LOVENOX (Brand for ENOXAPARIN SODIUM)

General Administration Information
For storage information, see specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Administered via subcutaneous or intravenous administration. Do not administer intramuscularly.
-Evaluate all patients for a bleeding disorder prior to administration, unless the medication is needed urgently.
-If withdrawing from the multi-dose vial, utilize a tuberculin or equivalent graduated syringe to ensure proper measurement of the required dose. Do not mix with other injections or parenteral fluids.
-Enoxaparin cannot be used interchangeably (unit for unit) with heparin sodium or other low molecular weight heparins.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Storage: Discard the multi-dose vial 28 days after the first use.

Preparation and stability of enoxaparin 20 mg/mL dilution for parenteral administration:
NOTE: Enoxaparin is not FDA-approved to be prepared as a 20 mg/mL dilution. Prepare in a sterile environment, using aseptic technique.
-Add the contents of 4 enoxaparin 60 mg/0.6 mL syringes and 9.6 mL preservative-free Sterile Water for Injection to a sterile glass vial.
-Storage: The dilution may be stored for up to 4 weeks in the glass vial at room temperature (22 to 26 degrees C) or up to 2 weeks in tuberculin syringes with rubber stoppers at room temperature or under refrigeration (2 to 6 degrees C) without significant loss of anti-Xa activity.
-The cited stability study was conducted in a class 100 environment and did not test microbiologic properties.

Preparation and stability of enoxaparin 8 mg/mL dilution for SUBCUTANEOUS administration:
NOTE: Enoxaparin is not FDA-approved to be prepared as an 8 mg/mL dilution. Prepare in a sterile environment, using aseptic technique.
-It has been suggested that an enoxaparin dilution of 8 mg/mL be used in smaller patients receiving single doses less than 8 mg/dose to ensure adequate dosing and titration. Clinicians should be aware of when to switch to a more concentrated dilution, so the patient does not receive a subcutaneous injection volume more than 1 mL/dose.
-Add the contents of 1 enoxaparin 40 mg/0.4 mL syringe and 4.6 mL Sterile Water for Injection to a 10 mL sterile vial.
-Storage: The dilution may be stored for up to 14 days in polypropylene syringes under refrigeration at 2 to 6 degrees C.
Intravenous Administration
-Use the multiple-dose vial for intravenous injection. Use a tuberculin or equivalent graduated syringe to ensure proper measurement of the required dose.
-Administer via IV bolus through an intravenous line. Do not mix or coadminister with other drugs. To avoid the possible mixing with other drugs, flush the IV access port with a sufficient amount of saline or dextrose solution before and after enoxaparin administration.
-May be safely administered with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

Subcutaneous Administration
-Patients should be in a supine position.
-Administer by deep subcutaneous injection. Inject into the left and right anterolateral or posterolateral abdominal wall. Using the thumb and forefinger, you must lift a fold of skin while giving the injection.
-Insert the entire length of the needle vertically at a 90-degree angle.
-Alternate the injection site with each injection. Do not rub the injection site after administration.
-To avoid loss of drug when using the 30 mg or 40 mg prefilled syringes, do not expel the air bubble from the syringe before subcutaneous injection.
-Prefilled syringes for the 30 mg and 40 mg doses are not graduated. Do not use these syringes to administer partial doses.
-When using the prefilled syringes, after injection, a safety system to prevent inadvertent needle sticks can be activated by firmly pressing down on the plunger rod. An audible click will be heard once the protective sleeve is in place. Dispose of the syringe in a sharps container. The safety system can only be activated once the syringe is empty. Do not activate the safety system until the syringe is away from the skin.

