Enoxaparin Sodium

1 INDICATIONS AND USAGE Enoxaparin sodium injection is a low molecular weight heparin (LMWH) indicated for: Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness ( 1.1 ) Inpatient treatment of acute DVT with or without pulmonary embolism ( 1.2 ) Outpatient treatment of acute DVT without pulmonary embolism ( 1.2 ) Prophylaxis of ischemic complications of unstable angina and non−Q-wave myocardial infarction (MI) ( 1.3 ) Treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI) ( 1.4 ) 1.1 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 [see Clinical Studies (14.1) ] 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 1.2 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 1.3 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. 1.4 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).

2 DOSAGE AND ADMINISTRATION See full prescribing information for dosing and administration information. ( 2 ) 2.1 Pretreatment Evaluation Evaluate all patients for a bleeding disorder before starting enoxaparin sodium treatment, unless treatment is urgently needed. 2.2 Adult Dosage Abdominal Surgery The recommended dose of enoxaparin sodium is 40 mg by subcutaneous injection once a day (with the initial dose given 2 hours prior to surgery) in patients undergoing abdominal surgery who are at risk for thromboembolic complications. The usual duration of administration is 7 to 10 days [see Clinical Studies (14.1) ]. Hip or Knee Replacement Surgery The recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by subcutaneous injection in patients undergoing hip or knee replacement surgery. Administer the initial dose 12 to 24 hours after surgery, provided that hemostasis has been established. The usual duration of administration is 7 to 10 days [see Clinical Studies (14.2) ]. A dose of enoxaparin sodium of 40 mg once a day subcutaneously may be considered for hip replacement surgery for up to 3 weeks. Administer the initial dose 12 (±3) hours prior to surgery. Medical Patients during Acute Illness The recommended dose of enoxaparin sodium is 40 mg once a day administered by subcutaneous injection for medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness. The usual duration of administration is 6 to 11 days [see Clinical Studies (14.3) ]. Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism The recommended dose of enoxaparin sodium injection is 1 mg/kg every 12 hours administered subcutaneously in patients with acute deep vein thrombosis without pulmonary embolism, who can be treated at home in an outpatient setting. The recommended dose of enoxaparin sodium injection is 1 mg/kg every 12 hours administered subcutaneously or 1.5 mg/kg once a day administered subcutaneously at the same time every day for inpatient (hospital) treatment of patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment). In both outpatient and inpatient (hospital) treatments, initiate warfarin sodium therapy when appropriate (usually within 72 hours of enoxaparin sodium injection). Continue enoxaparin sodium injection for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2 to 3). The average duration of administration is 7 days[see Clinical Studies (14.4) ]. Unstable Angina and Non-Q-Wave Myocardial Infarction The recommended dose of enoxaparin sodium injection is 1 mg/kg administered subcutaneously every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily) in patients with unstable angina or non–Q-wave myocardial infarction. Treat with enoxaparin sodium injection for a minimum of 2 days and continue until clinical stabilization. The usual duration of treatment is 2 to 8 days [see Warnings and Precautions (5.2) and Clinical Studies (14.5) ]. Treatment of Acute ST-Segment Elevation Myocardial Infarction The recommended dose of enoxaparin sodium injection is a single intravenous bolus of 30 mg plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg administered subcutaneously every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses) in patients with acute ST-segment elevation myocardial infarction. Reduce the dosage in patients ≥75 years of age [see Dosage and Administration (2.4)]. Unless contraindicated, administer aspirin to all patients as soon as they are identified as having STEMI and continue dosing with 75 to 325 mg once daily. When administered in conjunction with a thrombolytic (fibrin specific or non–fibrin specific), administer enoxaparin sodium injection between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. The usual duration of enoxaparin sodium injection therapy is 8 days or until hospital discharge. For patients managed with percutaneous coronary intervention (PCI), if the last enoxaparin sodium injection subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last enoxaparin sodium injection subcutaneous administration was given more than 8 hours before balloon inflation, administer an intravenous bolus of 0.3 mg/kg of enoxaparin sodium injection [see Warnings and Precautions (5.2) ]. 2.3 Dose Reduction for Patients with Severe Renal Impairment The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Table 1: Dosage Regimens for Patients with Severe Renal Impairment (creatinine clearance <30 mL/minute) Indication Dosage Regimen Prophylaxis in abdominal surgery 30 mg administered subcutaneously once daily Prophylaxis in hip or knee replacement surgery 30 mg administered subcutaneously once daily Prophylaxis in medical patients during acute illness 30 mg administered subcutaneously once daily Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered subcutaneously once daily Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered subcutaneously once daily Prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction, when concurrently administered with aspirin 1 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 aspirin 30 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 aspirin 1 mg/kg administered subcutaneously once daily (no initial bolus) Although no dose adjustment is recommended in patients with creatinine clearance 30 to 50 mL/min and creatinine clearance 50 to 80 mL/min, observe these patients for signs and symptoms of bleeding. 2.4 Recommended Dosage for Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial intravenous bolus . Initiate dosing with 0.75 mg/kg subcutaneously every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] . No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2) ] . 2.5 Administration Do not administer enoxaparin sodium injection by intramuscular injection. Administer enoxaparin sodium by subcutaneous injection only. Enoxaparin sodium injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration. Patients may self-inject by the subcutaneous route of administration only after their physicians determine that it is appropriate and with medical follow-up, as necessary. Provide proper training in subcutaneous injection technique before allowing self-injection (with or without the assistance of an injection device). Subcutaneous Injection Technique • Position patients in a supine position for enoxaparin sodium administration by deep subcutaneous injection. • Do not expel the air bubble from the prefilled syringes before the injection, to avoid the loss of drug. • Do not inject into skin that has bruises or scars. Do not inject through clothes. • Alternate injection sites between the left and right anterolateral and left and right posterolateral abdominal wall. • Introduce the whole length of the needle into a skin fold held between the thumb and forefinger; hold the skin fold throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection. Enoxaparin sodium prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection. Remove the prefilled syringe from the packaging by peeling at the arrow as directed on the lid. Do not remove by pulling on the plunger as this may damage the syringe. 1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If less than the full syringe volume is needed to administer the prescribed dose, eject syringe contents until the prescribed dose is left in the syringe. 2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B). 3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C). 4. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (see Figure D). 5. Immediately dispose of the syringe in the nearest sharps container (see Figure E). NOTE: The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient’s skin. Do not replace the needle shield after injection. The safety system should not be sterilized. Activation of the safety system may cause minimal splatter of fluid. For optimal safety, activate the system while orienting it downwards away from yourself and others. figure-a figure-b figure-c figure-d figure-e 2.6 Monitoring for Safety During therapy monitor complete blood counts including platelets and stool occult blood. Assess for signs and symptoms of bleeding. In patients with renal impairment anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium injection. 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 [see Clinical Pharmacology (12.3) ]. Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are not adequate for monitoring the anticoagulant effects of enoxaparin sodium injection.

