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 n 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 …

3 DOSAGE FORMS AND STRENGTHS Enoxaparin Sodium Injection USP 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 150 mg/mL Concentration - Single-Dose Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL 100 mg/mL concentration ( 3 ): 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 150 mg/mL concentration ( 3 ): Single-dose graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL

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

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 maj …

7 DRUG INTERACTIONS Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium injection therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring [see Warnings and Precautions ( 5.1 )] . Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium injection or conduct close clinical and laboratory monitoring. ( 2.6 , 7 )

8 USE IN SPECIFIC POPULATIONS Severe Renal Impairment: Adjust dose for patients with creatinine clearance 30 kg/m 2 ) has not been fully determined and there is no consensus for dose adjustment. Observe these patients carefully for signs and symptoms of thromboembolism.

12.1 Mechanism of Action Enoxaparin is a low molecular weight heparin which has antithrombotic properties.

11 DESCRIPTION Enoxaparin sodium injection, USP is a sterile aqueous solution containing enoxaparin sodium USP, 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 an 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: 8000 daltons ≤18% STRUCTURAL FORMULA *X = Percent of polysaccharide chain containing 1,6-anhydro derivative on the reducing end R X*=15 to 25% n=0 to 20 100-X H n=1 to 21 Enoxaparin sodium injection, USP 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. Enoxaparin sodium injection, USP 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 enoxaparin sodium injection, USP prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. [see Dosage and Administration (2) and How Supplied/Storage and Handling (16) ] . enoxaparin-str1 enoxaparin-str2

10 OVERDOSAGE Accidental overdosage following administration of enoxaparin sodium injection may lead to hemorrhagic complications. Injected enoxaparin sodium injection may be largely neutralized by the slow intravenous injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of enoxaparin sodium injected: 1 mg protamine sulfate should be administered to neutralize 1 mg enoxaparin sodium injection, if enoxaparin sodium injection was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of enoxaparin may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.

16 HOW SUPPLIED/STORAGE AND HANDLING Enoxaparin sodium injection, USP is available in two concentrations (see Tables 26 and 27). Table 26: 100 mg/mL Concentration * Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium injection, USP 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection. † Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each enoxaparin sodium injection, USP prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x 1/2-inch needle. Dosage Unit / Strength * Anti-Xa Activity † Package Size (per carton) Label Color NDC Single-Dose Prefilled Syringes ‡ 30 mg/0.3 mL 3000 IU 10 syringes Medium Blue 72603-165-10 40 mg/0.4 mL 4000 IU 10 syringes Yellow 72603-175-10 Single-Dose Graduated Prefilled Syringes ‡ 60 mg/0.6 mL 6000 IU 10 syringes Orange 72603-185-10 80 mg/0.8 mL 8000 IU 10 syringes Red 72603-195-10 100 mg/1 mL 10,000 IU 10 syringes Black 72603-205-10 Table 27: 150 mg/mL Concentration * Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium injection, USP 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection. † Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each enoxaparin sodium injection, USP graduated prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x 1/2-inch needle. Dosage Unit / Strength * Anti-Xa Activity † Package Size (per carton) Syringe Label Color NDC Single-Dose Graduated Prefilled Syringes ‡ 120 mg/0.8 mL 12,000 IU 10 syringes Purple 72603-215-10 150 mg/1 mL 15,000 IU 10 syringes Navy Blue 72603-225-10 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original carton or packaging until ready to use.