The most serious adverse reaction associated with enoxaparin therapy is bleeding, which can occur from any site. Minor bleeding events, including bruising and minor leaking at the injection site, have been reported in 6% to 56% of pediatric patients receiving enoxaparin. Major bleeding events have been reported in 2.9% to 5% of pediatric patients and have included major bleeding or hematoma at the administration site, compartment syndrome, GI bleeding, intracranial bleeding, hemorrhagic infarction, and hemorrhagic pericardial effusion. General bleeding or hemorrhage was reported in 4% to 13% of adult patients during trials. Major bleeding was reported in less than 1% to 4% of adult patients. Bleeding complications were considered major if the hemorrhage caused a significant clinical event or was accompanied by a decrease in hemoglobin of at least 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal bleeding, ocular hemorrhage, and intracranial bleeding were always considered major. Intracranial bleeding was reported in 0.8% of adult patients with acute ST-segment elevation during myocardial infarction. Minor bleeding events, such as hematuria, were reported in less than 1% to 2% of adult patients in clinical trials. Injection site hematoma occurred in less than 1% to 9% of adult patients during trials. If bleeding is serious, discontinue enoxaparin therapy, and protamine can be administered as an antagonist. Several cases of bleeding or hematoma within the spinal column have been reported with concurrent use of enoxaparin and epidural/spinal anesthesia or spinal puncture. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. The risk of epidural or spinal hematoma is higher with the use of postoperative indwelling epidural catheters, traumatic or repeated spinal or epidural punctures, or in patients treated concomitantly with NSAIDs, platelet inhibitors, or other anticoagulants. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during treatment with enoxaparin. 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 activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.

During clinical trials, local adverse reactions included injection site reaction (irritation, pain, hematoma, ecchymosis, and erythema). Injection site ecchymosis was reported in less than 1% to 3% of enoxaparin-treated adult patients. Other skin and soft-tissue or allergic adverse reactions reported during postmarketing safety surveillance included injection site reaction (nodules, inflammation, oozing), vesiculobullous rash (vesicular rash/bullous rash), purpura, alopecia, systemic allergic reactions (i.e., pruritus, urticaria, anaphylactic/anaphylactoid reactions, anaphylactic shock), hypersensitivity cutaneous vasculitis, and skin necrosis (at the injection site or distant from the injection site).

Rare cases of thrombocytopenia with thrombosis have been reported during postmarketing surveillance. The incidence of enoxaparin-induced thrombocytopenia is slightly lower than for heparin. Drug-induced thrombocytopenia occurred in 9 of 332 patients receiving heparin compared to none of 333 patients who received enoxaparin for DVT prophylaxis after hip surgery. Moderate thrombocytopenia (platelet count of 50,000 to 100,000/mm3) has been reported in 1.3% of adult patients receiving enoxaparin and platelet counts of less than 50,000/mm3 have been reported in 0.1% of enoxaparin-treated adult patients. Thrombocytopenia was reported in 1.5% to 2.8% of adults with acute medical illness or myocardial infarction receiving enoxaparin. Cases of thrombocytopenia complicated with limb ischemia, organ infarction, disseminated thrombosis (disseminated intravascular coagulation (DIC)), or fatalities have been observed in clinical practice with heparins and low molecular weight heparins, including enoxaparin. Cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic valves who have received enoxaparin for thromboprophylaxis. The use of enoxaparin is not recommended for thrombosis prophylaxis in patients with prosthetic heart valves. Thrombocytosis has also been noted in postmarketing surveillance.

Rare cases of hyperlipidemia have been reported with the use of enoxaparin during postmarketing surveillance. The precise relationship to enoxaparin has not been established.

Elevated hepatic enzymes (AST, ALT) greater than 3-times the upper limit of normal have been reported in 5.9% to 6.1% of adult patients treated with enoxaparin. Increases in aminotransferase have also been reported; interpret with caution in patients with myocardial infarction, liver disease, and pulmonary emboli. Such elevations are fully reversible and rarely associated with hyperbilirubinemia. During postmarketing use of enoxaparin, hepatocellular and cholestatic liver injury (cholestasis) have been reported.

Osteoporosis may occur in patients receiving long-term low-molecular-weight heparin (LMWH) therapy (e.g., more than 1 month) such as enoxaparin; however, LMWH likely causes less osteopenia than unfractionated heparin (UFH). In animal studies, LMWH appears to only decrease the rate of bone formation, while UFH has been found to stimulate bone resorption in addition to decreasing bone formation.

Cases of hyperkalemia have been reported in patients using enoxaparin. Most cases occurred in patients with a predisposing condition such as renal dysfunction, concomitant use of potassium-sparing diuretics, administration of potassium, or hematoma in body tissues.

General adverse reactions reported during enoxaparin clinical trials in adults include anemia (less than 2% to 16%), fever (5% to 8%), edema (2%), confusion (2.2%), and peripheral edema (3% to 6%). Hemorrhagic anemia, eosinophilia, and headache have been reported during postmarketing use of enoxaparin.