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 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.

12.3 Pharmacokinetics Absorption Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after subcutaneous injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg clinically tested subcutaneous doses, respectively. Mean (n=46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg subcutaneously every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given subcutaneously, based on anti-Factor Xa activity is approximately 100% in healthy subjects. A 30 mg intravenous bolus immediately followed by a 1 mg/kg subcutaneously every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 84% of steady-state levels. Steady state is achieved on the second day of treatment. Enoxaparin pharmacokinetics appears to be linear over the recommended dosage ranges [see Dosage and Administration (2) ] . After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once-daily regimens in healthy volunteers, the steady state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice-daily regimen, the steady state is reached from day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range. Although not studied clinically, the 150 mg/mL concentration of enoxaparin sodium is projected to result in anticoagulant activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the same enoxaparin dose. When a daily 1.5 mg/kg subcutaneous injection of enoxaparin sodium was given to 25 healthy male and female subjects using a 100 mg/mL or a 200 mg/mL concentration the following pharmacokinetic profiles were obtained (see Table 13). Table 13: Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg Subcutaneously Once-Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations * Means ±SD at Day 5 and 90% Confidence Interval (CI) of the ratio † Median (range) Concentration Anti-Xa Anti-IIa Heptest aPTT A max (IU/mL or Δ sec) 100 mg/mL 1.37 (±0.23) 0.23 (±0.05) 105 (±17) 19 (±5) 200 mg/mL 1.45 (±0.22) 0.26 (±0.05) 111 (±17) 22 (±7) 90% CI 102%-110% 102%-111% t max † (h) 100 mg/mL 3 (2-6) 4 (2-5) 2.5 (2-4.5) 3 (2-4.5) 200 mg/mL 3.5 (2-6) 4.5 (2.5-6) 3.3 (2-5) 3 (2-5) AUC (ss) (h*IU/mL or h* Δ sec) 100 mg/mL 14.26 (±2.93) 1.54 (±0.61) 1321 (±219) 200 mg/mL 15.43 (±2.96) 1.77 (±0.67) 1401 (±227) 90% CI 105%-112% 103%-109% Distribution The volume of distribution of anti-Factor Xa activity is about 4.3 L. Elimination Following intravenous dosing, the total body clearance of enoxaparin is 26 mL/min. After intravenous dosing of enoxaparin labeled with the gamma-emitter, 99m Tc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single subcutaneous dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg subcutaneous once a day dose. Following subcutaneous dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min. Metabolism Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose. Special Populations Gender Apparent clearance and A max derived from anti-Factor Xa values following single subcutaneous dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the gender difference in these parameters has not been conclusively identified; however, body weight may be a contributing factor. Geriatric Apparent clearance and A max derived from anti-Factor Xa values following single and multiple subcutaneous dosing in geriatric subjects were close to those observed in young subjects. Following once a day subcutaneous dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC value [see Dosage and Administration (2.3) and Use in Specific Populations (8.5) ] . Renal Impairment A linear relationship between anti-Factor Xa plasma clearance and creatinine clearance at steady state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Factor Xa exposure represented by AUC, at steady state, is marginally increased in patients with creatinine clearance 50 to 80 mL/min and patients with creatinine clearance 30 to <50 mL/min after repeated subcutaneous 40 mg once-daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once-daily doses [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) ] . Hemodialysis In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.5 mg/kg intravenous dose. Hepatic Impairment Studies with enoxaparin in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown. Weight After repeated subcutaneous 1.5 mg/kg once-daily dosing, mean AUC of anti-Factor Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m 2 ) compared to non-obese control subjects, while A max is not increased. When non – weight-adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Factor Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects [see Use in Specific Populations (8.8)] . Pharmacokinetic Interaction No pharmacokinetic interaction was observed between enoxaparin and thrombolytics when administered concomitantly.