FDA Label for Enoxaparin Sodium

Warning: Spinal/Epidural Hematomas

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• Use of indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
• Optimal timing between the administration of enoxaparin sodium and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].

1.1 Prophylaxis Of Deep Vein Thrombosis

Enoxaparin sodium 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 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 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, 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

All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring enoxaparin sodium activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].

For subcutaneous use, enoxaparin sodium should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

Enoxaparin sodium is not intended for intramuscular administration.

2.2 Renal Impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

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)].

2.3 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)].

2.4 Administration

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.

The use of a tuberculin syringe or equivalent is recommended when using enoxaparin sodium multiple-dose vials to assure withdrawal of the appropriate volume of drug.

Enoxaparin sodium must not be administered by intramuscular injection. Enoxaparin sodium is intended for use under the guidance of a physician.

For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.

3 Dosage Forms And Strengths

Enoxaparin sodium injection is available in two concentrations.

3.1 100 Mg/Ml Concentration

3.2 150 Mg/Ml Concentration

4 Contraindications

• 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
• Known hypersensitivity to benzyl alcohol (which is in only the multidose formulation of enoxaparin sodium) [see Warnings and Precautions (5.8)]

5.1 Increased Risk Of Hemorrhage

Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of enoxaparin sodium 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 and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin 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 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. 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 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 dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30 mL/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin sodium (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), 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 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. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

5.2 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 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. 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 Use Of Enoxaparin Sodium With Concomitant Medical Conditions

Enoxaparin sodium should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.

5.4 History Of Heparin-Induced Thrombocytopenia

Use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated [see Contraindications (4)]. Circulating antibodies may persist for several years.

In patients with a history of HIT, enoxaparin sodium should only be used if more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present. Because HIT may still occur in these circumstances, the decision to use enoxaparin sodium in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.

5.5 Thrombocytopenia

Thrombocytopenia can occur with the administration of enoxaparin sodium.

Moderate thrombocytopenia (platelet counts between 100,000/mm³ and 50,000/mm³) occurred at a rate of 1.3% in patients given enoxaparin sodium, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials.

Platelet counts less than 50,000/mm³ occurred at a rate of 0.1% in patients given enoxaparin sodium, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm³, enoxaparin sodium should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4)].

5.6 Interchangeability With Other Heparins

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

5.7 Pregnant Women With Mechanical Prosthetic Heart Valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (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. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. No patients in the heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin 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 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 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 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 is needed during pregnancy, use the preservative-free formulations where possible [see Use in Specific Populations (8.1)].

5.9 Laboratory Tests

Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin sodium. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of enoxaparin sodium activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium in patients with significant renal impairment. If during enoxaparin sodium therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium [see Clinical Pharmacology (12.3)].

6.1 Clinical Trials Experience

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)]

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of enoxaparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been reports of epidural or spinal hematoma formation with concurrent use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had a postoperative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis.

Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis [see Warnings and Precautions (5.5)] have been reported.

Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.

Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported.

Osteoporosis has also been reported following long-term therapy.

7 Drug Interactions

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium 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 [see Warnings and Precautions (5.9)].

8.3 Nursing Mothers

It is not known whether enoxaparin sodium is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from enoxaparin sodium, a decision should be made whether to discontinue nursing or discontinue enoxaparin sodium, taking into account the importance of enoxaparin sodium to the mother and the known benefits of nursing.

8.4 Pediatric Use

Safety and effectiveness of enoxaparin sodium in pediatric patients have not been established.

Enoxaparin sodium 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 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)].

8.6 Patients With Mechanical Prosthetic Heart Valves

The use of enoxaparin sodium 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 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 moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia [see Adverse Reactions (6.2)].

8.8 Hepatic Impairment

The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.

8.9 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). All such patients should be observed carefully for signs and symptoms of bleeding [see Clinical Pharmacology (12.3)].

