Enoxaparin Sodium

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 Injection treatment, unless treatment is urgently needed.

2.2 Adult Dosage Abdominal Surgery The recommended dose of Enoxaparin Sodium Injection 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 Injection 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 Injection 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 Injection 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 frequently 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 Injection by intravenous or 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. Use a tuberculin syringe or equivalent when using Enoxaparin Sodium Injection 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 Enoxaparin Sodium Injection 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 Injection 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 blister packaging by peeling the lid completely off at the arrow as directed on the blister. Then gently lift the syringe straight up by grasping either the middle of the syringe or the needle guard. Do not remove by pulling on the plunger as this may damage the syringe. Remove needle cover by pulling straight off of needle. DO NOT twist the needle cover or touch the needle/plunger. If required, adjust dose prior to injecting into the patient. Administer by subcutaneous (SC) injection as instructed by your pharmacist or health- care provider. Push the plunger with slow constant pressure while grasping the finger flanges. Push the plunger all the way down as far as it will go to inject entire dose. NOTE: The passive needle guard will not activate unless the entire dose is injected. Remove needle from injection site, then let go of the plunger and allow syringe to move up until the entire needle is guarded. Keep fingers in place on flanges. Dispose of syringe / needle guard assembly in approved sharps container. NOTE: The safety system should only activate 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. Intravenous (Bolus) Injection Technique Use the multiple-dose vial for intravenous injections. Administer Enoxaparin Sodium Injection through an intravenous line. Do not mix or coadminister Enoxaparin Sodium Injection 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 Enoxaparin Sodium Injection, to prevent mixing of drugs. Enoxaparin Sodium Injection is compatible with normal saline solution (0.9%) or 5% dextrose in water. instruction1 instruction2 instruction3 instruction4 instruction5 instruction6 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 Injection [ 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.

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 <30mL/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 Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.

5.4 Risk of Heparin-Induced Thrombocytopenia with or without Thrombosis Enoxaparin Sodium Injection 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 Injection 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 Injection 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 Injection 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 Injection. Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given Enoxaparin Sodium Injection, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm 3 occurred at a rate of 0.1% in patients given Enoxaparin Sodium Injection, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3 , Enoxaparin Sodium Injection should be discontinued.

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

5.7 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/warfin 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 ) ].

5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative Enoxaparin Sodium Injection 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 Enoxaparin Sodium Injection 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 (Enoxaparin Sodium Injection multiple-dose vials contain 15 mg of benzyl alcohol per mL) [ see Use in Specific Populations ( 8.4 ) ]. Because benzyl alcohol may cross the placenta, if anticoagulation with Enoxaparin Sodium Injection is needed during pregnancy, use the preservative-free formulations where possible [ see Use in Specific Populations ( 8.1 ) ].

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 Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are also discussed in other sections of the labeling:

