VA Class:BL110

AHFS Class:

• Heparins 20:12.04.16

Generic Name(s):

• Enoxaparin Sodium

Enoxaparin, a low molecular weight heparin (LMWH) prepared by alkaline degradation of unfractionated benzylated heparin of porcine intestinal mucosa origin, is an anticoagulant.1,2,3,4

Enoxaparin is used for the prevention of venous thromboembolism (VTE) in patients undergoing orthopedic surgery or general (e.g., abdominal, gynecologic, urologic) surgery, and in medical patients with severely restricted mobility during acute illness.1,2,3,5,6,7,20,21,22,27,34,35,36,37,66,67,1003,1101,1102 Enoxaparin also is used for the treatment of VTE in hospitalized patients with acute deep-vein thrombosis (DVT) with or without pulmonary embolism (PE) and in outpatients with acute DVT without accompanying PE.1,28

Enoxaparin also is used in the management of acute coronary syndrome (ACS), both in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) and those with acute ST-segment-elevation MI (STEMI) undergoing conservative (medical) management or revascularization strategies (e.g., percutaneous coronary intervention [PCI]).1,40,41,42,43,48,76,162,527,991,994

Other uses of LMWHs include VTE prophylaxis in patients with major trauma† (e.g., brain injury, acute spinal injury), selected patients undergoing intracranial surgery† (e.g., craniotomy for malignant disease), selected cancer patients, and patients with acute ischemic stroke†.1001,1002,1009,1013 Therapy with an LMWH also has been recommended for the prevention and treatment of thromboembolism during pregnancy96,97,98,138,996,1012,1017 and for prevention of embolism in selected patients with atrial fibrillation or atrial flutter† who require temporary interruption of oral anticoagulant therapy for diagnostic or surgical procedures.996,999 Enoxaparin also has been used to reduce the risk of thromboembolism in pregnant women with mechanical prosthetic heart valves†; however, cases of valve thrombosis resulting in death (including maternal and fetal deaths) and/or requiring surgical intervention have been reported with such use.1,68,69,70,71,83,97,98,996 (See Patients with Mechanical Prosthetic Heart Valves under Cautions.)

Venous Thromboembolism

Prophylaxis

General/Abdominal Surgery

Enoxaparin is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing general (abdominal) surgery who are at risk for thromboembolic complications.1 The manufacturer states that risk factors in abdominal surgery patients include age >40 years, obesity, use of general anesthesia for more than 30 minutes, malignancy, and history of venous thromboembolism (VTE).1 While enoxaparin is specifically labeled for use in the abdominal surgery setting, the scope of general and abdominal surgery in clinical practice guidelines include GI, urologic, gynecologic, bariatric, vascular, plastic, and reconstructive surgeries.1002,1101

Decisions regarding use of thromboprophylaxis in patients undergoing general surgery should be based on the patient's level of risk for thromboembolism and bleeding.1002,1101 The American College of Chest Physicians (ACCP) guidelines state that no additional thromboprophylaxis measures other than ambulation are necessary in patients with very low VTE risk.1002 Pharmacologic prophylaxis (with low molecular weight heparin [LMWH] or low-dose unfractionated heparin) is generally recommended in patients with moderate to high risk of VTE who do not have a high risk of bleeding.1002,1101,1103 The risk of VTE remains elevated for at least 12 weeks following surgery.1002 Extended VTE prophylaxis (generally considered as beyond 3 weeks) may be considered in selected patients undergoing major surgery.1101 Because the risk of VTE is particularly high in patients undergoing major abdominal or pelvic surgery for cancer, extended (up to 4 weeks) prophylaxis with an LMWH is recommended in such patients.1002,1103

Use of enoxaparin for VTE prophylaxis in patients undergoing abdominal surgery was established in a randomized, double-blind multicenter trial (ENOXACAN)1,27 comparing enoxaparin sodium (40 mg subcutaneously once daily) with unfractionated heparin sodium (5000 units subcutaneously every 8 hours) administered 2 hours prior to initiation of GI, urologic, or gynecologic surgery in cancer patients and continuing for a maximum of 12 days after surgery.1,27 Enoxaparin and unfractionated heparin demonstrated similar efficacy in preventing thromboembolic events (DVT, PE, or death associated with thromboembolism); these events occurred in 10.1 or 11.3% of patients receiving enoxaparin or unfractionated heparin, respectively (based on intent-to-treat analysis).1,7,71 Data from another randomized double blind trial (Canadian Colorectal DVT Prophylaxis trial) of similar design and treatment duration in patients undergoing colorectal surgery (one-third of whom had cancer) also indicated similar efficacy for enoxaparin sodium (40 mg daily given subcutaneously) and unfractionated heparin sodium (5000 units subcutaneously every 8 hours);1,66 thromboembolic events occurred in 7.1 or 6.7% of patients receiving enoxaparin or unfractionated heparin, respectively (based on intent-to-treat analysis).1,71

Orthopedic Surgery

Enoxaparin is used for the prevention of postoperative DVT, which may lead to PE, in patients undergoing hip-replacement surgery.1,2,3,5,6,7,20,21,22,27,34,35,36,37,38,1003 The drug also is used for the prevention of postoperative DVT and/or PE in patients undergoing knee-replacement surgery.1,20,22,1003 Although enoxaparin is not FDA-labeled for thromboprophylaxis in patients undergoing hip-fracture surgery†, the drug also has been used in such patients.1003

The risk of VTE in major orthopedic surgery is among the highest of all surgical specialties.1003 ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method [e.g., intermittent pneumatic compression]) in all patients undergoing major orthopedic surgery, including total hip-replacement, total knee-replacement, and hip-fracture surgery; thromboprophylaxis should be continued for at least 10-14 days.1003 Among the various antithrombotic agents (e.g., LMWHs, fondaparinux, direct oral anticoagulants [DOACs], low-dose unfractionated heparin, warfarin, aspirin), ACCP states that LMWHs are generally preferred because of their relative efficacy and safety and extensive clinical experience; alternative agents may be considered in situations in which an LMWH is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia [HIT] or in those who refuse or are uncooperative with subcutaneous injections).1003 More recent guidelines issued by the American Society of Hematology (ASH) include additional evidence from studies with DOACs (e.g., apixaban, rivaroxaban).1101 In patients undergoing total hip or total knee arthroplasty, the ASH guideline panel suggests the use of aspirin or an anticoagulant for VTE prophylaxis.1101 If an anticoagulant is used, DOACs are suggested over LMWHs; if DOACs are not used, LMWHs are generally preferred to warfarin or unfractionated heparin.1101 For patients undergoing hip fracture repair, ASH suggests the use of either LMWHs or unfractionated heparin for VTE prophylaxis.1101 When selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered.1003

Efficacy of enoxaparin for prevention of VTE in orthopedic patients has been established in several studies.1 In one study in patients undergoing hip-replacement surgery in whom thromboprophylaxis was initiated 12-24 hours postoperatively and continued for 10-14 days, DVT occurred in 10% of patients treated with enoxaparin sodium 30 mg twice daily versus 46% of placebo-treated patients.1 Limited data from comparative studies suggest that enoxaparin has efficacy similar to or exceeding that of unfractionated heparin in preventing DVT in patients undergoing hip-replacement surgery.2,7,8,18 In a large dose-ranging study in patients undergoing hip-replacement surgery and receiving prophylactic enoxaparin sodium 10 mg once daily, 30 mg twice daily (every 12 hours), or 40 mg once daily 24-48 hours following surgery and continuing for 7-11 days, the incidence of DVT was 25, 11, or 14%, respectively.1,34 Thus, a prophylactic enoxaparin sodium dosage of 40 mg once daily is an alternative to 30 mg twice daily in patients undergoing hip-replacement surgery.1,34

In a double-blind study in patients undergoing knee-replacement surgery in whom prophylaxis was initiated 12-24 hours postoperatively and continued for up to 15 days, DVT occurred in 11% of patients treated with enoxaparin sodium 30 mg twice daily versus 62% of placebo-treated patients.1,20,22 Limited data from an unblinded comparative study suggest that enoxaparin sodium (30 mg subcutaneously every 12 hours) has efficacy similar to or exceeding that of unfractionated heparin sodium (5000 units subcutaneously every 8 hours) in preventing DVT in patients undergoing knee-replacement surgery.1,21,22