Gastrointestinal adverse reactions reported in adult patients receiving enoxaparin include nausea (2.5% to 3%) and diarrhea (2.2%).

Cardiovascular and pulmonary adverse reactions reported in adult patients receiving enoxaparin include dyspnea (3.3%), atrial fibrillation (0.7%), heart failure (0.95%), pulmonary edema (0.7%), and pneumonia (0.82%).

Enoxaparin is contraindicated in patients with porcine protein hypersensitivity and enoxaparin or heparin hypersensitivity. Multiple-dose vials of enoxaparin contain benzyl alcohol (1.5%) as a preservative; administration of this formulation of enoxaparin is contraindicated in patients with benzyl alcohol hypersensitivity.

Enoxaparin is contraindicated for use in patients with a history of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies. If more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present, use enoxaparin only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered. Although LMWHs are less likely to trigger the formation of HIT antibodies than unfractionated heparin (UFH), LMWHs are just as effective as UFH at triggering platelet activation by HIT antibodies (i.e., LMWHs have essentially 100% in vitro cross-reactivity). Circulating antibodies may last for several years, and HIT may still occur if more than 100 days have passed or if no circulating antibodies are present. Monitor the platelet count in patients receiving enoxaparin. If thrombocytopenia (platelet count less than 100,000/mm3) occurs, discontinue enoxaparin. Cases of HIT with thrombosis have been observed in clinical practice.

Bleeding is the major risk associated with use of enoxaparin. Enoxaparin is contraindicated in patients with active major bleeding, such as GI bleeding. Before initiating therapy, rule out coagulopathy. Avoid use of enoxaparin in patients with severe bleeding disorders, such as hemophilia or immune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP). Use enoxaparin with caution in any disease state in which there is an increased risk of hemorrhage, such as acute infective endocarditis, dissecting aneurysm, peptic ulcer disease, recent GI bleeding, non-hemorrhagic stroke, diverticulitis, inflammatory bowel disease, decreased platelets, abnormal vaginal bleeding, severe hepatic disease or renal disease, uncontrolled hypertension, hypertensive or diabetic retinopathy, recent brain, spinal, or ophthalmological surgery, and in patients with a bleeding diathesis. Monitor patients closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. 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 activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.

Epidural or spinal hemorrhage and subsequent hematomas can occur in patients receiving enoxaparin while epidural or spinal anesthesia/analgesia or spinal puncture procedures are performed. The FDA-approved product labeling provides recommendations based on typical adult pharmacokinetic/pharmacodynamic parameters to help minimize risk. Pediatric-specific recommendations are not available, and while data are limited, pediatric patients appear to have faster enoxaparin clearance compared to adults. Carefully assess pediatric patients on an individual basis; decisions should be based on the patient's age, size, procedure, and individual risk of bleeding vs. risk of thrombosis. The bleeding risk for spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with use of postoperative indwelling epidural catheters, in patients with a history of traumatic or repeated epidural or spinal puncture, a history of spinal deformity, a history of spinal surgery, or concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. Although the optimal timing between the administration of enoxaparin and neuraxial procedures in adult and pediatric patients is not known, if epidural anesthesia, lumbar puncture, or spinal anesthesia is performed, it is best done when the anticoagulant effect of enoxaparin is low. The FDA-approved product labeling recommends delaying the placement or removal of epidural catheters for at least 12 hours after administration in adult patients receiving low doses (30 mg twice daily or 40 mg once daily) and at least 24 hours after administration in adult patients receiving high doses (0.75 to 1 mg/kg/dose twice daily or 1.5 mg/kg/dose once daily); these delays are not a guarantee that neuraxial hematoma will be avoided. Patients receiving twice daily enoxaparin should not receive the second dose in the twice daily regimen to allow a longer delay before catheter placement or removal. In patients with severe renal dysfunction (CrCl less than 30 mL/minute), consider delaying the placement or removal of epidural catheters for at least 24 hours after administration in adult patients receiving low doses and 48 hours after administration in adult patients receiving high doses because of slower enoxaparin clearance. Although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, the manufacturer recommends considering delaying subsequent enoxaparin doses for at least 4 hours after catheter removal. If neuraxial procedures are employed, monitor patients frequently for symptoms of neurological impairment such as midline back pain, sensory and motor deficits, and bowel and/or bladder dysfunction. Consider the risk versus benefit of neuraxial intervention in patients anticoagulated or to be anticoagulated. If neurological compromise is noted, urgent treatment is necessary; however, such treatment may not prevent or reverse neurological sequelae. In addition, monitor patients closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. 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 activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.