8.10 Obese Patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses of enoxaparin sodium in obese patients (BMI >30 kg/m²) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

10 Overdosage

Accidental overdosage following administration of enoxaparin sodium may lead to hemorrhagic complications. Injected enoxaparin sodium 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, if enoxaparin sodium 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 sodium 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.

11 Description

Enoxaparin sodium injection 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 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:

             <2000 daltons             ≤20%

             2000 to 8000 daltons  ≥68%

             >8000 daltons             ≤18%
 

STRUCTURAL FORMULA

Enoxaparin sodium injection 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 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 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 [see Dosage and Administration (2) and How Supplied (16)].

12.1 Mechanism Of Action

Enoxaparin sodium 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous doses up to 20 mg/kg/day or 141 mg/m²/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or 78 mg/m²/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of 1.8 m²).

13.2 Animal Toxicology And/Or Pharmacology

A single subcutaneous dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility, dyspnea, cyanosis, and coma.

13.3 Reproductive And Developmental Toxicology

Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 30 mg/kg/day corresponding to 211 mg/m²/day and 410 mg/m²/day in rats and rabbits respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.

14.1 Prophylaxis Of Deep Vein Thrombosis Following Abdominal Surgery In Patients At Risk For Thromboembolic Complications

Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).

In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Enoxaparin sodium 40 mg subcutaneously, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours subcutaneously in reducing the risk of DVT. The efficacy data are provided below (see Table 14).

In a second double-blind, parallel group study, enoxaparin sodium 40 mg subcutaneously once a day was compared to heparin 5000 U every 8 hours subcutaneously in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below (see Table 15).

14.2 Prophylaxis Of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery

Enoxaparin sodium has been shown to reduce the risk of postoperative deep vein thrombosis (DVT) following hip or knee replacement surgery.

In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below (see Table 16).

A double-blind, multicenter study compared three dosing regimens of enoxaparin sodium in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below (see Table 17).

There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, enoxaparin sodium 30 mg every 12 hours subcutaneously was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for enoxaparin sodium compared to placebo. The efficacy data are provided below (see Table 18).

Additionally, in an open-label, parallel group, randomized clinical study, enoxaparin sodium 30 mg every 12 hours subcutaneously in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours subcutaneously. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was lower for enoxaparin sodium compared to heparin.

Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin sodium 40 mg subcutaneously, initiated up to 12 hours prior to surgery for the prophylaxis of postoperative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo. The efficacy data are provided below (see Table 19).

In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with enoxaparin sodium 40 mg subcutaneously, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n=131) once a day subcutaneously or to placebo (n=131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, with a statistically significant difference in both total DVT (enoxaparin sodium 21 [16%] versus placebo 45 [34%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6%] versus placebo 28 [21%]; p=<0.001).

14.3 Prophylaxis Of Deep Vein Thrombosis In Medical Patients With Severely Restricted Mobility During Acute Illness

In a double blind multicenter, parallel group study, enoxaparin sodium 20 mg or 40 mg once a day subcutaneously was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder (acute lumbar or sciatic pain, vertebral compression [due to osteoporosis or tumor], acute arthritic episodes of the lower extremities). A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a day subcutaneously, enoxaparin sodium significantly reduced the incidence of DVT as compared to placebo. The efficacy data are provided below (see Table 20).

At approximately 3 months following enrollment, the incidence of venous thromboembolism remained lower in the enoxaparin sodium 40 mg treatment group versus the placebo treatment group.

14.4 Treatment Of Deep Vein Thrombosis With Or Without Pulmonary Embolism

In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium 1.5 mg/kg once a day subcutaneously, (ii) enoxaparin sodium 1 mg/kg every 12 hours subcutaneously, or (iii) heparin intravenous bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below (see Table 21).

Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to enoxaparin sodium or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated comorbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY enoxaparin sodium patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days. Enoxaparin sodium was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below (see Table 22).

14.5 Prophylaxis Of Ischemic Complications In Unstable Angina And Non–Q-Wave Myocardial Infarction

In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non–Q-wave myocardial infarction were randomized to either enoxaparin sodium 1 mg/kg every 12 hours subcutaneously or heparin intravenous bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25 to 94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for enoxaparin sodium compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below (see Table 23).