Some evidence suggests that extended prophylaxis (i.e., up to 35 days post-surgery) with LMWHs may provide additional protection against thromboembolism in patients undergoing total-hip or total-knee replacement surgery.1003 The risk of DVT is greater for the first several months following hip- or knee-replacement surgery compared with general surgery.35,36,38 While the manufacturer states that the usual duration of enoxaparin therapy following hip- or knee-replacement surgery is 7-10 days, with up to 14 days administered in clinical trials,1 ACCP suggests extended prophylaxis for up to 35 days in patients undergoing major orthopedic surgery and the ASH guidelines state that extended VTE prophylaxis (generally considered as beyond 3 weeks) may be considered in selected patients undergoing major surgery.1003,1101 Results from several placebo-controlled trials that included an extended treatment phase in outpatients with a hip prosthesis who had received short-term prophylaxis with enoxaparin sodium (40 mg once daily initiated 12 hours prior to surgery and continued for 10-15 days) while hospitalized indicate that extended prophylaxis with enoxaparin sodium (40 mg once daily for 3 additional weeks) decreased the incidence of DVT, including asymptomatic thrombosis (as determined by venography), compared with placebo.1,35,36 In one controlled trial in outpatients who had a normal phlebogram at study entry, DVT occurred in 7% of patients receiving extended therapy with enoxaparin compared with 20% of patients receiving placebo; PE was not detected.1,35 In another placebo-controlled trial in patients who had no clinical evidence of VTE at study entry, DVT (as determined by venography) occurred in 16% of patients receiving extended enoxaparin therapy versus 34% of those receiving placebo; most thromboembolic events were asymptomatic.1,36 Broader inclusion criteria of one trial may have contributed to the relatively greater incidence of later thromboembolic events in these patients with a hip prosthesis receiving extended enoxaparin therapy.35,36,38

Other Surgical Settings

Enoxaparin also has been used for VTE prophylaxis in patients undergoing other types of surgery including neurosurgery, cardiac, and vascular surgery.1002,1101

LMWHs have been used for the prevention of VTE in patients undergoing neurosurgery†; however, the benefits of pharmacologic thromboprophylaxis in patients undergoing neurosurgery may be outweighed by the possible increased risk of intracranial hemorrhage.1002,1101 Experts generally suggest the use of a mechanical method of prophylaxis (preferably intermittent pneumatic compression) in neurosurgery patients; for patients considered to be at very high risk for thromboembolism, such as those undergoing craniotomy for malignant disease, a pharmacologic method may be added once adequate hemostasis has been established and the risk of bleeding decreases.1002,1101 For patients in whom pharmacologic prophylaxis is warranted, the ASH guidelines suggest use of LMWHs over unfractionated heparin.1101

LMWHs also have been used for prevention of VTE in patients undergoing cardiac or major vascular surgery†.1002,1101 Because the risk of VTE in most patients undergoing cardiac surgery is considered to be moderate, ACCP generally recommends mechanical methods of prophylaxis (preferably with an intermittent pneumatic compression device) over pharmacologic prophylaxis.1002 If pharmacologic prophylaxis is used, the ASH guidelines suggest LMWHs or unfractionated heparin.1101

Acutely Ill Medical Patients

Enoxaparin is used for the prevention of DVT, which may lead to PE in patients who are at risk of thromboembolic complications due to severely restricted mobility during acute illness.1,67,1001

Efficacy of enoxaparin for this use was established in a placebo-controlled trial in hospitalized patients with acute illness (e.g., congestive heart failure, acute or chronic respiratory failure/insufficiency, acute infection, acute rheumatic disorder, acute arthritic episodes involving the lower extremities) who were considered to be at moderate risk for thromboembolism.1,67 In this study, VTE events (DVT, PE, and death associated with thromboembolism) between days 1 and 14 (the primary outcome) occurred in 4.4% of patients treated with enoxaparin sodium (40 mg daily given subcutaneously for 6-14 days) versus 11.9% of patients receiving placebo (based on intent-to-treat analysis).1,67,71 Therapy with enoxaparin sodium at a dosage of 20 mg daily was no more effective than placebo in these patients.1,67

Treatment decisions regarding the use of prophylactic anticoagulants in acutely ill hospitalized patients should include an assessment of the patient's individual risk of VTE and risk of bleeding.1001 In general, pharmacologic thromboprophylaxis is recommended only in patients who are considered to be at high risk of VTE because the risk-to-benefit trade-off between the reduction in VTE events and bleeding is considered to be more favorable in such patients.1001 Factors that should be considered when choosing an appropriate anticoagulant include patient preference, compliance, ease of administration, and costs associated with the individual agents.1001 LMWHs are recommended in clinical practice guidelines as one of several anticoagulant options for thromboprophylaxis in acutely ill, hospitalized medical patients (including those in the ICU) with an increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding.1001,1108 The ASH guideline panel suggests the use of unfractionated heparin, LMWHs, or fondaparinux for VTE prophylaxis in acutely ill medical patients, and unfractionated heparin or LMWHs in critically ill patients.1108 When considering whether to use an LMWH or DOAC, ASH recommends LMWHs over DOACs unless the patient is receiving a DOAC for other reasons.1108

The manufacturer states that the usual duration of enoxaparin therapy in acute ill hospitalized patients is 6-11 days.1 ACCP guidelines suggest continued thromboprophylaxis for 6-21 days until full mobility is restored or hospital discharge, whichever comes first, and generally does not recommend extended prophylaxis beyond this period.1001 Several studies have evaluated the effects of extended thromboprophylaxis after hospital discharge in acutely ill medical patients; findings with regard to efficacy and bleeding have varied depending on the anticoagulants used.1108,1109 Additional study is required to provide guidance on extended VTE prophylaxis in medical patients.1109

Because risk of VTE is particularly high in acutely ill hospitalized patients with cancer, thromboprophylaxis is generally recommended.1001,1102,1103 ASH suggests the use of LMWHs over unfractionated heparin for thromboprophylaxis in these patients.1103 Routine pharmacologic thromboprophylaxis generally is not recommended in cancer patients in the outpatient setting who have no additional risk factors for VTE.1001 However, thromboprophylaxis with an LMWH may be considered in selected outpatients with cancer who have a high risk of thrombosis (e.g., patients with multiple myeloma receiving lenalidomide-, pomalidomide-, or thalidomide-based regimens).1102,1103

Trauma

LMWHs also have been used for VTE prophylaxis in trauma patients†.1002,1101 In general, some form of thromboprophylaxis (with LMWHs, low-dose unfractionated heparin, or a mechanical method) is suggested by ACCP in all major trauma patients.1002 For patients at high risk of VTE, including those with acute spinal cord injury, traumatic brain injury, or spinal surgery for trauma, ACCP suggests the use of both a pharmacologic and mechanical method of prophylaxis, unless contraindications exist.1002

Treatment and Secondary Prevention

VTE Treatment in Adults

Enoxaparin is used for the treatment of DVT with or without PE in hospitalized patients and also in outpatients for the treatment of acute DVT without PE.1

The labeled indication includes the use of warfarin in conjunction with enoxaparin for the treatment of VTE; however, anticoagulants other than warfarin (e.g., the direct oral anticoagulants [DOACs]) have been used for long-term anticoagulation following initial treatment with enoxaparin.1104 In the principal efficacy studies, enoxaparin was used in conjunction with warfarin (starting within 72 hours of initiating enoxaparin and continuing for 90 days).1 When warfarin therapy is being considered for the long-term treatment of VTE, the drug should be initiated concurrently with enoxaparin, and such therapy should be continued for at least 5 days and until the international normalized ratio (INR) is at least 2 for 24 hours or longer.1005

LMWHs are recommended by ACCP as one of several parenteral anticoagulant options for initial treatment of VTE.1005,1104 However, initial treatment with a parenteral anticoagulant may not always be necessary since oral anticoagulant options are available.1005,1102,1103,1104 For patients treated with initial parenteral anticoagulation, ACCP generally recommends fondaparinux or LMWHs over unfractionated heparin because of more convenient administration and less risk of HIT.1005 LMWHs and fondaparinux are considered to be comparable; therefore, the choice between these agents should be dictated by local considerations such as cost, availability, and familiarity of use.1005 In cancer patients with VTE, ASH suggests use of either an LMWH or DOAC for initial treatment.1103

In patients with VTE, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on whether the VTE event was unprovoked or provoked by a transient risk factor (e.g., surgery), the presence of cancer, and the patient's risk of bleeding.1005,1104 In patients with cancer, anticoagulation therapy is recommended for at least 6 months; treatment beyond 6 months may be considered in selected patients.1102 DOACs are generally preferred for long-term treatment of VTE in patients without cancer.1104 In patients with cancer and established VTE, LMWHs or DOACs are generally recommended over warfarin for long-term anticoagulation.1102,1103,1104 ACCP suggests the use of LMWHs in these patients because of possibly greater efficacy and reliability (in those who may have difficulty with oral therapy).1104 LMWHs are preferred to DOACs in settings with an increased risk of bleeding (e.g, hemorrhagic lesion, renal/hepatic impairment, thrombocytopenia, GI or genitourinary malignancy, mucosal lesion, CNS malignancy or bleeding, recent surgery), and also may be preferred in patients with obesity (body weight greater than 120 kg or BMI greater than 40 mg/m²), drug-drug interactions, or GI complications affecting oral therapy (e.g., poor absorption, nausea and vomiting).1102,1104 Recurrent VTE while on therapeutic anticoagulation is unusual and should prompt investigation of causative factors (e.g., noncompliance, underlying malignancy).1104 In patients experiencing recurrent VTE during therapy with an LMWH, ACCP suggests increasing the dosage (by about one-quarter to one-third).1104