Enoxaparin is not intended for intramuscular administration. Avoid intramuscular injections of other medications in patients receiving enoxaparin. IM injections may cause bleeding, bruising, or hematoma formation in patients who are anticoagulated.

Patients with renal impairment may have decreased elimination of enoxaparin; monitor these patients frequently for signs and symptoms of bleeding. Monitor patients with severe renal impairment (CrCl less than 30 mL/minute/1.73m2) or renal failure closely and adjust the dose as required. Monitoring of anti-factor Xa activity is prudent, especially in patients receiving chronic therapy. A linear relationship between anti-factor Xa plasma clearance and creatinine clearance at steady-state has been observed in adult patients, indicating reduced enoxaparin clearance and increased anticoagulant exposure in patients with renal impairment. In adult patients receiving hemodialysis (dialysis), the AUC appears to be 2-fold higher than the control population. Also, hyperkalemia has been associated with enoxaparin treatment in patients with renal failure.

Benzyl alcohol, which is used as a preservative in multiple-dose vials of enoxaparin, can cause a gasping syndrome in neonates and low birth weight infants; avoid the use of this formulation in these populations. 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.

Patients who are anticoagulated using enoxaparin are at increased risk of bleeding during dental procedures. Instruct patients to inform health care providers of anticoagulant therapy prior to having dental work performed. Instruct patients, especially those with dental disease, in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Enoxaparin has not been adequately studied for thromboprophylaxis in patients with 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. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Regardless, the ACCP recommends the use of LMWHs for thromboprophylaxis in patients with prosthetic heart valves after prosthetic valve insertion or when vitamin K antagonists must be discontinued.

Obesity may place patients at higher risk for thromboembolism; carefully monitor obese patients receiving enoxaparin for signs and symptoms of thromboembolism. The safety and efficacy of enoxaparin have not been established in obese patients (BMI more than 30 kg/m2) and a consensus regarding dose adjustment in these patients is not available.

Description: Enoxaparin is a low molecular weight heparin (LMWH) produced through partial depolymerization of porcine mucosal heparin. While unfractionated heparin (UFH) contains molecules ranging from 3,000 to 30,000 (mean 15,000) daltons, enoxaparin molecules are 2,000 to 8,000 daltons (average 4,500 daltons). In pediatric patients, enoxaparin is used for the prophylaxis and management of systemic thromboembolism, including deep venous thrombosis, pulmonary embolism, and thromboembolism associated with central venous access devices. Enoxaparin and other low molecular weight heparins produce a more predictable anticoagulant response than UFH, reflecting their better bioavailability after subcutaneous injection, longer half-life, and dose-independent clearance. The risk of adverse reactions associated with heparin use, such as heparin-induced thrombocytopenia (HIT) and osteoporosis, also appear to be reduced with enoxaparin compared to UFH. The anticoagulant effects of enoxaparin are also less likely to be influenced by other drugs or diet compared to oral anticoagulants, such as warfarin. For these reasons, enoxaparin is widely used in pediatric patients. However, the predictability of the anticoagulant response to enoxaparin is less in pediatric patients than adults, due to developmental changes in pharmacokinetics, and routine monitoring of anti-factor Xa concentrations is recommended. Although not FDA-approved, enoxaparin has been used in pediatric patients as young as neonates.

