INN monograph
Enoxaparin
Anticoagulant · POM
Source-linked · Updated 03 Aug 2026 · Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Anticoagulant)
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Risk first
Contraindications
- with: • Active major bleeding • History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies [see Warnings and Precautions (5.4) ] • Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/ anaphylactoid reactions) [see Adverse Reactions (6.2) ] • Known hypersensitivity to heparin or pork products Active major bleeding ( 4 ) History of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies ( 4 ) Hypersensitivity to enoxaparin sodium ( 4 ) Hypersensitivity to heparin or pork products ( 4 )
Precautions
- 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 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
Point of care
Dosing
Adult
information. ( 2 ) 2.1 Pretreatment Evaluation Evaluate all patients for a bleeding disorder before starting enoxaparin sodium treatment, unless treatment is urgently needed. 2.2 Adult Dosage Abdominal Surgery The recommended dose of enoxaparin sodium is 40 mg by subcutaneous injection once a day (with the initial dose given 2 hours prior to surgery) in patients undergoing abdominal surgery who are at risk for thromboembolic complications. The usual duration of administration is 7 to 10 days [see Clinical Studies (14.1) ]. Hip or Knee Replacement Surgery The recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by subcutaneous injection in patients undergoing hip or knee replacement surgery. Administer the initial dose 12 to 24 hours after surgery, provided that hemostasis has been established. The usual duration of administration is 7 to 10 days [see Clinical Studies (14.2) ]. A dose of enoxaparin sodium of 40 mg once a day subcutaneously may be considered for hip replacement surgery for up to 3 weeks. Administer the initial dose 12 (±3) hours prior to surgery. Medical Patients during Acute Illness The recommended dose of enoxaparin sodium is 40 mg once a day administered by subcutaneous injection for medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness. The usual duration of administration is 6 to 11 days [see Clinical Studies (14.3) ]. Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism The recommended dose of enoxaparin sodium injection is 1 mg/kg every 12 hours administered subcutaneously in patients with acute deep vein thrombosis without pulmonary embolism, who can be treated at home in an outpatient setting. The recommended dose of enoxaparin sodium injection is 1 mg/kg every 12 hours administered subcutaneously or 1.5 mg/kg once a day administered subcutaneously at the same time every day for inpatient (hospital) treatment of patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment). In both outpatient and inpatient (hospital) treatments, initiate warfarin sodium therapy when appropriate (usually within 72 hours of enoxaparin sodium injection). Continue enoxaparin sodium injection for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2 to 3). The average duration of administration is 7 days[see Clinical Studies (14.4) ]. Unstable Angina and Non-Q-Wave Myocardial Infarction The recommended dose of enoxaparin sodium injection is 1 mg/kg administered subcutaneously every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily) in 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 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 by 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. 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 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 prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection. Remove the prefilled syringe from the packaging by peeling at the arrow as directed on the lid. Do not remove by pulling on the plunger as this may damage the syringe. 1. Remove the needle shield by pulling it straight off the syringe (see Figure A). If less than the full syringe volume is needed to administer the prescribed dose, eject syringe contents until the prescribed dose is left in the syringe. 2. Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B). 3. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C). 4. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (see Figure D). 5. Immediately dispose of the syringe in the nearest sharps container (see Figure E). NOTE: The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient’s skin. Do not replace the needle shield after injection. The safety system should not be sterilized. Activation of the safety system may cause minimal splatter of fluid. For optimal safety, activate the system while orienting it downwards away from yourself and others. figure-a figure-b figure-c figure-d figure-e 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 [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.
Paediatric
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.
Renal
Critical for LMWH/DOAC dosing and selection.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Hepatic
Warfarin sensitivity increases in liver disease; many DOACs restricted in Child-Pugh C.
Safety
Drug interactions
- Low-molecular-weight heparins with an average molecular weight of 4000 to 6500 daltons.
- They have an attenuated effect on coagulation and prolongation of the activated partial thromboplastin time compared with unfractionated heparin.
Safety
Adverse effects
- labeling: • Spinal/epidural hematomas [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Increased Risk of Hemorrhage [see Warnings and Precautions ( 5.1 )] • Thrombocytopenia [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, nausea, ecchymosis, fever, edema, peripheral edema, dyspnea, confusion, and injection site pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium.
- These included 1,228 for prophylaxis of deep vein thrombosis following abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non – Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosis with or without pulmonary embolism.
- Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg subcutaneously once daily to 30 mg subcutaneously twice daily.
- In the clinical studies for prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg intravenous bolus followed by 1 mg/kg every 12 hours subcutaneously.
- Hemorrhage The following rates of major bleeding events have been reported during clinical trials with enoxaparin sodium (see Tables 2 to 7).
- Table 2: Major Bleeding Episodes following Abdominal and Colorectal Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg -daily subcutaneously Heparin 5000 U q8h subcutaneously Abdominal Surgery n=555 23 (4%) n=560 16 (3%) Colorectal Surgery n=673 28 (4%) n=674 21 (3%) *Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products.
- Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major.