Data from numerous randomized studies comparing enoxaparin sodium (1 mg/kg twice daily or 1.5 mg/kg daily for a minimum of 5 days) to unfractionated heparin sodium (dosage adjusted to prolong the aPTT between 55 and 85 seconds) in patients with acute lower extremity DVT with or without PE indicate that enoxaparin is as effective as unfractionated heparin in the treatment and secondary prevention of recurrent thromboembolic events.1,28,29,1005 In these studies, warfarin was initiated within 72 hours of initiation of enoxaparin or unfractionated heparin and was continued for 90 days.1,29 Other randomized controlled studies have compared LMWHs with warfarin or other oral anticoagulants in the treatment of VTE.172,173,1104

VTE Treatment in Pediatric Patients

LMWHs also have been used for the treatment and secondary prevention of VTE in pediatric patients†.1013 Unlike adults, most episodes of VTE in children are secondary to an identifiable risk factor such as the presence of a central venous access device.1013 Recommendations regarding the use of antithrombotic therapy in children generally are extrapolated from adult guidelines.1013

Acute Coronary Syndrome

Enoxaparin is used (in conjunction with aspirin) to reduce the risk of ischemic complications in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS), including those managed with conservative (medical) therapies or revascularization strategies (e.g., percutaneous coronary intervention [PCI] with coronary stent implantation, coronary artery bypass grafting [CABG]); the drug is also used (in conjunction with aspirin) in patients with acute ST-segment-elevation myocardial infarction (STEMI) who are being managed medically (with fibrinolytic therapy) or with subsequent PCI.1,40,41,42,43,76,146,162,527,991,994

Non-ST-Segment-Elevation Acute Coronary Syndrome

The spectrum of patients with NSTE-ACS includes those with unstable angina and non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.805,991 The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with NSTE-ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as PCI with coronary artery stent implantation or CABG) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE-ACS; standard medical therapies for all patients should include an anticoagulant agent regardless of the initial management approach.991 Initial parenteral anticoagulants with established efficacy in patients with NSTE-ACS include enoxaparin, unfractionated heparin, bivalirudin (only in patients who are being managed with an early invasive strategy), and fondaparinux.991 In patients with NSTE-ACS who are subsequently undergoing PCI, an additional IV dose of enoxaparin may be required depending on the timing of the last administered subcutaneous dose.1,527,994 (See Non-ST-Segment-Elevation Acute Coronary Syndrome under Dosage and Administration.) Anticoagulation therapy is necessary during PCI to prevent thrombus formation at the site of arterial injury, on the coronary guidewire, and in the catheters used for the procedure.994

Data from several trials comparing an LMWH (e.g., enoxaparin, dalteparin) with unfractionated heparin in patients with NSTE-ACS indicate that LMWHs are at least as effective as unfractionated heparin in preventing MI and death during the acute phase (e.g., first week) of therapy.1,40,41,42,43,53,121 While some patients with unstable angina in these trials had a low risk of further ischemic complications (e.g., effort angina only, no ECG changes indicative of myocardial ischemia),43,49,52,53,54 most patients studied were at intermediate to high risk of further ischemic complications.41,42,43,44,48,49,54

In the acute phase (first 14 days after hospitalization) of a large comparative trial (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events [ESSENCE]) evaluating short-term therapy with aspirin and enoxaparin sodium (1 mg/kg twice daily) or unfractionated heparin sodium (loading dose of 5000 units, then a continuous infusion adjusted to maintain the aPTT between 55 and 85 seconds) for a median duration of 2.6 days (range: 2-8 days) in patients with NSTE-ACS, the frequency of the combined outcome of death, nonfatal MI, or recurrent angina was reduced in patients receiving enoxaparin compared with unfractionated heparin.1,41,43 Combined end points in this study occurred in about 16.5 or 19.8% of patients receiving enoxaparin or unfractionated heparin, respectively, at 14 days. 1,71 The incidence of these end points increased to about 19.8 or 23.4% in those receiving enoxaparin or unfractionated heparin, respectively, at 30 days1,71 and to about 32 or 35.7% of those receiving enoxaparin or unfractionated heparin, respectively, at 1 year: differences in these combined end points were statistically significant at all these time points evaluated. 1,71,72 Urgent revascularization procedures were performed less frequently in patients receiving enoxaparin (6.3%) than unfractionated heparin (8.2%) at 30 days after initiation of treatment. 1 Of the combined end points, reduction of recurrent angina was most striking with enoxaparin therapy.1,40,41,43 When the incidence of death or MI was considered separately, the effect of enoxaparin on these remaining end points was similar to unfractionated heparin. 1,41

In another comparative trial (Thrombolysis in Myocardial Infarction [TIMI] 11B) evaluating enoxaparin sodium (30 mg loading dose followed by 1 mg/kg twice daily for approximately 5 days) and unfractionated heparin sodium (70 units/kg loading dose followed by an infusion with dosage adjusted to maintain the aPTT between 1.5-2.5 times the control value for 3 days), the combined incidence of death, nonfatal MI, or need for urgent revascularization was 12.4% in those receiving enoxaparin and 14.5% in those receiving unfractionated heparin at 8 days; the relative risk reduction in these end points was 14.6%.42 The effect of trial therapies of unequal duration on the observed outcome is uncertain.40,42

In a randomized, open-label comparative study (SYNERGY) in approximately 10,000 high-risk patients with NSTE-ACS, therapy with enoxaparin was noninferior to therapy with unfractionated heparin in terms of the incidence of the combined outcome of all-cause death or nonfatal MI at 30 days (primary efficacy end point).136 The primary efficacy end point occurred in 14% of patients receiving enoxaparin sodium (1 mg/kg subcutaneously every 12 hours) versus 14.5% of patients receiving unfractionated heparin sodium (60 units/kg by direct IV [“bolus”] injection followed by initial infusion of 12 units/kg per hour with subsequent dosage adjustment to achieve an aPTT of 1.5-2 times the upper limit of normal or 50-70 seconds).135,136 Patients were intended to be treated with an early invasive strategy, and most received concomitant therapy with aspirin (162-325 mg daily) and GP IIb/IIIa-receptor inhibitors.136 Approximately 47% of total patients underwent PCI and 19% had surgical revascularization procedures.136 Major bleeding (defined as intracranial bleeding or a decrease of at least 5 g/dL in hemoglobin or at least 15% in hematocrit, according to TIMI criteria) occurred more frequently in enoxaparin-treated patients and was related principally to CABG.136

ST-Segment-Elevation Myocardial Infarction

The current standard of care in patients with STEMI is timely reperfusion (with primary PCI or thrombolytic therapy).527,994 Adjunctive therapy with anticoagulant and antiplatelet agents should be used during and after successful coronary artery reperfusion for the prevention of early reocclusion and death, unless contraindicated.527 Adjunctive use of an LMWH in patients with STEMI has been associated with improvement in short-term clinical outcomes (e.g., death, reinfarction, recurrent ischemia) with generally similar rates of bleeding complications compared with unfractionated heparin or placebo.129,130,131,132,133 When used in conjunction with aspirin, enoxaparin has been shown to reduce the rate of a composite end point of recurrent MI or death in such patients.1,162

The American College of Cardiology Foundation (ACCF) and AHA guidelines state that patients with STEMI undergoing thrombolytic therapy should receive an anticoagulant (e.g., unfractionated heparin, enoxaparin, fondaparinux) for a minimum of 48 hours, and preferably for the duration of the index hospitalization, up to 8 days or until revascularization is performed.527 Enoxaparin is preferred over unfractionated heparin if extended anticoagulation is necessary beyond 48 hours.527 In patients with STEMI who are subsequently undergoing PCI, an additional IV dose of enoxaparin may be required depending on the timing of the last administered subcutaneous dose.1,527,994 (See ST-Segment-Elevation Myocardial Infarction under Dosage and Administration.) Anticoagulation therapy is necessary during PCI to prevent thrombus formation at the site of arterial injury, on the coronary guidewire, and in the catheters used for the procedure.994