General dosing information for systemic anticoagulation:
-A duration of 6 weeks to 3 months is recommended by the American College of Chest Physicians (ACCP) for many indications, including thromboembolism associated with central venous access devices (CVAD) or umbilical vein catheters (UVC), cerebral sinovenous thrombosis, and renal vein thrombosis.
-In general, it is recommended that CVADs or UVCs that are in situ be removed as greater than 80% of VTE are secondary to the placement of CVADs; administer anticoagulation therapy for 3 to 5 days prior to the removal of the CVAD. If the CVAD or UVC is still in place at the end of anticoagulation therapy, it is recommended that prophylactic doses of enoxaparin be instituted until the line can be removed.
-Treatment with enoxaparin for at least 5 days is recommended for the initial treatment of acute deep vein thrombosis (DVT) or pulmonary embolism (PE) or until a therapeutic INR is achieved, if the patient is to continue anticoagulation therapy with warfarin.
-Enoxaparin can be given for the duration of anticoagulation, which is for 6 to 12 months in patients with idiopathic venous thromboembolism (VTE) or, in patients with secondary thromboembolism until the risk factor for VTE is no longer present and at least 3 months of treatment have lapsed. In those patients with ongoing risk factors (e.g., active nephrotic syndrome, asparaginase therapy), treatment or prophylactic doses of enoxaparin can be used after the initial 3 months of treatment.
-For subcutaneous administration, the use of insulin syringes and rounding of weight-based dose to the nearest whole milligram (1 mg of enoxaparin = 1 unit on the insulin syringe) has been used successfully in a cohort of 514 pediatric patients (2 days to 17 years of age); 5 children had supratherapeutic anti-factor Xa concentrations requiring a dose decrease without associated hemorrhagic events.

For the treatment of thromboembolism including deep venous thrombosis (DVT)*, pulmonary embolism*, renal vein thrombosis*, and thromboembolism associated with central venous access devices (CVAD) or umbilical vein catheters (UVC)*:
Subcutaneous dosage:
Premature neonates: 2 mg/kg/dose subcutaneous every 12 hours, which is based on several studies indicating that premature neonates require higher doses than term neonates. A lower initial dose of 1.5 mg/kg/dose subcutaneous every 12 hours is recommended by the American College of Chest Physicians (ACCP). Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Neonates: 1.7 mg/kg/dose subcutaneous every 12 hours, which is based on several studies indicating that neonates require higher doses than older pediatric patients. A lower initial dose of 1.5 mg/kg/dose subcutaneous every 12 hours is recommended by the American College of Chest Physicians (ACCP). Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Infants 1 month: 1.5 mg/kg/dose subcutaneous every 12 hours. Alternatively, a higher initial dose of 1.8 mg/kg/dose subcutaneous every 12 hours has been recommended. Patients treated with a higher initial dose achieved a therapeutic anti-factor Xa level 1 day earlier and required 1 less venipuncture on average than those treated with a standard dose (1.5 mg/kg/dose subcutaneous). Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Infants 2 to 11 months: 1 mg/kg/dose subcutaneous every 12 hours. Alternatively, a higher initial dose of 1.5 mg/kg/dose subcutaneous every 12 hours has been recommended. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Children 1 to 5 years: 1 mg/kg/dose subcutaneous every 12 hours. Alternatively, a higher initial dose of 1.2 mg/kg/dose subcutaneous every 12 hours has been recommended. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Children and Adolescents 6 to 17 years: 1 mg/kg/dose subcutaneous every 12 hours. Adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.
Intravenous dosage:
Neonates: Limited data are available; the mean dose required to achieve a therapeutic anti-factor Xa concentration was 2.4 +/- 0.58 mg/kg/dose IV every 8 hours in a small retrospective study (n = 7, 5 patients younger than 1 year) of critically ill patients, the majority of which were unable to achieve therapeutic anti-factor Xa concentrations with subcutaneous administration. Anti-factor Xa concentrations peaked 1 to 2 hours after the dose and were subtherapeutic 6 to 8 hours after the dose in most patients.
Infants: Limited data are available; the mean dose required to achieve a therapeutic anti-factor Xa concentration was 2.4 +/- 0.58 mg/kg/dose IV every 8 hours in a small retrospective study (n = 7, 5 patients younger than 1 year) of critically ill patients, the majority of which were unable to achieve therapeutic anti-factor Xa concentrations with subcutaneous administration. Anti-factor Xa concentrations peaked 1 to 2 hours after the dose and were subtherapeutic 6 to 8 hours after the dose in most patients.
Children: Limited data are available; the mean dose required to achieve a therapeutic anti-factor Xa concentration was 1.11 +/- 0.13 mg/kg/dose IV every 12 hours in a small retrospective study (n = 7, 2 of which were 1 year of age) of critically ill patients, the majority of which were unable to achieve therapeutic anti-factor Xa concentrations with subcutaneous administration. Anti-factor Xa concentrations peaked 1 to 2 hours after the dose and were subtherapeutic 6 to 8 hours after the dose in most patients.