- Table 3: Major Bleeding Episodes Following Hip or Knee Replacement Surgery* Indications Dosing Regimen Enoxaparin Sodium 40 mg daily subcutaneously Enoxaparin Sodium 30 mg q12h subcutaneously Heparin 15,000 U/24h subcutaneously Hip Replacement Surgery without Extended Prophylaxis † – n=786 31 (4%) n=541 32 (6%) Hip Replacement Surgery with Extended Prophylaxis Peri-operative Period ‡ Extended Prophylaxis Period § – – – n=288 4 (2%) – – n=221 0 (0%) – – Knee Replacement Surgery without Extended Prophylaxis † – n=294 3 (1%) n=225 3 (1%) * Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products.
- Retroperitoneal and intracranial hemorrhages were always considered major.
- In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages. † Enoxaparin sodium 30 mg every 12 hours subcutaneously initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery ‡ Enoxaparin sodium 40 mg subcutaneously once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery § Enoxaparin sodium 40 mg subcutaneously once a day for up to 21 days after discharge 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 patients versus 1.8% of the placebo patients.
- Table 4: Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility during Acute Illness* Indication Dosing Regimen Enoxaparin Sodium † 20 mg daily subcutaneously Enoxaparin Sodium † 40 mg daily subcutaneously Placebo † Medical Patients during Acute Illness n=351 1 (<1%) n=360 3 (<1%) n=362 2 (<1%) * 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. † The rates represent major bleeding on study medication up to 24 hours after last dose.
Use
Indications
- (LMWH) indicated for: Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness ( 1.1 ) Inpatient treatment of acute DVT with or without pulmonary embolism ( 1.2 ) Outpatient treatment of acute DVT without pulmonary embolism ( 1.2 ) Prophylaxis of ischemic complications of unstable angina and non−Q-wave myocardial infarction (MI) ( 1.3 ) Treatment of acute ST-segment elevation myocardial infarction (STEMI) managed medically or with subsequent percutaneous coronary intervention (PCI) ( 1.4 ) 1.1 Prophylaxis of Deep Vein Thrombosis Enoxaparin sodium injection is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.1) ] in patients undergoing hip replacement surgery, during and following hospitalization in patients undergoing knee replacement surgery in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness 1.2 Treatment of Acute Deep Vein Thrombosis Enoxaparin sodium injection is indicated for: the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism , when administered in conjunction with warfarin sodium the outpatient treatment of acute deep vein thrombosis without pulmonary embolism , when administered in conjunction with warfarin sodium 1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non−Q-Wave Myocardial Infarction Enoxaparin sodium injection is indicated for the prophylaxis of ischemic complications of unstable angina and non – Q-wave myocardial infarction, when concurrently administered with aspirin.
- 1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin sodium injection, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).
Pharmacology
Mode of action
Heparin interacts with anti- thrombin III heparin co-factor to produce a substance that immediately neutralizes thrombin by forming a complex with it at its active serine center.
Full mechanism text
Heparin interacts with anti- thrombin III heparin co-factor to produce a substance that immediately neutralizes thrombin by forming a complex with it at its active serine center. It also inhibits platelet function, increases the permeability of vessel walls, inhibits the proliferation of vascular smooth muscle cells, inhibits delayed hypersensitivity reactions, and is involved in the regulation of angiogenesis.
ADME
Pharmacokinetics & PD
| Onset | Immediate (UFH IV) to hours (DOAC/LMWH); warfarin days |
|---|---|
| Duration | Hours–days (agent-dependent) |
| Route | SUBCUTANEOUS |
| 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/m... |
| Distribution | The volume of distribution of anti-Factor Xa activity is about 4.3 L. |
| 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 |
| 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 app... |
Full PK/PD text
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 appears 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 Subcutaneously Once-Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations * Means ±SD at Day 5 and 90% Confidence Interval (CI) of the ratio † Median (range) Concentration Anti-Xa Anti-IIa Heptest aPTT A max (IU/mL or Δ 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 † (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* Δ 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 (2.3) 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 (2.2) 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 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 Interaction No pharmacokinetic interaction was observed between enoxaparin and thrombolytics when administered concomitantly.
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Special populations
Pregnancy & lactation
Pregnancy
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 sodium does not increase the risk of major developmental abnormalities [see Data]. Based on animal data, enoxaparin 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 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 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 affect the safety and the efficacy of the drug during pregnancy. 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 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. 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 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.
Lactation
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 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 sodium does not increase the risk of major developmental abnormalities [see Data]. Based on animal data, enoxaparin 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 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 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 affect the safety and the efficacy of the drug during pregnancy. 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 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. 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 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 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 and any potential adverse effects on the breastfed child from enoxaparin sodium or from the underlying maternal condition. 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. 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 in clinical trials. The efficacy of enoxaparin sodium 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 were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when enoxaparin sodium was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of enoxaparin sodium-associated bleeding increased with age. Serious adverse events increased with age for patients receiving enoxaparin sodium. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of enoxaparin sodium between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Enoxaparin sodium 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 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 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 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 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.
Diet
Food & alcohol
- Drug & food interactions (label) 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 (5.1) ] . Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium or conduct close clinical and laboratory monitoring ( 2.6 , 7 )
Trust
Sources & disclaimer
Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Anticoagulant)
Clinical review date not recorded.
Decision support only — not a substitute for clinical judgment, product SmPC, or Kenya STG/EML.