Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5. Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains a 1,6-anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is: <2000 daltons ≤20% 2000 to 8000 daltons ≥68% >8000 daltons ≤18% STRUCTURAL FORMULA R1 = H or SO3Na and R2 = SO3Na or COCH3 R1 = H or SO3Na and R2 = SO3Na or COCH3 R X X = Percent of polysaccharide chain containing 1,6-anhydro derivative on the reducing end =15 to 25% n=0 to 20 100-X H n=1 to 21 Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection. Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection. The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative . Chemical Structure Chemical Structure

Lovenox 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 • Inpatient treatment of acute DVT with or without pulmonary embolism • Outpatient treatment of acute DVT without pulmonary embolism • Prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction (MI) • Treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI) 1.1 Prophylaxis of Deep Vein Thrombosis Lovenox ® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): • in patients undergoing abdominal surgery who are at risk for thromboembolic complications • in patients undergoing hip replacement surgery, during and following hospitalization • in patients undergoing knee replacement surgery • in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness 1.2 Treatment of Acute Deep Vein Thrombosis Lovenox 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 Lovenox is indicated for the prophylaxis of ischemic complications of unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin

Treatment of Acute ST-Segment Elevation Myocardial Infarction Lovenox, 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).

Lovenox is a clear, colorless to pale-yellow solution available in two concentrations. 100 mg/mL Concentration – Single-Dose Prefilled Syringes 30 mg/0.3 mL, 40 mg/0.4 mL – Single-Dose Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL – Multiple-Dose Vial 300 mg/3 mL 150 mg/mL Concentration – Single-Dose Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL 100 mg/mL concentration: • Single-dose prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL • Single-dose graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL • Multiple-dose vial: 300 mg/3 mL 150 mg/mL concentration: • Single-dose graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL

See full prescribing information for dosing and administration information

Pretreatment Evaluation Evaluate all patients for a bleeding disorder before starting Lovenox treatment, unless treatment is urgently needed

Adult Dosage Abdominal Surgery The recommended dose of Lovenox 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 . Hip or Knee Replacement Surgery The recommended dose of Lovenox 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 . A dose of Lovenox 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 Lovenox 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 . Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism The recommended dose of Lovenox 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 Lovenox 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 Lovenox). Continue Lovenox 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 . Unstable Angina and Non–Q-Wave Myocardial Infarction The recommended dose of Lovenox 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 Lovenox for a minimum of 2 days and continue until clinical stabilization. The usual duration of treatment is 2 to 8 days . Treatment of Acute ST-Segment Elevation Myocardial Infarction The recommended dose of Lovenox 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 . 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 Lovenox between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. The usual duration of Lovenox therapy is 8 days or until hospital discharge. For patients managed with percutaneous coronary intervention (PCI), if the last Lovenox subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox subcutaneous administration was given more than 8 hours before balloon inflation, administer an intravenous bolus of 0.3 mg/kg of Lovenox

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 . 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 frequently for signs and symptoms of bleeding

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) . No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired

Administration Do not administer Lovenox by intramuscular injection. Administer Lovenox by intravenous or subcutaneous injection only. Lovenox 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. Use a tuberculin syringe or equivalent when using Lovenox multiple-dose vials to assure withdrawal of the appropriate volume of drug. 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 Lovenox 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. Lovenox 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 . 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. Figure A 2. 3. Inject using standard technique, pushing the plunger to the bottom of the syringe . Figure B 4. 5. Remove the syringe from the injection site keeping your finger on the plunger rod . Figure C 6. 7. 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 . Figure D 8. 9. Immediately dispose of the syringe in the nearest sharps container . Figure E 10. 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 Intravenous (Bolus) Injection Technique Use the multiple-dose vial for intravenous injections. Administer Lovenox through an intravenous line. Do not mix or coadminister Lovenox with other medications. Flush the intravenous access device with a sufficient volume of saline or dextrose solution prior to and following the intravenous bolus administration of Lovenox, to prevent mixing of drugs. Lovenox is compatible with normal saline solution (0.9%) or 5% dextrose in water

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 Lovenox. If during Lovenox therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of Lovenox . Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are not adequate for monitoring the anticoagulant effects of Lovenox.

• Increased Risk of Hemorrhage: Monitor for signs of bleeding. ( 5.1 , 5.2 , 5.3 ) • Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis. • Thrombocytopenia: Monitor platelet count closely. • Interchangeability with other heparins: Do not exchange with heparin or other LMWHs. • 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. 5.1 Increased Risk of Hemorrhage Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of Lovenox and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of postoperative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity . To reduce the potential risk of bleeding associated with the concurrent use of Lovenox and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of Lovenox . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of Lovenox 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 Lovenox 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 Lovenox. 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 Lovenox 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 Lovenox 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 Lovenox is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of Lovenox (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day) . Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), 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 Lovenox 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 Lovenox. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site

Increased Risk of Bleeding following Percutaneous Coronary Revascularization Procedures To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non–Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between Lovenox 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 Lovenox. If the treatment with Lovenox is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation

Increased Risk of Bleeding in Patients with Concomitant Medical Conditions Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage

Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis Lovenox 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 Lovenox in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated . Circulating antibodies may persist for several years. Only use Lovenox 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 Lovenox in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered

Thrombocytopenia Thrombocytopenia can occur with the administration of Lovenox. Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given Lovenox, 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 Lovenox, 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 , Lovenox should be discontinued

Interchangeability with other Heparins Lovenox cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use

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

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative Lovenox multiple-dose vials are not approved for use in neonates or infants. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs, including Lovenox multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Lovenox multiple-dose vials contain 15 mg of benzyl alcohol per mL) . Because benzyl alcohol may cross the placenta, if anticoagulation with Lovenox is needed during pregnancy, use the preservative-free formulations where possible .

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If coadministration is essential, conduct close clinical and laboratory monitoring . Discontinue agents which may enhance hemorrhage risk prior to initiation of Lovenox or conduct close clinical and laboratory monitoring. ( 2.6 , 7 )