Efficacy of enoxaparin as adjunctive therapy in the management of acute STEMI has been established in more than 20,000 patients with acute STEMI who were scheduled to undergo thrombolytic therapy with tenecteplase, alteplase, reteplase, or streptokinase.1,162 In a multicenter, randomized, double-blind, double-dummy, parallel-group study (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction treatment-Thrombolysis in myocardial infarction 25 [EXTRACT-TIMI 25]), adjunctive treatment with enoxaparin was more effective than unfractionated heparin (17% relative risk reduction) in reducing the rate of the composite efficacy end point of death from any cause or nonfatal recurrent MI at 30 days; the treatment benefit of enoxaparin emerged after 48 hours and was observed both in patients who were managed medically as well as those managed with PCI.1,162 The benefit of enoxaparin on the primary efficacy end point during the first 30 days of treatment was maintained over a 12-month follow-up period;1,165 however, there was no additional reduction in recurrent MI after 30 days and no mortality reduction at 1 year.165 In addition, an increased risk of major bleeding (including intracranial hemorrhage) was observed in patients receiving enoxaparin compared with those receiving unfractionated heparin.1 Careful patient selection is needed to ensure that the benefits of enoxaparin outweigh the increased risk of bleeding associated with the drug.162,164

In the EXTRACT-TIMI 25 study, enoxaparin was given in an initial dose of 30 mg by direct IV injection in conjunction with a 1-mg/kg subcutaneous dose, followed by 1 mg/kg every 12 hours by subcutaneous injection for patients younger than 75 years of age, or in a dosage of 0.75 mg/kg every 12 hours by subcutaneous injection without an initial direct IV dose for patients 75 years of age or older; unfractionated heparin was administered in an initial dose of 60 units/kg (maximum 4000 units) by direct IV injection followed by continuous IV infusion of 12 units/kg per hour.1,162 All patients received aspirin (150-325 mg initially, then 75-325 mg daily) for at least 30 days.1,162 Enoxaparin was administered throughout the index hospitalization period (mean treatment duration of 6.6 days), while unfractionated heparin was administered for at least 48 hours (mean duration of 54 hours).1 The relatively longer duration of enoxaparin treatment compared with that of unfractionated heparin and a possible rebound increase in thrombotic events following discontinuance of heparin therapy may have contributed to the treatment differences in this study.1,162

Acute Ischemic Stroke

Although therapeutic-dose anticoagulation has been used in patients with acute ischemic stroke†, there is strong evidence that such treatment is associated with worse outcomes than aspirin therapy in terms of increased mortality and rates of nonfatal major extracranial bleeding.1009 Therefore, the American College of Chest Physicians (ACCP) recommends early treatment (within 48 hours) with aspirin over therapeutic anticoagulation to prevent recurrent cerebral thromboembolism in patients with acute ischemic stroke or TIA.1009

Low molecular weight heparins (LMWHs) have been used for thromboprophylaxis in patients with acute ischemic stroke; those with additional risk factors for venous thromboembolism (VTE) (e.g., restricted mobility) are more likely to benefit from such prophylaxis.1009,1017

LMWHs also have been used in the management of acute arterial ischemic stroke in children† until dissection and embolic causes have been excluded.1013

Thromboembolism During Pregnancy

Low molecular weight heparins (LMWHs) are used for prevention and treatment of venous thromboembolism (VTE) during pregnancy† and also for prevention of thrombotic complications associated with prosthetic mechanical heart valves in pregnant women†.138,996,1012,1104 LMWHs also may be used in combination with aspirin for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies†.1012 Pregnancy is associated with a hypercoagulable state and an increased risk of thromboembolism,85,86,87,88,91,92,94,95,98,99 and pregnant women with thromboembolic disease or hereditary or acquired thrombophilias are at greater risk for fetal loss as a result of stillbirth, spontaneous abortion, or premature delivery.1,82,83,1012 (See Thromboembolism Associated with Prosthetic Heart Valves under Uses.)

The American College of Chest Physicians (ACCP) states that LMWHs are the anticoagulant of choice for prevention and treatment of thromboembolism during pregnancy; there is a potential for other agents to cross the placenta.1012,1104 In pregnant women with acute VTE†, LMWHs are recommended for initial treatment and secondary prevention throughout the remainder of the pregnancy.1012 Anticoagulant therapy should be continued for at least 6 weeks postpartum and a minimum total duration of 3 months to prevent recurrence of VTE.1012

Recommendations regarding the use of anticoagulant prophylaxis during the antepartum period in pregnant women who have a history of thromboembolism† are based on the patient's risk for recurrent events.1012 In general, thromboprophylaxis (e.g., with LMWHs) is suggested only in patients with moderate to high risk of recurrent thromboembolism (e.g., unprovoked VTE, pregnancy- or estrogen-related VTE, history of multiple unprovoked events).1012

The presence of hereditary thrombophilias and a family history of VTE substantially increases the risk of pregnancy-related VTE.1012 Homozygous genetic mutations for factor V Leiden or prothrombin G20210A are associated with the highest risks of thromboembolism in pregnant women.1012 ACCP therefore suggests antepartum prophylaxis with LMWHs (in prophylactic or intermediate dosages) in selected pregnant women with these genetic mutations.1012

To avoid an unwanted anticoagulant effect on the fetus during delivery, therapy with LMWHs should be discontinued prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia).996,1012 (See Dosage under Dosage and Administration.)

Cardioversion of Atrial Fibrillation/Flutter

Low molecular weight heparins (LMWHs) also have been used for the prevention of stroke and systemic embolism in patients with atrial fibrillation undergoing electrical or pharmacologic cardioversion†.999,1007,1105 Because the risk of thromboembolism appears to be greatest when atrial fibrillation has been present for >48 hours, recommendations for the use of anticoagulant therapy in such patients vary based on the duration of the arrhythmia.999,1007 The American College of Chest Physicians (ACCP) and other experts recommend that patients with atrial fibrillation of ≥48 hours' duration or of an unknown duration who are to undergo elective cardioversion receive therapeutic anticoagulation (with warfarin or a direct oral anticoagulant [DOAC]) for at least 3 weeks prior to cardioversion; an alternative strategy is to perform transesophageal echocardiography (TEE) to exclude thrombus and then administer therapeutic anticoagulation with an LMWH or unfractionated heparin prior to cardioversion.999,1007,1105 Patients with atrial fibrillation of <48 hours' duration and a high risk of stroke (e.g., CHA₂DS₂-VASc score of 2 or more for males or 3 or more for females) usually do not require prolonged anticoagulation or TEE prior to cardioversion; such patients may receive therapeutic anticoagulation (e.g., with an LMWH, unfractionated heparin, or DOAC) at presentation, followed by immediate cardioversion and long-term anticoagulant therapy.999,1007,1105 In patients with atrial fibrillation of <48 hours' duration and a low risk of stroke (e.g., CHA₂DS₂-VASc score of 0 for males and 1 for females), the same therapeutic anticoagulation strategies or no anticoagulation therapy may be considered for cardioversion.999,1105 After successful cardioversion in patients with atrial fibrillation of ≥48 hours' duration, experts recommend that patients receive therapeutic anticoagulation for at least 4 weeks;999,1007 patients with atrial fibrillation of <48 hours' duration who have a low risk of stroke generally do not need oral anticoagulation postcardioversion.999,1105 In all patients, the decision to administer long-term anticoagulation following cardioversion should be based on the patient's risk of thromboembolism and risk of bleeding.999,1105

In patients undergoing cardioversion for atrial flutter†, the same approach to thromboprophylaxis should be used as for those with atrial fibrillation.999,1007,1105

Thromboembolism Associated with Prosthetic Heart Valves

Low molecular weight heparins (LMWHs) have been used to reduce the risk of thromboembolism (e.g., stroke) during conversion to maintenance oral anticoagulant therapy (e.g., warfarin) in patients with prosthetic mechanical heart valves†.64,83,87,90,93,97,98,1008 (See Bridging Anticoagulation under Uses.) In the absence of a bleeding risk, the American College of Chest Physicians (ACCP) suggests bridging therapy (e.g., administration of an LMWH in either prophylactic or therapeutic dosages) during the early postoperative period after insertion of a mechanical heart valve until an adequate response to the oral anticoagulant is obtained.1008 (See Dosage under Dosage and Administration.)