For the treatment of cerebral thromboembolism* (e.g., cerebral venous sinus thrombosis*):
Subcutaneous dosage:
Neonates: An initial dose of 1.5 mg/kg/dose subcutaneous every 12 hours adjusted to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL was used in patients younger than 2 months in a small, pilot study. Patients were randomized to unfractionated heparin (n = 10), enoxaparin (n = 12), or no treatment (n = 8). The majority of patients received warfarin after the initial treatment; however, 4 patients received enoxaparin for the entire treatment period of 3 months. Recurrent thrombosis was not reported in patients taking enoxaparin or heparin; however, 1 patient in the heparin group experienced clinically silent bleeding. Three patients that did not receive an anticoagulant died versus zero patients that did receive anticoagulant therapy. The American College of Chest Physicians (ACCP) guidelines recommend LMWH for 6 weeks to 3 months in patients without significant hemorrhage; in patients with significant hemorrhage, anticoagulation or radiologic monitoring with subsequent anticoagulation if thrombus extension occurs is recommended.
Infants 1 month: An initial dose of 1.5 mg/kg/dose subcutaneous every 12 hours adjusted to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL was used in patients younger than 2 months in a small, pilot study. Patients were randomized to unfractionated heparin (n = 10), enoxaparin (n = 12), or no treatment (n = 8). The majority of patients received warfarin after the initial treatment; however, 4 patients received enoxaparin for the entire treatment period of 3 months. Recurrent thrombosis was not reported in patients taking enoxaparin or heparin; however, 1 patient in the heparin group experienced clinically silent bleeding. Three patients that did not receive an anticoagulant died versus zero patients that did receive anticoagulant therapy. The American College of Chest Physicians (ACCP) guidelines recommend LMWH for 6 weeks to 3 months in patients without significant hemorrhage; in patients with significant hemorrhage, anticoagulation or radiologic monitoring with subsequent anticoagulation if thrombus extension occurs is recommended.
Infants, Children, and Adolescents 2 months to 17 years: An initial dose of 1 mg/kg/dose subcutaneous every 12 hours adjusted to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL was used in patients aged 2 months or older in a small, pilot study. Patients were randomized to unfractionated heparin (n = 10), enoxaparin (n = 12), or no treatment (n = 8). The majority of patients received warfarin after the initial treatment; however, 4 patients received enoxaparin for the entire treatment period of 3 months. Recurrent thrombosis was not reported in patients taking enoxaparin or heparin; however, 1 patient in the heparin group experienced clinically silent bleeding. Three patients that did not receive an anticoagulant died versus zero patients that did receive anticoagulant therapy. The American College of Chest Physicians (ACCP) guidelines recommend treatment with LMWH initially, followed by warfarin or continued treatment with enoxaparin for a minimum of 3 months in patients without significant hemorrhage; in patients with significant hemorrhage, anticoagulation or radiologic monitoring with subsequent anticoagulation if thrombus extension occurs is recommended.

For thrombosis prophylaxis*, including deep venous thrombosis (DVT) prophylaxis* and pulmonary embolism prophylaxis*:
Subcutaneous dosage:
Neonates: 0.75 mg/kg/dose subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
Infants 1 month: 0.75 mg/kg/dose subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.
Infants, Children, and Adolescents 2 months to 17 years: 0.5 mg/kg/dose subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL.

For the management of multisystem inflammatory syndrome in children (MIS-C) post SARS-CoV-2 exposure*:
-for prophylaxis:
Subcutaneous dosage:
Infants, Children, and Adolescents 2 months to 17 years: 0.5 mg/kg/dose (Max: 30 mg/dose) subcutaneous every 12 hours.
-for treatment:
Subcutaneous dosage:
Infants, Children, and Adolescents 2 months to 17 years: 1 mg/kg/dose subcutaneous every 12 hours. Adjust dose to maintain anti-factor Xa concentration of 0.5 to 1 units/mL. Patients with coronary artery aneurysms and a maximal z-score of 10 or more should be treated with low dose aspirin and therapeutic anticoagulation with enoxaparin for at least 2 weeks before transitioning to warfarin. Patients with an ejection fraction (EF) less than 35% should receive low dose aspirin and therapeutic anticoagulation (enoxaparin or warfarin) until EF exceeds 35%. Patients with documented thrombosis should receive low dose aspirin and therapeutic anticoagulation (enoxaparin or warfarin) for 3 months, pending thrombosis resolution.