The combined incidence of death or myocardial infarction at all time points was lower for enoxaparin sodium compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below (see Table 24).

In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for enoxaparin sodium versus heparin (32.0% vs 35.7%).

Urgent revascularization procedures were performed less frequently in the enoxaparin sodium group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p=0.047).

14.6 Treatment Of Acute St-Segment Elevation Myocardial Infarction

In a multicenter, double-blind, double-dummy, parallel-group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either enoxaparin sodium or unfractionated heparin.

Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an intravenous bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The intravenous infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg subcutaneous dose followed by a subcutaneous injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the intravenous bolus was not given and the subcutaneous dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The subcutaneous injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours.

When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last subcutaneous administration was less than 8 hours before balloon inflation, intravenous bolus of 0.3 mg/kg enoxaparin if the last subcutaneous administration was more than 8 hours before balloon inflation.

All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase.

Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%.

The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.

The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) (see Table 25).

16 How Supplied/Storage And Handling

Enoxaparin sodium injection is available in two concentrations (see Tables 26 and 27).

17 Patient Counseling Information

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, advise them to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. Instruct the patient to seek immediate medical attention if any of these symptoms occur.

Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. When possible, discontinue their use prior to enoxaparin sodium therapy. Monitor the patient's clinical and laboratory status if coadministration is essential [see Drug Interactions (7)].

Inform patients:

• of the instructions for injecting enoxaparin sodium if they continue enoxaparin sodium therapy after discharge from the hospital.
• that it may take them longer than usual to stop bleeding.
• that they may bruise and/or bleed more easily when they use enoxaparin sodium.
• that they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions (5.1, 5.5)].
• that risks are associated with the use of benzyl alcohol, a preservative in enoxaparin sodium multidose vials, in neonates, infants, and pregnant women.
• to tell their physicians and dentists they are taking enoxaparin sodium and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.3)].
• to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions (7)].

Package Label.Principal Display Panel

PRINCIPAL DISPLAY PANEL - 30 mg/0.3 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1003-10

Enoxaparin Sodium
Injection

30 ^mg/0.3 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 0.3 mL Syringes

PRINCIPAL DISPLAY PANEL - 40 mg/0.4 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1004-10

Enoxaparin Sodium
Injection

40 ^mg/0.4 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 0.4 mL Syringes

PRINCIPAL DISPLAY PANEL - 60 mg/0.6 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1006-10

Enoxaparin Sodium
Injection

60 ^mg/0.6 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 0.6 mL Syringes

PRINCIPAL DISPLAY PANEL - 80 mg/0.8 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1008-10

Enoxaparin Sodium
Injection

80 ^mg/0.8 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 0.8 mL Syringes

PRINCIPAL DISPLAY PANEL - 100 mg/1 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1010-10

Enoxaparin Sodium
Injection

100 ^mg/1 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 1 mL Syringes

PRINCIPAL DISPLAY PANEL - 300 mg/3 mL Vial Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1016-01

Enoxaparin
Sodium
Injection

300^mg/3^mL
(100mg/1mL)

For Subcutaneous or
Intravenous Injection

Multiple Dose Vial

Rx Only

1 3 mL Vial

SANOFI

PRINCIPAL DISPLAY PANEL - 120 mg/0.8 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1012-10

Enoxaparin Sodium
Injection

120 ^mg/0.8 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 0.8 mL Syringes

PRINCIPAL DISPLAY PANEL - 150 mg/1 mL Syringe Carton

Winthrop
A SANOFI COMPANY

NDC 0955-1015-10

Enoxaparin Sodium
Injection

150 ^mg/1 ^mL

SINGLE DOSE SYRINGES WITH
AUTOMATIC SAFETY DEVICE

FOR SUBCUTANEOUS INJECTION

SANOFI

Rx Only

10 1 mL Syringes