heparin-Induced Thrombocytopenia Enoxaparin sodium injection should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia. 5.5 Thrombocytopenia Thrombocytopenia can occur with the administration of enoxaparin sodium injection. 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 injection, 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 injection, 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 injection should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4) ]. 5.6 Interchangeability with Other Heparins Enoxaparin sodium injection 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. 5.7 Pregnant Women with Mechanical Prosthetic Heart Valves The use of enoxaparin sodium injection for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. 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. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. 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 [see Use in Specific Populations (8.6) ]. 5.9 Laboratory Tests Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin sodium injection. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of enoxaparin sodium injection activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium injection in patients with significant renal impairment. If during enoxaparin sodium injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium injection [see Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience The following serious adverse reactions are also discussed in other sections of the labeling: • Spinal/epidural hematoma [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) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in 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 SC once daily to 30 mg SC 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 IV bolus followed by 1 mg/kg every 12 hours SC. Hemorrhage The incidence of major hemorrhagic complications during enoxaparin sodium injection treatment has been low. The following rates of major bleeding events have been reported during clinical trials with enoxaparin sodium injection [see Tables 2 to 7]. Table 2 Major Bleeding Episodes Following Abdominal and Colorectal Surgery 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. Dosing Regimen Indications Enoxaparin Sodium Injection 40 mg q.d. SC Heparin 5000 U q8h SC Abdominal Surgery n = 555 23 (4%) n = 560 16 (3%) Colorectal Surgery n = 673 28 (4%) n = 674 21 (3%) Table 3 Major Bleeding Episodes Following Hip or Knee Replacement Surgery 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. Dosing Regimen Indications Enoxaparin Sodium Injection 40 mg q.d. SC Enoxaparin Sodium Injection 30 mg q12h SC Heparin 15,000 U/24h SC Hip Replacement Surgery Without Extended Prophylaxis Enoxaparin sodium injection 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery. n = 786 31 (4%) n = 541 32 (6%) Hip Replacement Surgery With Extended Prophylaxis Peri-operative Period Enoxaparin sodium injection 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery. n = 288 4 (2%) Extended Prophylaxis Period Enoxaparin sodium injection 40 mg SC once a day for up to 21 days after discharge. n = 221 0 (0%) Knee Replacement Surgery Without Extended Prophylaxis n = 294 3 (1%) n = 225 3 (1%) NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative 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 injection patients versus 1.8% of the placebo patients. Table 4 Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During Acute Illness 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. Dosing Regimen Indications Enoxaparin Sodium Injection The rates represent major bleeding on study medication up to 24 hours after last dose. 20 mg q.d. SC Enoxaparin Sodium Injection 40 mg q.d. SC Placebo Medical Patients During Acute Illness n = 351 1 (<1%) n = 360 3 (<1%) n = 362 2 (<1%) Table 5 Major Bleeding Episodes in Deep Vein Thrombosis With or Without Pulmonary Embolism Treatment 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. Dosing Regimen 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 injection or standard heparin therapy and continuing for up to 90 days. Indication Enoxaparin Sodium Injection 1.5 mg/kg q.d. SC Enoxaparin Sodium Injection 1 mg/kg q12h SC Heparin aPTT Adjusted I.V. Therapy Treatment of DVT and PE n = 298 5 (2%) n = 559 9 (2%) n = 554 9 (2%) Table 6 Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction Dosing Regimen Indication Enoxaparin Sodium Injection The rates represent major bleeding on study medication up to 12 hours after dose. 1 mg/kg q12h SC Heparin aPTT Adjusted I.V. Therapy Unstable Angina and Non-Q-Wave MI 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. n = 1578 17 (1%) n = 1529 18 (1%) Table 7 Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction Indication Dosing Regimen Enoxaparin Sodium Injection The rates represent major bleeding (including ICH) up to 30 days Initial 30 mg IV bolus followed by 1 mg/kg q12h SC Heparin aPTT Adjusted IV Therapy Acute ST-Segment Elevation Myocardial Infarction - Major bleeding (including ICH) 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. - Intracranial hemorrhages (ICH) n = 10176 n (%) 211 (2.1) 84 (0.8) n = 10151 n (%) 138 (1.4) 66 (0.7) 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 injection. Similar significant increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin. 