Therapeutic Drug Monitoring:
The following anti-factor Xa concentrations are recommended by the American College of Chest Physicians (ACCP) for pediatric patients:
Prophylaxis: 0.1 to 0.3 unit/mL drawn 4 to 6 hours post-dose.
Therapeutic: 0.5 to 1 unit/mL drawn 4 to 6 hours post-dose or 0.5 to 0.8 unit/mL drawn 2 to 6 hours post-dose.

The following dosage adjustments and monitoring have been recommended based on anti-factor Xa concentrations:
Less than 0.35 unit/mL: Increase dose by 25% and repeat 4 hours after the next dose.
0.35 to 0.49 unit/mL: Increase dose by 10% and repeat 4 hours after the next dose.
0.5 to 1 unit/mL: Repeat next day, then 1 week later, and monthly while receiving LMWH (4 hours after the morning dose).
1.1 to 1.5 units/mL: Decrease dose by 20% and repeat before the next dose.
1.6 to 2 units/mL: Hold next dose 3 hours, dose decrease by 30%, and repeat before next dose and 4 hours after the next dose.
More than 2 units/mL: Hold dose until anti-factor Xa concentration is 0.5 unit/mL, decrease dose by 40%, and repeat before next dose if not less than 0.5 unit/mL repeat every 12 hours.

Maximum Dosage Limits:
Enoxaparin has a narrow therapeutic index, specific for the patient population and indication. The maximum dosage is individualized based on anti-factor Xa concentrations and assessment of efficacy and safety parameters.

Patients with Hepatic Impairment Dosing
Enoxaparin therapy has not been studied in patients with hepatic impairment; exposure to enoxaparin in this patient population is unknown.

Patients with Renal Impairment Dosing
The following initial dosage adjustments have been recommended for pediatric patients. Adjust dose further based on anti-factor Xa concentrations. Although no dosage adjustment is recommended for CrCl 30 to 80 mL/min, observe these patients frequently for signs and symptoms of bleeding.
CrCl 30 mL/minute/1.73 m2 or more: No dosage adjustment needed.
CrCl 10 to 29 mL/minute/1.73 m2: Reduce initial dose by 30%.
CrCl less than 10 mL/minute/1.73 m2: Reduce initial dose by 50% and administer every 24 hours.

Intermittent hemodialysis and Peritoneal dialysis
Reduce the initial dose by 50%.

Continuous renal replacement therapy (CRRT)
Reduce the initial dose by 30% (assuming a dialysis dose of 2,000 mL/minute/1.73 m2).

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Enoxaparin exerts its antithrombotic activity by binding to and accelerating the activity of antithrombin III (AT III). The interaction with antithrombin is mediated by a unique pentasaccharide sequence distributed along the heparin chains. Only 15% to 25% of the chains of enoxaparin contain this pentasaccharide sequence, compared with about one-third of the chains of unfractionated heparin (UFH). By activating antithrombin, coagulation factor Xa and factor IIa (thrombin) are inhibited. Enoxaparin and other low molecular weight heparins (LMWHs) are more selective inhibitors of factor Xa than UFH. Although any pentasaccharide chain can inhibit factor Xa, only those at least 18 saccharide units long can inactivate thrombin, since a long chain is required to form a ternary complex between heparin, antithrombin, and thrombin. Although most of the chains of UFH are at least 18 saccharide units long, less than 50% of those of enoxaparin and other LMWHs are of adequate length to bind both antithrombin and thrombin (factor IIa). Therefore, the anti-factor Xa:anti-factor IIa inhibitory ratio of enoxaparin is 2 to 4:1, compared to 1:1 for UFH. Ultimately, thrombin inhibition prevents the formation of fibrin clots. At recommended doses, enoxaparin does not significantly affect platelet activity, prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Pharmacokinetics: Enoxaparin is administered by subcutaneous or intravenous (IV) injection. Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. Enoxaparin has a low affinity for binding to endothelial cells. A significant route of elimination for enoxaparin is renal, which appears to be dose-independent. After IV radiolabeled enoxaparin, 40% of total radioactivity and 8% to 20% of anti-factor Xa is recovered in the urine within 24 hours.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
A 30 mg IV bolus immediately followed by 1 mg/kg subcutaneously every 12 hours provides initial peak anti-factor Xa concentrations of 1.16 International Units/mL and average exposure corresponding to 84% of steady-state concentrations. After IV dosing, the total body clearance of enoxaparin in adults is 26 mL/minute. Results of a small (n = 7) retrospective study in critically ill pediatric patients indicate the peak anti-factor Xa concentrations may occur sooner after IV dosing (1 to 2 hours) vs. subcutaneous dosing (4 to 6 hours).