• Spinal/epidural hematoma [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ]
• Increased Risk of Hemorrhage [ see Warnings and Precautions ( 5.1 ) ]
• Thrombocytopenia [ see Warnings and Precautions ( 5.5 ) ] 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 Injection. 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 Injection 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 Injection 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 Injection (see Tables 2 to 7). Table 2 Major Bleeding Episodes Following Abdominal and Colorectal Surgery Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. Dosing Regimen Indications Enoxaparin Sodium Injection 40 mg 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%) Table 3 Major Bleeding Episodes Following Hip or Knee Replacement Surgery Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, Intraocular hemorrhages were also considered major hemorrhages. Dosing Regimen Indications Enoxaparin Sodium Injection 40 mg daily subcutaneously Enoxaparin Sodium Injection 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Hip Replacement Surgery without Extended Prophylaxis Enoxaparin Sodium Injection 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery. - n = 786 31 (4%) n = 541 32 (6%) Hip Replacement Surgery with Extended Prophylaxis - - - Peri-operative Period Enoxaparin Sodium Injection 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery. n = 288 4 (2%) - - Extended Prophylaxis Period Enoxaparin Sodium Injection 40 mg subcutaneously once a day for up to 21 days after discharge. n = 221 0 (0%) - - Knee Replacement Surgery without Extended Prophylaxis - n = 294 3 (1%) n = 225 3 (1%) 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 Injection patients versus 1.8% of the placebo patients. Table 4 Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility During Acute Illness Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) if the hemorrhage caused a decrease in hemoglobin of 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial. Dosing Regimen Indications Enoxaparin Sodium Injection The rates represent major bleeding on study medication up to 24 hours after last dose. 20 mg daily subcutaneously Enoxaparin Sodium Injection † 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. Dosing Regimen All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing within 72 hours of Enoxaparin Sodium Injection or standard heparin therapy and continuing for up to 90 days. Indication Enoxaparin Sodium Injection 1.5 mg/kg daily subcutaneously Enoxaparin Sodium Injection 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 Dosing Regimen Indications Enoxaparin Sodium Injection The rates represent major bleeding on study medication up to 12 hours after dose. 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Unstable Angina and Non-Q-Wave MI Aspirin therapy was administered concurrently (100 to 325 mg per day). Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease by ≥3 g/dL or transfusion of 2 or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages were always considered major. n = 1578 17 (1%) n = 1529 18 (1%) Table 7 Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction Dosing Regimen Indication Enoxaparin Sodium Injection The rates represent major bleeding (including ICH) up to 30 days Initial 30 mg intravenous bolus followed by 1 mg/kg q12h subcutaneously Heparin * aPTT Adjusted Intravenous Therapy Acute ST-Segment Elevation Myocardial Infarction n = 10176 n (%) n = 10151 n (%) Major bleeding (including ICH) Bleedings were considered major if the hemorrhage caused a significant clinical event associated with hemoglobin decrease by ≥5 g/dL. ICH were always considered major. 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 Injection. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like Enoxaparin Sodium Injection should be interpreted with caution. Local Reactions Local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection of Enoxaparin Sodium Injection. Adverse Reactions in Patients Receiving Enoxaparin Sodium Injection for Prophylaxis or Treatment of DVT, PE Other adverse reactions that were thought to be possibly or probably related to treatment with Enoxaparin Sodium Injection, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Enoxaparin Sodium Injection group, are provided below (see Tables 8 to 11). Table 8 Adverse Reactions Occurring at 2% Incidence in Enoxaparin Sodium Injection-Treated Patients Undergoing Abdominal or Colorectal Surgery Dosing Regimen Enoxaparin Sodium Injection 40 mg daily subcutaneously n = 1228 % Heparin 5000 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 Injection-Treated Patients Undergoing Hip or Knee Replacement Surgery Dosing Regimen Enoxaparin Sodium Injection 40 mg daily subcutaneously Enoxaparin Sodium Injection 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Placebo q12h subcutaneously Peri-operative Period Extended Prophylaxis Period n = 288 Data represent Enoxaparin Sodium Injection 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received Enoxaparin Sodium Injection peri-operatively in an unblinded fashion in one clinical trial. % n = 131 Data represent Enoxaparin Sodium Injection 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. % n = 1080 % n = 766 % n = 115 % Adverse Reaction Severe Total Severe Total Severe Total Severe Total Severe Total Fever 0 8 0 0 <1 5 <1 4 0 3 Hemorrhage <1 13 0 5 <1 4 1 4 0 3 Nausea - - - - <1 3 <1 2 0 2 Anemia 0 16 0 <2 <1 2 2 5 <1 7 Edema - - - - <1 2 <1 2 0 2 Peripheral edema 0 6 0 0 <1 3 <1 4 0 3 Table 10 Adverse Reactions Occurring at 2% Incidence in Enoxaparin Sodium Injection-Treated Medical Patients with Severely Restricted Mobility During Acute Illness Adverse Reaction Dosing Regimen Enoxaparin Sodium Injection 40 mg 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 Injection-Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism Adverse Event Dosing Regimen Enoxaparin Sodium Injection 1.5 mg/kg daily subcutaneously n = 298 % Enoxaparin Sodium Injection 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 Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial Infarction Non-hemorrhagic clinical events reported to be related to Enoxaparin Sodium Injection therapy occurred at an incidence of ≤ 1%. Non-major hemorrhagic events, primarily injection site ecchymosis and hematomas, were more frequently reported in patients treated with subcutaneous Enoxaparin Sodium Injection than in patients treated with intravenous heparin. Serious adverse events with Enoxaparin Sodium Injection or heparin in a clinical trial in patients with unstable angina or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Enoxaparin Sodium Injection group are provided below (see Table 12). Table 12 Serious Adverse Events Occurring at ≥ 0.5% Incidence in Enoxaparin Sodium Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial Infarction Adverse Event Dosing Regimen Enoxaparin Sodium Injection 1 mg/kg q12h 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 Injection-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 Injection. 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 Injection 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, rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis [ see Warnings and Precautions ( 5.5 ) ] have been reported. Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined. Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported. Osteoporosis has also been reported following long-term therapy.