In patients with a mechanical heart valve in whom therapy with an oral anticoagulant must be temporarily discontinued (e.g., those undergoing major surgery), bridging anticoagulation† with an LMWH has been used in selected patients (e.g., those at high risk of thromboembolism).996,1004

Pregnant women with prosthetic mechanical heart valves† may be at even higher risk for thromboembolism;1,85,89,91,92,95 thrombosis of prosthetic heart valves has occurred in some pregnant women receiving enoxaparin prophylaxis and in some cases has resulted in maternal and/or fetal death.1,68,69,70,71,82,83,85,87,88,90,93 (See Patients with Mechanical Prosthetic Heart Valves under Cautions.) Pregnant women with prosthetic mechanical heart valves should receive therapeutic anticoagulation with frequent monitoring during pregnancy.996 No anticoagulation strategy is optimal in terms of safety to the mother and fetus.996 While warfarin is safest for the mother, the drug crosses the placenta and can cause adverse fetal effects; although unfractionated heparin and LMWHs do not cross the placenta, both are associated with higher rates of maternal complications than warfarin.996 There is evidence indicating that fixed-dose LMWHs or adjusted-dose, poorly controlled unfractionated heparin therapy is not effective in preventing systemic embolism in pregnant women with prosthetic mechanical heart valves.83,84,85,87,88,89,90,93,94,95,99,996 Strategies using LMWHs include an option where dose-adjusted LMWH (i.e., given twice daily and adjusted to maintain peak anti-factor Xa concentration of 0.8-1.2 units/mL at 4-6 hours postinjection) is used throughout pregnancy and an alternative option where dose-adjusted LMWH is used for the first trimester followed by warfarin for the second and third trimesters.996

If enoxaparin is used for anticoagulation in pregnant women with mechanical prosthetic heart valves, frequent monitoring of peak and trough anti-factor Xa levels and dosage adjustments may be required to ensure consistent anticoagulation.1,71,83,93 (See Pregnancy under Cautions.)

Cerebral Venous Sinus Thrombosis

Low molecular weight heparins (LMWHs) have been used for the treatment of acute cerebral venous sinus (sinovenous) thrombosis† in adults and pediatric patients.1009,1013,1017

Bridging Anticoagulation

Low molecular weight heparins (LMWHs) have been used for bridging anticoagulation† during temporary interruption of long-term oral anticoagulant therapy in patients undergoing surgery or other invasive procedures†.996,1004,1014 Perioperative use of LMWHs has been recommended during the period of interruption of oral anticoagulant therapy in some patients with venous thromboembolism (VTE), atrial fibrillation, or mechanical prosthetic heart valves depending on the patient's risk of thromboembolism and risk of bleeding.1004 Bridging anticoagulation has been associated with an increased risk of major bleeding without a significant effect on arterial thromboembolism in some settings and therefore should be considered on an individual basis.996,1014 (See Thromboembolism Associated with Prosthetic Heart Valves under Uses.)

General

Patient Monitoring

• The possibility of an underlying bleeding disorder should be ruled out before initiating enoxaparin therapy.1 Since prothrombin time (PT) and activated partial thromboplastin time (aPTT) are insensitive for monitoring enoxaparin activity, routine monitoring of coagulation parameters generally is not required.1,135 In pregnant patients, patients at extremes of weight, or if abnormal coagulation parameters, appreciable renal impairment, or bleeding should occur, anti-factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin.1,135 (See Special Populations under Dosage and Administration.)
• If enoxaparin is used for anticoagulation in pregnant women with mechanical prosthetic heart valves, frequent monitoring of peak and trough anti-factor Xa concentrations is recommended to assess anticoagulation, and dosage should be adjusted as necessary.1,83 (See Patients with Mechanical Prosthetic Heart Valves under Cautions.) The American College of Chest Physicians (ACCP) and other clinicians recommend twice-daily dosing of LMWHs in pregnant women, at least initially, because of altered pharmacokinetics during pregnancy.996,1012

Administration

Enoxaparin sodium is administered by deep subcutaneous injection; it must not be given IM .1 The drug also is administered IV (as a direct IV injection) in certain situations.1,162,994 (See ST-Segment-Elevation Myocardial Infarction and also see Non-ST-Segment-Elevation Acute Coronary Syndrome under Dosage and Administration.)

Patients should be supine during administration of the drug.1

To avoid loss of drug when using the prefilled syringes, the manufacturer states that air should not be expelled from the syringe prior to injection.1 If the prescribed dose is less than the full syringe volume, the excess syringe volume should be ejected until only the prescribed dose remains in the syringe.1

Subcutaneous Administration

When injecting enoxaparin subcutaneously, the entire length of the needle should be inserted into a skin fold created by the thumb and the forefinger; the skin fold should be held until the needle is withdrawn.1 Injections should be made into the left and right anterolateral and posterolateral abdominal wall; injection sites should be alternated frequently.1 To minimize bruising, injection sites should not be massaged after injection.1

IV Administration

When enoxaparin is administered IV, the multiple-dose vial preparation should be used.1 Enoxaparin should not be mixed with other drugs.1 The IV line should be flushed before and after enoxaparin administration with either 0.9% sodium chloride injection or 5% dextrose injection.1

Dosage

Dosages for enoxaparin sodium or other low molecular weight heparins (LMWHs) or unfractionated heparin sodium cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis .1 Enoxaparin sodium has an approximate anti-factor Xa activity of 100 units/mg according to the World Health Organization (WHO) First International Low Molecular Weight Heparin Reference Standard.1

If an LMWH is used for anticoagulation in children, ACCP suggests that dosage of the drug be adjusted to a target anti-factor Xa level of 0.5-1 units/mL based on a sample taken 4-6 hours, or 0.5-0.8 units/mL based on a sample taken 2-6 hours, following subcutaneous administration.1013

Prevention of Venous Thromboembolism

General/Abdominal Surgery

For venous thromboembolism (VTE) prophylaxis in patients undergoing general (abdominal) surgery who are at risk for thromboembolic complications, the manufacturer recommends an enoxaparin sodium dosage of 40 mg once daily by subcutaneous injection.1 The initial dosage should be given 2 hours prior to surgery.1 Enoxaparin should be administered throughout the postoperative period, generally for 7-10 days;1 however, the manufacturer states that treatment with enoxaparin has been well tolerated for up to 12 days in patients undergoing abdominal surgery in clinical trials.1,71 Extended VTE prophylaxis (generally considered as beyond 3 weeks) may be considered in selected patients undergoing major general surgery.1101 Because the risk of VTE is particularly high in patients undergoing abdominal or pelvic surgery for cancer, the American College of Chest Physicians (ACCP) recommends that therapy with LMWHs be continued for up to 4 weeks in such patients.1002

Hip- or Knee-Replacement Surgery

For VTE prophylaxis in patients undergoing hip-replacement or knee-replacement surgery, the manufacturer recommends an enoxaparin sodium dosage of 30 mg twice daily (every 12 hours) by subcutaneous injection beginning 12-24 hours postoperatively, provided hemostasis has been established.1 Alternatively, in patients undergoing hip-replacement surgery, the manufacturer states that an enoxaparin sodium dosage of 40 mg once daily (every 24 hours) by subcutaneous injection beginning 12 (±3) hours preoperatively may be considered, based on dose-comparison data indicating that a dosage of 40 mg once daily may be as effective as 30 mg twice daily (every 12 hours) in preventing DVT in such patients.1,2,10,34,71 ACCP states that risk of bleeding is closely associated with the timing of initiation of thromboprophylaxis around surgery and recommends that LMWHs be initiated at least 12 hours preoperatively or at least 12 hours postoperatively in patients undergoing major orthopedic surgery.1003

Enoxaparin should be administered throughout the postoperative period, generally for 7-10 days, until the risk of DVT has diminished; ACCP recommends a minimum of 10-14 days of thromboprophylaxis, with extended prophylaxis suggested for up to 35 days on an outpatient basis.1,1003 Treatment with enoxaparin for up to 14 days has been well tolerated in clinical trials.1 Following the initial phase of thromboprophylaxis during the acute postoperative period in patients undergoing hip-replacement surgery, the manufacturer recommends continued prophylaxis with subcutaneous enoxaparin sodium 40 mg once daily for 3 weeks.1

Medical Conditions Associated with Thromboembolism

For VTE prophylaxis in patients at increased risk of thromboembolism due to severely restricted mobility during acute illness (e.g., cancer, heart failure, severe lung disease, those confined to bedrest), the manufacturer recommends an enoxaparin sodium dosage of 40 mg daily, usually given for 6-11 days;1 treatment with the drug for up to 14 days has been well tolerated in clinical trials.1 ACCP suggests against the use of extended thromboprophylaxis beyond the period of patient immobilization or acute hospitalization in acutely ill medical patients because of an increased risk of bleeding and the burden and costs of daily injections.1001 However, extended thromboprophylaxis has been used in selected patients after hospital discharge.1108,1109

Treatment of Venous Thromboembolism

For the outpatient treatment of uncomplicated deep-vein thrombosis (DVT) without pulmonary embolism (PE), the usual dosage of enoxaparin sodium is 1 mg/kg twice daily given subcutaneously.1,29

In hospitalized patients with venous thromboembolism (VTE), the usual dosage of enoxaparin sodium is 1 mg/kg twice daily or 1.5 mg/kg once daily administered subcutaneously at the same time every day.1

The manufacturer states that the average duration of therapy is 7 days.1 In patients with VTE, the American College of Chest Physicians (ACCP) recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on whether the VTE event was unprovoked or provoked by a transient risk factor (e.g., surgery), the presence of cancer, and the patient's risk of bleeding.1005,1104