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 injection should be interpreted with caution. Local Reactions Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of enoxaparin sodium injection. Adverse Reactions in Patients Receiving Enoxaparin Sodium Injection for Prophylaxis or Treatment of DVT, PE: Other adverse reactions that were thought to be possibly or probably related to treatment with enoxaparin sodium injection, 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 injection group, are provided below [see Tables 8 to 11]. Table 8 Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium Injection-Treated Patients Undergoing Abdominal or Colorectal Surgery Adverse Reaction Dosing Regimen Enoxaparin Sodium Injection 40 mg q.d. SC n = 1228 % Heparin 5000 U q8h SC 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 Injection-Treated Patients Undergoing Hip or Knee Replacement Surgery Dosing Regimen Enoxaparin Sodium Injection 40 mg q.d. SC Enoxaparin Sodium Injection 30 mg q12h SC Heparin 15,000 U/24h SC Placebo q12h SC Peri-Operative Period n = 288 Data represent enoxaparin sodium injection 40 mg SC once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received enoxaparin sodium injection peri-operatively in an unblinded fashion in one clinical trial. % Extended Prophylaxis Period n = 131 Data represent enoxaparin sodium injection 40 mg SC 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. % n = 1080 % n = 766 % n = 115 % Adverse Reaction 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 Table 10 Adverse Reactions Occurring at ≥2% Incidence in Enoxaparin Sodium Injection-Treated Medical Patients With Severely Restricted Mobility During Acute Illness Adverse Reaction Dosing Regimen Enoxaparin Sodium Injection 40 mg q.d. SC n = 360 % Placebo q.d. SC 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 Injection-Treated Patients Undergoing Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism Adverse Reaction Dosing Regimen Enoxaparin Sodium Injection 1.5 mg/kg q.d. SC n = 298 % Enoxaparin Sodium Injection 1 mg/kg q12h SC n = 559 % Heparin aPTT Adjusted I.V. 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 Injection-Treated Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction Non-hemorrhagic clinical events reported to be related to enoxaparin sodium injection 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 SC enoxaparin sodium injection than in patients treated with IV heparin. Serious adverse events with enoxaparin sodium injection 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 injection group are provided below [see Table 12 ]. Table 12 Serious Adverse Events Occurring at ≥0.5% Incidence in Enoxaparin Sodium Injection-Treated Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction Adverse Event Dosing Regimen Enoxaparin Sodium Injection 1 mg/kg q12h SC n = 1578 n (%) Heparin aPTT Adjusted IV 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 Injection-Treated Patients with Acute ST-Segment Elevation Myocardial Infarction In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only adverse reaction that occurred at a rate of at least 0.5% in the enoxaparin sodium injection group was thrombocytopenia (1.5%). 6.2 Post-Marketing Experience There have been reports of epidural or spinal hematoma formation with concurrent use of enoxaparin sodium injection and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative 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), vesiculobullous rash, rare 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

<table ID="_RefID7B1E8BE05AB8468A90FF779AD0B08FA1" width="100%"> <caption>Table 2 Major Bleeding Episodes Following Abdominal and Colorectal Surgery<footnote ID="_RefID6DED223F8EE74514A3C8E4ECF794D03B">Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease &#x2265;2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major.</footnote> </caption> <col width="34%"/> <col width="33%"/> <col width="33%"/> <thead> <tr> <th align="left" styleCode="Lrule Toprule " valign="top"/> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Dosing Regimen</content> </th> </tr> <tr> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">Indications</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Enoxaparin Sodium Injection</content> </content> <content styleCode="bold">40 mg q.d. SC</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Heparin</content> </content> <content styleCode="bold">5000 U q8h SC</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Abdominal Surgery</content> </paragraph> </td> <td styleCode="Lrule Toprule Botrule " valign="top"> <paragraph>n = 555 23 (4%)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n = 560 16 (3%)</paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Colorectal Surgery</content> </paragraph> </td> <td styleCode="Botrule Lrule " valign="top"> <paragraph>n = 673 28 (4%)</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>n = 674 21 (3%)</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefID3B127329F49A4590977B308EE3428D26" width="100%"> <caption>Table 3 Major Bleeding Episodes Following Hip or Knee Replacement Surgery<footnote ID="_RefID2BC40C864EE04764BFE7E3B545A7157E">Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease &#x2265;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.