• Severe Renal Impairment: Adjust dose for patients with creatinine clearance <30 mL/min. ( 2.3 , 8.7 )
• Geriatric Patients: Monitor for increased risk of bleeding. ( 8.5 )
• Low-Weight Patients: Observe for signs of bleeding. ( 8.8 )

8.1 Pregnancy Risk Summar y Placental transfer of enoxaparin was observed in the animal studies. Human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin does not increase the risk of major developmental abnormalities ( see Data ). Based on animal data, Enoxaparin Sodium Injection is not predicted to increase the risk of major developmental abnormalities ( see Data ). Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [ see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.6 ) ]. Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving Enoxaparin Sodium Injection should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Boxed Warning] . Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if Enoxaparin Sodium Injection is administered during pregnancy. It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of Enoxaparin Sodium Injection affect the safety and the efficacy of the drug during pregnancy. Cases of “gasping syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-405 mg/kg/day). The multiple-dose vial of Enoxaparin Sodium Injection contains 15 mg benzyl alcohol per 1 mL as a preservative [ see Warnings and Precautions ( 5.8 ) ]. Data Human Data There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used Enoxaparin Sodium Injection during pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. There have been postmarketing reports of fetal death when pregnant women received Enoxaparin Sodium Injection. Causality for these cases has not been determined. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. A clinical study using Enoxaparin Sodium Injection in pregnant women with mechanical prosthetic heart valves has been conducted [ see Warnings and Precautions ( 5.7 ) ]. Animal data Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.2 Lactation Risk Summary It is unknown whether Enoxaparin Sodium Injection is excreted in human milk. In lactating rats, the passage of enoxaparin or its metabolites in the milk is very limited. There is no information available on the effect of enoxaparin or its metabolites on the breastfed child, or on the milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Enoxaparin Sodium Injection and any potential adverse effects on the breastfed child from Enoxaparin Sodium Injection or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness of Enoxaparin Sodium Injection in pediatric patients have not been established. Enoxaparin Sodium Injection is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Enoxaparin Sodium Injection multiple-dose vials contain 15 mg/mL of benzyl alcohol (at the dose of 1.5 mg/kg twice a day, benzyl alcohol exposure in patients is 0.45 mg/kg daily) [ see Warnings and Precautions ( 5.8 ) ].

8.5 Geriatric Use Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction Over 2800 patients, 65 years and older, have received Enoxaparin Sodium Injection in clinical trials. The efficacy of Enoxaparin Sodium Injection in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Enoxaparin Sodium Injection were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Enoxaparin Sodium Injection was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Enoxaparin Sodium Injection-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Enoxaparin Sodium Injection. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Enoxaparin Sodium Injection between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Enoxaparin Sodium Injection should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered [ see Warnings and Precautions ( 2.6 ) and Clinical Pharmacology ( 12.3 ) ] . Treatment of Acute ST-Segment Elevation Myocardial Infarction In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n = 9015). Patients ≥75 years of age did not receive a 30 mg intravenous bolus prior to the normal dosage regimen and had their subcutaneous dose adjusted to 0.75 mg/kg every 12 hours [ see Dosage and Administration ( 2.4 ) ] . The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).

8.6 Patients with Mechanical Prosthetic Heart Valves The use of Enoxaparin Sodium Injection has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received Enoxaparin Sodium Injection for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism [ see Warnings and Precautions ( 5.7 ) ].

8.7 Renal Impairment In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with creatinine clearance 30 to <50 mL/min and creatinine clearance 50 to 80 mL/min [ see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 ) ]. In patients with renal failure, treatment with Enoxaparin Sodium Injection has been associated with the development of hyperkalemia [ see Adverse Reactions ( 6.2 ) ].

8.8 Low-Weight Patients An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). Observe low-weight patients frequently for signs and symptoms of bleeding [ see Clinical Pharmacology ( 12.3 ) ] .

8.9 Obese Patients Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses of Enoxaparin Sodium Injection in obese patients (BMI >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.

12.2 Pharmacodynamics In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ±SD, 14.0±3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean ±SD, 1.22±0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered subcutaneously every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n=1607). A 30 mg intravenous bolus immediately followed by a 1 mg/kg subcutaneous administration resulted in aPTT postinjection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.

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 appear 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 Subcutaneous Once-Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations Concentration Anti-Xa Anti-IIa Heptest aPTT A max (IU/mL or 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 Median (range) (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 Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio IU/mL or h † 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 ( 2.4 ) 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 ( 2.3 ) 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 Sodium Injection 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 in teraction No pharmacokinetic interaction was observed between Enoxaparin Sodium Injection and thrombolytics when administered concomitantly.

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 appear 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 Subcutaneous Once-Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations Concentration Anti-Xa Anti-IIa Heptest aPTT A max (IU/mL or 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 Median (range) (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 Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio IU/mL or h † 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 ( 2.4 ) 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 ( 2.3 ) 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 Sodium Injection 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 in teraction No pharmacokinetic interaction was observed between Enoxaparin Sodium Injection and thrombolytics when administered concomitantly.