Enoxaparin Sodium

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, and other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium injection and neuraxial procedures is not known 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 HEMATOMAS See full prescribing information for complete boxed warning. 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, and other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium injection and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. ( 5.1 , 7 )

5 WARNINGS AND PRECAUTIONS Increased Risk of Hemorrhage: Monitor for signs of bleeding. ( 5.1 , 5.2 , 5.3 ) Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis. ( 5.4 ) Thrombocytopenia: Monitor platelet count closely. ( 5.5 ) Interchangeability with other heparins: Do not exchange with heparin or other LMWHs. ( 5.6 ) Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves: Women and their fetuses may be at increased risk. Monitor more frequently and adjust dosage as needed. ( 5.7 ) 5.1 Increased Risk of Hemorrhage Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of enoxaparin sodium injection 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 [see Boxed Warning , Adverse Reactions ( 6.2 ) and Drug Interactions ( 7 )] . To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium injection and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin sodium injection [see Clinical Pharmacology ( 12.3 )] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium injection 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 injection 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 injection. 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 sodium injection 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 injection 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 sodium injection is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin sodium injection (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day) [see Clinical Pharmacology ( 12.3 )] . 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), and 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 injection 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 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 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 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 [see Dosage and Administration ( 2.1 )] . 5.3 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. 5.4 Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis Enoxaparin sodium may cause heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia 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 [see Contraindications ( 4 )] . 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. 5.5 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. 5.6 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. 5.7 Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves Use of enoxaparin sodium injection for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves may result in valve thrombosis. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin sodium injection (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 sodium injection 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 )] .

6 ADVERSE REACTIONS 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 Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 5,000 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* * 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 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 ‡ n=288 4 (2%) – – Extended Prophylaxis Period § 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 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* * 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. 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%) 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. † 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. 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%) Table 6: Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction * 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. 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%) Table 7: Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction * 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. Dosing Regimen Indication Enoxaparin Sodium * Initial 30 mg intravenous bolus followed by 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Acute ST-Segment Elevation n=10176 n=10151 Myocardial Infarction n (%) n (%) Major bleeding (including ICH) † 211 (2.1) 138 (1.4) Intracranial hemorrhages (ICH) 84 (0.8) 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. 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 Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously n=1228 % Heparin 5,000 U q8h subcutaneously n=1234 % Adverse Reaction 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 * 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. 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 Extended Prophylaxis Period n=288* % n=131 † % 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-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 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 % Adverse Reaction 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 ecchymosis 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.

<table ID="_Reft2" width="100%"><caption>Table 2: Major Bleeding Episodes following Abdominal and Colorectal Surgery*</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> <content styleCode="bold">Indications</content></paragraph></td><td colspan="2" align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Dosing Regimen</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Enoxaparin Sodium</content></content> 40 mg daily subcutaneously </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Heparin</content></content> 5,000 U q8h subcutaneously </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Abdominal Surgery</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=555 23 (4%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=560 16 (3%) </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Colorectal Surgery</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=673 28 (4%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=674 21 (3%) </paragraph></td></tr></tbody></table>

<table ID="_Reft3" width="100%"><caption>Table 3: Major Bleeding Episodes following Hip or Knee Replacement Surgery*</caption><col width="33%"/><col width="33%"/><col width="17%"/><col width="17%"/><tfoot><tr><td align="left" colspan="4" valign="top">* 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.</td></tr><tr><td align="left" colspan="4" valign="top">^&#x2020;Enoxaparin sodium 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery </td></tr><tr><td align="left" colspan="4" valign="top">^&#x2021;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 </td></tr><tr><td align="left" colspan="4" valign="top">^&#xA7;Enoxaparin sodium 40 mg subcutaneously once a day for up to 21 days after discharge </td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Indications</content></paragraph></td><td colspan="3" align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Dosing Regimen</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Enoxaparin Sodium</content></content> 40 mg daily subcutaneously </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Enoxaparin Sodium</content></content> 30 mg q12h subcutaneously </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Heparin</content></content> 15,000 U/24h subcutaneously </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hip Replacement Surgery without Extended Prophylaxis</content>^&#x2020;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=786 31 (4%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=541 32 (6%) </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Hip Replacement Surgery with Extended Prophylaxis</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Peri-operative Period ^&#x2021;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=288 4 (2%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Extended Prophylaxis Period ^&#xA7;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=221 0 (0%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Knee Replacement Surgery without Extended Prophylaxis</content>^&#x2020;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=294 3 (1%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=225 3 (1%) </paragraph></td></tr></tbody></table>

<table ID="_Reft4" width="100%"><caption>Table 4: Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility during Acute Illness*</caption><col width="29%"/><col width="29%"/><col width="20%"/><col width="22%"/><tfoot><tr><td align="left" colspan="4" valign="top">* 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.</td></tr><tr><td align="left" colspan="4" valign="top">^&#x2020;The rates represent major bleeding on study medication up to 24 hours after last dose. </td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Indication</content></paragraph></td><td colspan="3" align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Dosing Regimen</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Enoxaparin Sodium</content></content>^&#x2020; 20 mg daily subcutaneously </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Enoxaparin Sodium</content></content>^&#x2020; 40 mg daily subcutaneously </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold"><content styleCode="underline">Placebo</content></content>^&#x2020;</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Medical Patients during Acute Illness</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=351 1 (&lt;1%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=360 3 (&lt;1%) </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>n=362 2 (&lt;1%) </paragraph></td></tr></tbody></table>