PRINCIPAL DISPLAY PANEL: Multiple-Dose Vial Carton

NDC 0548-5608-00

Enoxaparin Sodium
Injection, USP

300 mg/3 mL
[100 mg/mL]

Rx ONLY
For Subcutaneous or
Intravenous Injection

Multiple Dose Vial

One 3 mL Vial

AMPHASTAR PHARMACEUTICALS, INC.
Rancho Cucamonga, CA 91730, U.S.A.
© 2017
5656086B/7-17

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Deep Vein Thrombosis

Enoxaparin Sodium Injection is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

• in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.1)]
• in patients undergoing hip replacement surgery, during and following hospitalization
• in patients undergoing knee replacement surgery
• in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness

1.2 Treatment of Acute Deep Vein Thrombosis

Enoxaparin Sodium Injection is indicated for:

• the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium
• the outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium

1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave

Myocardial Infarction

Enoxaparin Sodium Injection is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin.

1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction

Enoxaparin Sodium Injection, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).

5 WARNINGS AND PRECAUTIONS

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 heparininduced 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 nonheparin alternative treatments are considered.

5.5 Thrombocytopenia

Thrombocytopenia can occur with the administration of Enoxaparin Sodium Injection.
Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) 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/mm3 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/mm3, 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)].

7 DRUG INTERACTIONS

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Enoxaparin Sodium Injection therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If coadministration is essential, conduct close clinical and laboratory monitoring [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Enoxaparin Sodium Injection USP is a clear, colorless to pale yellow solution available in two concentrations.

100 mg/mL Concentration

-Single-Dose Prefilled Syringes	30 mg / 0.3 mL, 40 mg / 0.4 mL
-Single-Dose Graduated Prefilled Syringes	60 mg / 0.6 mL, 80 mg / 0.8 mL, 100 mg / 1 mL
-Multiple-Dose Vials	300 mg / 3 mL

150 mg/mL Concentration

-Single-Dose Graduated Prefilled Syringes

120 mg / 0.8 mL, 150 mg / 1 mL

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
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/m2) has not been fully determined and there is no consensus for dose adjustment. Observe these patients carefully for signs and symptoms of thromboembolism.

11 DESCRIPTION

Enoxaparin Sodium Injection USP is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains a 1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is:

<2000 daltons	20%
2000 to 8000 daltons	68%
8000 daltons	18%

X = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end
STRUCTURAL FORMULA
R	X*******=15 to 25%**		n=0 to 20
100 - X	H	n=1 to 21

Enoxaparin Sodium Injection USP 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.

Enoxaparin Sodium Injection USP 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
The Enoxaparin Sodium Injection USP prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative [see Dosage and Administration (2) and How Supplied/Storage and Handling(16)].

12 CLINICAL PHARMACOLOGY

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
Median (range) † Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
Amax (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%
tmax*(h)	100 mg/mL	3 (2-6)	4 (2-5)	2.5 (2-4.5)	3 (2-4.5)
200 mg/mL	3.5 (2-6)	4.5 (2.5-6)	3.3 (2-5)	3 (2-5)
AUC (ss) (h†IU/mL or h† 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, 99mTc, 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 Amax 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 Amax 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/m2) compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single- subcutaneous 40 mg dose, that anti-Factor Xa exposure is 52% higher in low- weight women (<45 kg) and 27% higher in low-weight men (< 57 kg) when compared to normal weight control subjects [see Use in Specific Populations (8.8)].

Pharmacokinetic interaction
No pharmacokinetic interaction was observed between Enoxaparin Sodium Injection and thrombolytics when administered concomitantly.

13 NONCLINICAL TOXICOLOGY

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Enoxaparin Sodium Injection USP is available in two concentrations (see Tables 26 and 27)

Table 26 100 mg/mL Concentration
Dosage Unit/Strength*	Anti-Xa Activity	Package Size (per carton)	Syringe Label Color	NDC# 0548-
Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin Sodium Injection USP, 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection. † Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each Enoxaparin Sodium Injection USP prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x 1/2 inch needle. § Each Enoxaparin Sodium Injection USP multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative.
Single-Dose Prefilled Syringes**†** 30 mg/0.3 mL	3000 IU	10 syringes	Medium Blue	5601-00
40 mg/0.4 mL	4000 IU	10 syringes	Yellow	5602-00
Single-Dose Graduated Prefilled Syringes**‡**
60 mg/0.6 mL	6000 IU	10 syringes	Orange	5603-00
80 mg/0.8 mL	8000 IU	10 syringes	Brown	5604-00
100 mg/1 mL	10,000 IU	10 syringes	Black	5605-00
Multiple-Dose Vial**§**
300 mg/3 mL	30,000 IU	1 vial	Red	5608-00

Table 27 150 mg/mL Concentration
Dosage Unit /Strength*	Anti-Xa Activity†	Package Size (per carton)	Syringe Label Color	NDC # 0548-
Strength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin Sodium Injection USP 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection. † Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. ‡ Each Enoxaparin Sodium Injection USP graduated prefilled syringe is for single, one-time use only and is affixed with a 27 gauge x 1/2 inch needle.
Single-Dose Graduated Prefilled Syringes**‡**
120 mg/0.8 mL	12,000 IU	10 syringes	Purple	5606-00
150 mg/1 mL	15,000 IU	10 syringes	Navy Blue	5607-00

Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Store in the original carton or packaging until ready to use.
Do not store the multiple-dose vials for more than 28 days after the first use.