Transitioning from Enoxaparin to Oral Anticoagulants

In patients transitioning to warfarin for long-term anticoagulant therapy, warfarin should be initiated when appropriate (usually within 72 hours of enoxaparin initiation) and continued for a minimum of 5 days and until a therapeutic international normalized ratio (INR of 2-3) has been achieved.1 Enoxaparin may be discontinued after this period of overlap with warfarin,29 generally after a total of 7 days of enoxaparin treatment.1

In patients transitioning to dabigatran for long-term anticoagulant therapy, enoxaparin should be administered for 5-10 days.168 Enoxaparin should then be discontinued, and dabigatran initiated 0-2 hours prior to the time of the next scheduled dose of enoxaparin.168

In patients transitioning to edoxaban for long-term anticoagulant therapy, enoxaparin should be administered for 5-10 days.169 Enoxaparin should then be discontinued and edoxaban initiated at the time of the next scheduled dose of enoxaparin.169

In patients transitioning to apixaban for long-term anticoagulant therapy, enoxaparin should be discontinued and apixaban initiated at the time of the next scheduled dose of enoxaparin.170

In patients transitioning to rivaroxaban for long-term anticoagulant therapy, enoxaparin should be discontinued and rivaroxaban initiated 0-2 hours prior to the time of the next scheduled dose of enoxaparin.171

Non-ST-Segment-Elevation Acute Coronary Syndrome

In patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) who are receiving concurrent therapy with aspirin (e.g., 75-325 mg once daily), the usual dosage of enoxaparin sodium is 1 mg/kg every 12 hours by subcutaneous injection. 1,41 Anticoagulant therapy should be administered as soon as possible after hospital admission.991 Treatment with enoxaparin should continue for a minimum of 2 days until the patient is clinically stabilized, generally for 2-8 days; the manufacturer states that treatment with enoxaparin for up to 12.5 days has been well tolerated in clinical trials. 1,41,42

The American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and the Society for Cardiovascular Angiography and Interventions (SCAI) state that it is reasonable to administer enoxaparin sodium (e.g., 0.5-0.75 mg/kg by direct IV injection †) for prevention of thrombus formation during percutaneous coronary intervention (PCI) in patients with NSTE-ACS who have not received prior anticoagulant therapy.994 In patients with NSTE-ACS in whom subcutaneous enoxaparin has been initiated prior to PCI (“upstream”), ACCF/AHA/SCAI state that an additional 0.3-mg/kg dose of enoxaparin sodium should be given by direct IV injection at the time of PCI if fewer than 2 prior therapeutic (e.g., 1 mg/kg) subcutaneous doses of enoxaparin sodium have been given or if the last subcutaneous dose of the drug was administered 8-12 hours before PCI†.994 To minimize the possibility of bleeding associated with vascular (e.g., vascular access sheath) instrumentation (e.g., PCI) during treatment of NSTE-ACS, strict adherence to dosage intervals of subcutaneous enoxaparin and precautions in the removal of the vascular access sheath should be observed.1 The next dose of enoxaparin sodium should be given no sooner than 6-8 hours after removal of the vascular access sheath;1 ACCF/AHA/SCAI suggest removal of femoral sheaths when the activated clotting time (ACT) falls to less than 150-180 seconds or when the activated partial thromboplastin time (aPTT) falls to less than 50 seconds.994 Careful monitoring of vascular access sites for signs of bleeding or hematoma formation should be undertaken after removal of the vascular sheath and during treatment with enoxaparin.1

ST-Segment-Elevation Myocardial Infarction

In patients with acute ST-segment-elevation myocardial infarction (STEMI) who are younger than 75 years of age, an initial direct IV injection of enoxaparin sodium 30 mg plus a 1-mg/kg subcutaneous dose is recommended by the manufacturer, followed by subcutaneous injections of enoxaparin sodium 1 mg/kg every 12 hours; a maximum of 100 mg is recommended for each of the first 2 subcutaneous doses.1,162 For the treatment of acute STEMI in patients 75 years of age or older, the recommended dosage of enoxaparin sodium is 0.75 mg/kg every 12 hours (not to exceed 75 mg per dose for the first 2 doses) by subcutaneous injection; an initial IV dose should not be given.1 Aspirin (75-325 mg once daily) should be administered in conjunction with enoxaparin therapy unless contraindicated.1 When used with thrombolytic therapy, enoxaparin therapy should be initiated between 15 minutes before and 30 minutes after the start of thrombolytic therapy.1 The manufacturer states that the usual duration of enoxaparin treatment is 8 days or until hospital discharge.1,162

In patients with acute STEMI undergoing percutaneous coronary intervention (PCI), the manufacturer recommends administration of an additional 0.3-mg/kg dose of enoxaparin sodium by direct IV injection during PCI if the last subcutaneous dose of enoxaparin sodium was administered more than 8 hours before balloon inflation; otherwise, no additional dose is recommended.1,166,167

Treatment and Prevention of Thromboembolism During Pregnancy

In pregnant women with acute venous thromboembolism (VTE)†, enoxaparin sodium 1 mg/kg twice daily is recommended by the American College of Chest Physicians (ACCP) for initial treatment and should be continued throughout the remainder of the pregnancy.1012 Anticoagulation should be continued postpartum for at least 6 weeks (for a minimum total duration of 3 months).1012

If enoxaparin sodium is used for postpartum prophylaxis in pregnant women with a prior VTE†, a prophylactic (e.g., 40 mg once daily) or intermediate dosage (e.g., 40 mg every 12 hours) is suggested.1012

In pregnant women with mechanical prosthetic heart valves receiving long-term warfarin anticoagulation†, if the decision is made to switch to an LMWH-based strategy, dose-adjusted LMWH is recommended.996 The LMWH may be administered throughout all 3 trimesters or, alternatively, the LMWH may be administered during the first trimester, followed by warfarin during the second and third trimesters.996 The LMWH should be administered at least 2 times daily with close monitoring of anti-factor Xa levels.996 Dosage should be adjusted to target factor Xa levels of 0.8-1.2 units/mL 4-6 hours after dosing.996 (See Patients with Mechanical Prosthetic Heart Valves under Cautions.)

If enoxaparin sodium is used for primary prevention of VTE in pregnant women with certain high-risk thrombophilias†, a prophylactic (e.g., 40 mg once daily) or intermediate (e.g., 40 mg every 12 hours) subcutaneous dosage is suggested.1012,1107 (See Pregnant Patients under Dosage and Administration.)

Cardioversion of Atrial Fibrillation/Flutter

If enoxaparin sodium is used for the prevention of stroke and systemic embolism in patients undergoing cardioversion for atrial fibrillation or atrial flutter†, administration of full-treatment dosages used for venous thromboembolism (VTE) is recommended.1007

Bridging Anticoagulation

In patients who are receiving bridging anticoagulation† with therapeutic-dose subcutaneous enoxaparin, the American College of Chest Physicians (ACCP) suggests administering the last preoperative dose of enoxaparin sodium approximately 24 hours prior to surgery to allow sufficient time for anticoagulant effects to dissipate.1004 Postoperative anticoagulation should be administered with caution and only when hemostasis has been achieved because of the potential for bleeding at the surgical site.1004 In patients undergoing procedures associated with a high risk of bleeding, ACCP suggests delaying the resumption of therapeutic-dose enoxaparin until 48-72 hours after surgery when adequate hemostasis has been achieved.1004

Special Populations

Renal Impairment

Caution is advised when using enoxaparin in patients with renal impairment since elimination of the drug may be delayed.1,3 Patients with renal impairment should be carefully monitored for signs and symptoms of bleeding.1 In addition, anti-factor Xa levels may be used to monitor the anticoagulant effect of enoxaparin in patients with substantial renal impairment.1,7,71 No dosage adjustment is recommended in patients with mild (creatinine clearance 50-80 mL/minute) or moderate (creatinine clearance 30-50 mL/minute) renal impairment.1 However, dosage should be adjusted in patients with severe renal impairment (creatinine clearance < 30 mL/minute).1,1000 (See Table 1.)