</footnote> </caption> <col width="34%"/> <col width="22%"/> <col width="22%"/> <col width="22%"/> <thead> <tr> <th align="left" styleCode="Lrule Toprule " valign="top"/> <th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Dosing Regimen</content> </th> </tr> <tr> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">Indications</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Enoxaparin Sodium Injection</content> </content> <content styleCode="bold">40 mg q.d. SC</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Enoxaparin Sodium Injection</content> </content> <content styleCode="bold">30 mg q12h SC</content> </th> <th align="center" styleCode="Rrule Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Heparin</content> </content> <content styleCode="bold">15,000 U/24h SC</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hip Replacement Surgery Without Extended Prophylaxis</content> <footnote ID="_RefID0EAA369F2FFE4FF282A396FFC264F989">Enoxaparin sodium injection 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery.</footnote> </paragraph> </td> <td styleCode="Lrule Toprule Botrule " valign="top"/> <td styleCode="Lrule Toprule Botrule " valign="top"> <paragraph>n = 786 31 (4%)</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n = 541 32 (6%)</paragraph> </td> </tr> <tr> <td styleCode="Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hip Replacement Surgery With Extended Prophylaxis</content> </paragraph> </td> <td styleCode="Lrule Botrule " valign="top"/> <td styleCode="Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Lrule Botrule " valign="top"> <paragraph> Peri-operative Period<footnote ID="_RefID8F4DEA78D5CC41FC84CD601E8A8954C7">Enoxaparin sodium injection 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery.</footnote> </paragraph> </td> <td styleCode="Lrule Botrule " valign="top"> <paragraph>n = 288 4 (2%)</paragraph> </td> <td styleCode="Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Lrule Botrule " valign="top"> <paragraph> Extended Prophylaxis Period<footnote ID="_RefIDB221DDC6F19B44659D16EF0DB40268CA">Enoxaparin sodium injection 40 mg SC once a day for up to 21 days after discharge.</footnote> </paragraph> </td> <td styleCode="Lrule Botrule " valign="top"> <paragraph>n = 221 0 (0%)</paragraph> </td> <td styleCode="Lrule Botrule " valign="top"/> <td styleCode="Rrule Lrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Botrule Lrule " valign="top"> <paragraph> <content styleCode="bold">Knee Replacement Surgery Without Extended Prophylaxis</content> <footnoteRef IDREF="_RefID0EAA369F2FFE4FF282A396FFC264F989"/> </paragraph> </td> <td styleCode="Botrule Lrule " valign="top"/> <td styleCode="Botrule Lrule " valign="top"> <paragraph>n = 294 3 (1%)</paragraph> </td> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>n = 225 3 (1%)</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefIDA167BE6692264033B4A42F895806F88F" width="100%"> <caption>Table 4 Major Bleeding Episodes in Medical Patients With Severely Restricted Mobility During Acute Illness<footnote ID="_RefID0BDEF3CB3D2B4A858B9F5038933ECFA1">Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of &#x2265;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.</footnote> </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <thead> <tr> <th align="left" styleCode="Lrule Toprule " valign="top"/> <th align="center" colspan="3" styleCode="Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Dosing Regimen</content> </th> </tr> <tr> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">Indications</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Enoxaparin Sodium Injection</content> </content> <footnote ID="_RefIDFF3DE38714104FB3BD089E6D2659D928">The rates represent major bleeding on study medication up to 24 hours after last dose.</footnote> <content styleCode="bold">20 mg q.d. SC</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Enoxaparin Sodium Injection</content> </content> <footnoteRef IDREF="_RefIDFF3DE38714104FB3BD089E6D2659D928"/> <content styleCode="bold">40 mg q.d. SC</content> </th> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold"> <content styleCode="underline">Placebo</content> </content> <footnoteRef IDREF="_RefIDFF3DE38714104FB3BD089E6D2659D928"/> </th> </tr> </thead> <tbody> <tr> <td styleCode="Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Medical Patients During Acute Illness</content> </paragraph> </td> <td styleCode="Botrule Lrule Toprule " valign="top"> <paragraph>n = 351 1 (&lt;1%)</paragraph> </td> <td styleCode="Botrule Lrule Toprule " valign="top"> <paragraph>n = 360 3 (&lt;1%)</paragraph> </td> <td styleCode="Botrule Lrule Toprule " valign="top"> <paragraph>n = 362 2 (&lt;1%)</paragraph> </td> </tr> </tbody> </table>