Subcutaneous Route
Based on anti-factor Xa activity, mean absolute bioavailability in adults after 1.5 mg/kg subcutaneously is approximately 100%. Peak plasma anti-factor Xa activity occurs 3 to 5 hours after subcutaneous injection. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy adult volunteers, steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity is well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen in adults, steady-state is reached from day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough serum concentrations of about 1.2 and 0.52 International Units/mL, respectively. Based on enoxaparin pharmacokinetics, this difference in steady-state is expected and is within the therapeutic range. The elimination half-life of enoxaparin in adults based on anti-factor Xa activity is 4.5 hours after a single subcutaneous dose and may increase to 7 hours after repeated dosing. After a 40 mg subcutaneous dose of enoxaparin in adults, significant anti-factor Xa activity persists in plasma for about 12 hours; the apparent clearance of subcutaneous enoxaparin is 15 mL/minute.


-Special Populations
Pediatrics
Neonates, Infants, Children, and Adolescents
The pharmacokinetics of enoxaparin in pediatric patients are variable with body weight being the most predictive covariate of clearance and volume of distribution. The apparent clearance and volume of distribution were reported as 15.2 mL/kg/hour and 169 mL/kg with an interindividual variability of 54% and 42%, respectively, in a cohort of 126 pediatric patients receiving enoxaparin for treatment of symptomatic venous thromboembolism. A small study (n = 14, age range 3 months to 16 years) assessing once-daily enoxaparin in pediatric patients with thromboembolism found a faster clearance compared to healthy adult volunteers receiving once-daily enoxaparin (0.88 L/hour vs. 0.74 L/hour). Anti-factor Xa concentrations were subtherapeutic (less than 0.5 units/mL) by 12 hours after the dose in 7 of 8 patients who had 24-hour pharmacodynamic monitoring available; in contrast, therapeutic concentrations were measurable in adult volunteers 13 to 18 hours after the dose.

Renal Impairment
Specific information regarding the pharmacokinetics of enoxaparin in pediatric patients with renal impairment is not available. A linear relationship between anti-factor Xa plasma clearance and creatinine clearance at steady-state has been observed in adult patients, indicating reduced enoxaparin clearance in patients with renal impairment. Anti-factor Xa exposure represented by AUC, at steady-state, is marginally increased in mild (CrCl 50 to 80 mL/minute) and moderate (CrCl 30 to 50 mL/minute) renal impairment after repeated subcutaneous doses of 40 mg once daily. In patients with severe renal impairment (CrCl less than 30 mL/minute), the AUC at steady-state is significantly increased on average by 65% after multiple doses of 40 mg subcutaneously once daily. In a single study of hemodialysis patients, the elimination rate appeared similar, but the AUC was 2-fold higher than the control population, after a single 0.25 or 0.5 mg/kg IV dose of enoxaparin.

Gender Differences
Pharmacokinetic differences in pediatric patients based on gender have not been determined. However, in adult patients, after a single subcutaneous 40 mg dose, the anti-factor Xa exposure is 52% higher in low-weight women (weighing less than 45 kg) and 27% higher in low-weight men (weighing less than 57 kg) relative to normal weight control subjects. The apparent clearance and maximal activity derived from anti-factor Xa values after single subcutaneous dosing (40 and 60 mg doses) are 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.

Obesity
The pharmacokinetics of enoxaparin in obese pediatric patients have not been determined. After repeated 1.5 mg/kg subcutaneous once daily dosing, the mean AUC of anti-factor Xa activity is marginally higher at steady-state in obese healthy adult volunteers (BMI 30 to 48 kg/m2) compared to non-obese control subjects, while maximal activity is not increased.