Pregnant Patients

Low molecular weight heparins (LMWHs) have lower peak plasma concentrations and shorter half-lives in pregnant women, which often requires higher doses and/or more frequent administration.1107 Adjusted-dose anticoagulation is recommended for all women with acute venous thromboembolism (VTE) during pregnancy.1107 For adjusted-dose LMWH, the American College of Obstetricians and Gynecologists (ACOG) recommends targeting anti-factor Xa levels of 0.6-1 units/mL 4 hours after the last injection of a twice-daily regimen; slightly higher doses may be need for once-daily regimens.1107

If enoxaparin is used in pregnant women with mechanical prosthetic heart valves, anti-factor Xa levels should be used to monitor the anticoagulant effect of enoxaparin, and enoxaparin sodium dosage should be adjusted as needed.1,83,996 The American College of Cardiology (ACC) and the American Heart Association (AHA) suggest that if an LMWH is used in pregnant women with a mechanical prosthetic heart valve, the dosage should be adjusted to maintain anti-factor Xa levels of 0.8-1.2 units/mL 4-6 hours after administration.996

To avoid an unwanted anticoagulant effect on the fetus during delivery, therapy with LMWHs should be discontinued at least 24 hours (or at least 12 hours if using prophylactic-dose LMWH) prior to induction of labor or cesarean section.1012 The American College of Chest Physicians (ACCP) states that if an at-term woman is at very high risk for recurrent VTE (e.g., occurrence of proximal deep-vein thrombosis [DVT] within the past 2 weeks), IV unfractionated heparin may be initiated at this time and then discontinued 4-6 hours prior to the expected time of delivery.1012 Pregnant women with mechanical heart valves who are receiving LMWHs should switch to unfractionated heparin at least 36 hours prior to planned delivery.996

Low Body Weight

Increased exposure to enoxaparin has been observed in patients with low body weight (<45 kg in women or <57 kg in men);1,71 all such patients should be carefully monitored for signs and symptoms of bleeding.1

Obese Patients

Safety and efficacy of thromboprophylactic dosages of enoxaparin in patients with body mass index (BMI) >30 kg/m² have not been established and there is no consensus on how dosage should be adjusted in such patients; these patients should be closely observed for signs and symptoms of thromboembolism during therapy.1 The American Society of Hematology (ASH) suggests that enoxaparin should be dosed according to the patient's actual body weight when the drug is used for treatment of acute venous thromboembolism (VTE) and does not recommend monitoring anti-factor Xa concentrations to guide dosage adjustments.1106

Contraindications

• Active major bleeding.1
• Immune-mediated heparin-induced thrombocytopenia within the prior 100 days or associated with circulating antiplatelet antibodies.1
• Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions), heparin, pork products, benzyl alcohol, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Spinal/Epidural Hematomas

Concurrent use of low molecular weight heparins (LMWHs) or heparinoids with neuraxial (spinal/epidural) anesthesia or spinal puncture procedures has been associated with epidural or spinal hematomas.1,37,142,163 The prescribing information for enoxaparin has a boxed warning regarding the risk of spinal/epidural hematomas.1 Hematomas occurring in such patients have resulted in neurologic injury, including long-term or permanent paralysis.1,37,142,161 The risk of these adverse events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs that affect hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet-aggregation inhibitors, or other anticoagulants.1,37,142,143 The risk also appears to be increased by a history of traumatic or repeated epidural or spinal puncture, spinal surgery, or spinal deformity.1,37 It is important to note that the risk of spinal hematoma applies to all anticoagulants when used in conjunction with neuraxial anesthesia or spinal puncture.161

FDA states that cases of epidural or spinal hematomas continue to be reported in patients receiving enoxaparin in the setting of neuraxial procedures.161 Between July 20, 1992 and January 31, 2013, at least 100 confirmed or probable cases of spinal/epidural hematoma associated with the concurrent use of enoxaparin thromboprophylaxis and neuraxial anesthesia were reported to FDA by the manufacturer.161 Risk factors that were present in many of these cases included female gender, older age (≥65 years of age), concomitant use of drugs affecting hemostasis, indwelling epidural catheter, epidural technique, twice-daily versus once-daily administration of enoxaparin, and underlying medical conditions with increased risk of hemorrhage.161 To address this safety concern, the FDA has recommended additional safety measures.1,161

Prior to performing a spinal or epidural procedure, healthcare professionals should determine as part of a preprocedure checklist whether a patient is receiving anticoagulants.161 In addition, clinicians should carefully consider the timing of spinal catheter placement and removal in relation to anticoagulant use, considering both the dosage and pharmacokinetic properties (e.g., elimination half-life) of the anticoagulant.1,161 Insertion or removal of a epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin is minimal.1,161 Although the optimal timing between the administration of enoxaparin and neuraxial procedures is not known, the following guidelines are recommended.1,161 In patients receiving low (prophylactic) dosages of enoxaparin sodium (30 mg once or twice daily or 40 mg once daily), insertion or removal of a spinal catheter should be delayed for at least 12 hours after a dose of enoxaparin.1 In patients receiving higher (treatment) dosages of enoxaparin sodium (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily), a delay of at least 24 hours is recommended between the enoxaparin dose and catheter placement/removal; if the patient is receiving a twice-daily treatment regimen, the second dose should be omitted to allow for a longer delay.1 In patients with renal impairment (creatinine clearance less than 30 mL/minute), a doubling of the recommended time delays is recommended to account for possible prolonged elimination of enoxaparin in such patients.1 The manufacturer suggests that clinicians consider delaying administration of enoxaparin for at least 4 hours after catheter removal, taking into account the patient's risk of bleeding versus thrombosis.1

Patients receiving LMWHs or heparinoids in the setting of epidural or spinal anesthesia or lumbar puncture should be monitored frequently for manifestations of neurologic impairment (e.g., midline back pain, numbness or weakness in lower limbs, bowel or bladder dysfunction).1,37,142,143 If spinal hematoma is suspected, urgent diagnosis and treatment is necessary; spinal cord decompression should be considered even though it may not prevent or reverse neurologic sequelae.1,26,37 Some experts recommend against the concomitant use of a low molecular weight heparin with other drugs affecting hemostasis (e.g., aspirin, NSAIAs, platelet-aggregation inhibitors, other anticoagulants) in patients receiving spinal anesthesia.163 Clinicians should fully consider the potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.1

Bleeding

Major hemorrhage (e.g., intracranial or retroperitoneal bleeding) has occurred in patients receiving enoxaparin, and sometimes resulted in fatalities.1 Bleeding can occur at any site during therapy.1 Women treated with LMWHs prior to percutaneous coronary intervention (PCI) appear to experience more bleeding complications than do men.135

Enoxaparin should be used with extreme caution in patients with an increased risk of hemorrhage (e.g., bacterial endocarditis; congenital or acquired bleeding disorders; active ulceration and angiodysplastic GI disease; hemorrhagic stroke; recent brain, spinal, or ophthalmic surgery; concomitant platelet inhibitor therapy).1 The manufacturer states that the drug also should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, history of recent GI ulceration, diabetic retinopathy, or hemorrhage.1 Patients with low body weight or renal impairment should be monitored carefully for signs and symptoms of bleeding; dosage adjustment may be necessary in such patients.1 Periodic complete blood cell counts, including platelet counts, and stool occult blood tests are recommended during use of enoxaparin.1 Hemorrhage should be seriously considered in anticoagulated patients with unexplained decreases in hematocrit or blood pressure.1 Protamine sulfate may be used to neutralize the anticoagulant effect of LMWHs in patients with bleeding.1,1010 Because fatal reactions resembling anaphylaxis have been reported with protamine sulfate administration, the drug should be used only when resuscitation techniques and treatment for anaphylactic shock are readily available.1

To minimize risk of bleeding following percutaneous revascularization procedures (i.e., PCI), clinicians should adhere precisely to the recommended dosing intervals for enoxaparin.1 (See Dosage under Dosage and Administration.) Recommendations for the timing of sheath removal is based on the method of post-PCI arterial closure.1 If a closure device is used, the sheath may be removed immediately; however, if manual compression is used, the sheath should be removed 6 hours after the last dose of enoxaparin.1 In patients in whom enoxaparin therapy will be continued, the next scheduled dose should be given no sooner than 6-8 hours after sheath removal.1 The site of the procedure should be closely monitored for signs of bleeding or hematoma formation; it is important that hemostasis be achieved at the puncture site after PCI.1

Thrombocytopenia

Moderate thrombocytopenia (platelet counts between 50,000 and 100,000/mm³) was reported in 1.3% of patients in clinical studies, and severe thrombocytopenia (platelet counts less than 50,000/mm³) was reported in 0.1% of patients.1 Thrombocytopenia of any degree should be monitored closely,1 and enoxaparin should be discontinued if platelet counts fall below 100,000/mm³.1 (See Contraindications under Cautions.)

Heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis (HITTS) can occur with the administration of enoxaparin; some cases of thrombocytopenia have been complicated by organ infarction with secondary organ dysfunction or limb ischemia, and deaths have resulted.1 Enoxaparin should be used with extreme caution in patients with a history of HIT/HITTS.1 In patients with a history of HIT/HITTS, enoxaparin should only be used if more than 100 days have elapsed since the prior episode and the patient has no circulating antiplatelet antibodies.1 Because of the possibility of HIT/HITTS recurrence in these patients, a careful risk-benefit assessment should occur and nonheparin anticoagulants should be considered.1

Interchangeability with Other Heparins

Enoxaparin should not be used interchangeably with other LMWHs or unfractionated heparin because of differences in manufacturing process, molecular weight distribution, anti-factor Xa and anti-factor II_a activities, dosage units, and dosage.1

Patients with Mechanical Prosthetic Heart Valves

The use of enoxaparin for prophylaxis of thromboembolism in patients with mechanical prosthetic heart valves has not been adequately studied, and a clinical consensus regarding optimal therapy remains to be established.1,71,83,85,88,89,90,91,93,94,101,996 Valve thrombosis that was fatal (including maternal and fetal death) or potentially fatal and/or required surgical intervention has been reported during prophylaxis with enoxaparin in some patients (including pregnant women) with mechanical prosthetic heart valves.1,68,69,70,71,82,83,85,87,90 (See Thromboembolism During Pregnancy under Uses.) Insufficient data, the presence of underlying conditions, and the possibility of inadequate anticoagulation complicate the evaluation of these events in such patients.1,68,69,70,71,83 However, women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy.85,89,91,92,94,95

The manufacturer and some clinicians currently state that if enoxaparin is used in pregnant women with mechanical prosthetic heart valves, frequent monitoring of peak and trough anti-factor Xa concentrations and adjustment of enoxaparin sodium dosage may be necessary.1,71,82,83,996 The American College of Chest Physicians (ACCP) recommends use of aggressive, adjusted-dose subcutaneous LMWH (i.e., given twice daily and adjusted to maintain the manufacturer-recommended peak anti-factor Xa concentrations 4 hours postinjection) in pregnant women with mechanical prosthetic heart valves.1012 Although empiric,1,83 the therapeutic monitoring recommendation for anti-factor Xa concentrations is based on differences in the pharmacokinetics of LMWHs that occur during pregnancy and is aimed at attempting to ensure that dosage is adjusted appropriately to ensure consistent anticoagulation.83,93,996

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of enoxaparin in pregnant women.1 Animal studies indicate that enoxaparin crosses the placenta; however, available data in humans indicate that low molecular weight heparins (LMWHs) do not cross the placenta.1,1107 Available human data also have not shown evidence of teratogenicity or fetotoxicity.1 In a review of approximately 600 retrospectively followed pregnancies in women exposed to enoxaparin, the incidences of congenital anomalies did not exceed what would be expected in the general population.1 Maternal and neonatal hemorrhage did occur in some of the followed pregnancies.1 The American College of Obstetricians and Gynecologists (ACOG) considers LMWHs to be generally safe in pregnancy.1107

Pregnancy alone is associated with an increased risk of thromboembolism, which is even higher in women with a history of thromboembolism and certain high-risk pregnancy conditions, including hereditary or acquired thrombophilias and the presence of a mechanical prosthetic heart valve.1,82,83 The pharmacokinetics of LMWHs differ in pregnant versus nonpregnant women because of changes in volume of distribution resulting in increased plasma volume, decreased half-life, and changes in renal clearance.83 Some clinicians recommend frequent monitoring of anti-factor Xa concentrations and adjustment of enoxaparin sodium dosage in pregnant women with mechanical prosthetic heart valves to ensure a consistent anticoagulant effect.83,93,996

All patients receiving anticoagulants such as enoxaparin, including pregnant women, are at risk for bleeding.1 Hemorrhage can occur at any site and may lead to death of mother and/or fetus.1 Pregnant women receiving enoxaparin should be apprised of the potential hazards to the mother and fetus associated with enoxaparin use during pregnancy, and such women should be carefully monitored for evidence of bleeding or excessive anticoagulation.1 Use of enoxaparin may result in epidural or spinal hematomas in women receiving neuraxial anesthesia during labor and delivery.1 Pregnant women receiving enoxaparin should be monitored for bleeding and for any unexpected changes in coagulation parameters.1 As delivery approaches, use of a shorter-acting anticoagulant should be considered.1

Use of enoxaparin in pregnant women with mechanical prosthetic heart valves may result in valve thrombosis.1 (See Patients with Mechanical Prosthetic Heart Valves under Cautions.)

Lactation

It is not known whether enoxaparin is distributed into milk; studies in lactating rats demonstrated very limited distribution of enoxaparin into milk.1 It is not known whether enoxaparin affects the breast-fed child or affects milk production.1 The benefits of breast-feeding should be considered along with the importance of the drug to the woman and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1

The American College of Obstetricians and Gynecologists (ACOG) considers low molecular weight heparins (LMWHs) to be compatible with lactation.1107 The American College of Chest Physicians (ACCP) recommends that LMWHs be continued in nursing women who are already receiving such therapy; the small amounts of drug detected in the milk of nursing women are not likely to be clinically important.1012

Pediatric Use

Safety and efficacy of enoxaparin have not been established in children younger than 18 years of age.1,7,71

Each mL of enoxaparin sodium injection in multiple-dose vials contains 15 mg of benzyl alcohol as a preservative.1 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates, including fatal reactions and the “gasping syndrome”.1,80,81 Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates.1,80,81 Because benzyl alcohol may cross the placenta, the manufacturer states that the preservative-free formulations of enoxaparin should be used in pregnant women whenever possible.1

Geriatric Use

No substantial differences in efficacy have been observed in geriatric patients relative to younger adults.1 In geriatric patients, a higher incidence of bleeding complications has been observed following administration of enoxaparin sodium at a dosage of 1.5 mg/kg once daily or 1 mg/kg every 12 hours, and the risk of bleeding complications increases with age.1 Enoxaparin should be used with care in geriatric patients, and careful attention to dosing intervals and concomitant medications (particularly antiplatelet drugs) is advised.1 Monitoring (e.g., using anti-factor Xa assay) of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.1,71

Renal Impairment

Patients with renal impairment may have increased exposure to enoxaparin; such patients should be closely observed for signs of bleeding.1 Dosage adjustment is required in patients with severe renal impairment (creatinine clearance <30 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

The most common adverse effects of enoxaparin (i.e., occurring in at least 1% of patients receiving the drug in clinical studies) include bleeding, anemia, ecchymosis, thrombocytopenia, elevation of serum aminotransferase concentrations, fever, nausea, diarrhea, peripheral edema, dyspnea, injection site pain, and confusion.1

Drugs Affecting Hemostasis

Concomitant use of drugs that affect hemostasis (e.g., anticoagulants, platelet aggregation inhibitors [e.g., salicylates or other nonsteroidal anti-inflammatory agents, dipyridamole, sulfinpyrazone]) can increase the risk of bleeding associated with enoxaparin.1 The manufacturer recommends that such drugs be discontinued prior to initiating enoxaparin therapy; if concomitant use is essential, careful clinical and laboratory monitoring is advised.1

Description

Enoxaparin, a depolymerized heparin prepared by alkaline degradation of benzylated heparin of porcine intestinal mucosa origin, is an anticoagulant.1,2,3,4 Enoxaparin is commercially available as the sodium salt.1 The average molecular weight of enoxaparin is approximately one-third that of unfractionated heparin (4500 vs 12,000 daltons);11 therefore, enoxaparin is referred to as a low molecular weight heparin (LMWH).1,2,3,4

Enoxaparin has an approximate anti-factor Xa activity of 100 units/mg according to the World Health Organization (WHO) First International Low Molecular Weight Heparin Reference Standard.1 At a given level of anti-factor Xa activity, enoxaparin has less effect on thrombin than does unfractionated heparin.1,2 However, enoxaparin administration has been associated with a prolongation of some global clotting function tests (i.e., thrombin time, activated partial thromboplastin time [aPTT]) by up to 1.8 times the control value.1 In patients receiving enoxaparin sodium (1 mg/kg of the 100 mg/mL concentration subcutaneously every 12 hours) in a large clinical trial, the aPTT was 45 seconds or less in most treated patients.1 The manufacturer states that enoxaparin sodium in a concentration of 150 mg/mL is projected to produce anticoagulant activities similar to those of 100 or 200 mg/mL concentrations of the drug, although the 150 mg/mL concentration has not been studied clinically.1 Compared with unfractionated heparin, enoxaparin has greater bioavailability (based on anti-factor Xa activity) after subcutaneous administration and a longer half-life, allowing less frequent administration.2,4

The molecular weight, pharmacokinetics, and in vitro and in vivo activity of enoxaparin differ from those of unfractionated heparin or other LMWHs;1,2,4,12,13,14,15,16 therefore, the drugs are not interchangeable on a unit-for-unit (or mg-for-mg) basis.1

Advice to Patients

• Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., tingling or numbness in lower limbs, muscle weakness), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors (e.g., clopidogrel), or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1
• If therapy is to continue after hospital discharge, importance of instructing patient on proper injection technique of enoxaparin.1
• Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking enoxaparin.1 Importance of patients reporting any unusual bleeding, bruising, or signs of thrombocytopenia (e.g., dark red spots under skin) to clinician.1
• Importance of patients informing clinicians (including dentists) that they are receiving enoxaparin therapy before scheduling any invasive procedures.1
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, contraindications, potential drug interactions, and acute toxicity.

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