Drug class: Heparins
- Low molecular weight Heparins
- LMWHs
CAS number: 9005-49-6

Medically reviewed by Drugs.com on Sep 24, 2024. Written by ASHP.

Introduction

Anticoagulant; LMWH.^{1 2 3 4}

Uses for Enoxaparin

Thromboprophylaxis in General/Abdominal Surgery

Prevention of venous thromboembolism (VTE; DVT and/or PE) in patients undergoing general/abdominal surgery who are at risk for thromboembolic complications.^{1 27 66 71}

Decisions regarding use of thromboprophylaxis in patients undergoing general surgery should be based on patient’s level of risk for thromboembolism and bleeding.^{1002 1101}

Pharmacologic prophylaxis (with LMWHs or low-dose unfractionated heparin) generally recommended in patients with moderate to high risk of VTE who do not have a high risk of bleeding.^{1002 1101 1103}

Extended VTE prophylaxis may be considered in selected patients undergoing major surgery.^{1002 1101} Because risk of VTE is particularly high in patients undergoing abdominal or pelvic surgery for cancer, extended (up to 4 weeks) prophylaxis with LMWHs is recommended in such patients.^{1002 1103}

The American College of Chest Physicians (ACCP) states that recommendations for use of antithrombotic agents in general surgery patients can be applied to patients undergoing bariatric, vascular, and plastic/reconstructive surgery.¹⁰⁰²

Thromboprophylaxis in Hip-Replacement, Knee-Replacement, or Hip-Fracture Surgery

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 1101}

Prevention of DVT and/or PE in patients undergoing knee-replacement surgery.^{1 20 22 1003 1101}

Also has been used for thromboprophylaxis in patients undergoing hip-fracture surgery^{† [off-label]}.^{1003 1101}

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method) in all patients undergoing major orthopedic surgery because of high risk of postoperative VTE; continue thromboprophylaxis 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 relative efficacy and safety and extensive clinical experience; alternative agents may be considered if LMWHs are not available or cannot be used (e.g., patients with heparin-induced thrombocytopenia [HIT] or those who refuse or are uncooperative with sub-Q injections).¹⁰⁰³

More recent guidelines from the American Society of Hematology (ASH) suggest aspirin or an anticoagulant for VTE prophylaxis in patients undergoing total hip or total knee arthroplasty.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 either LMWHs or unfractionated heparin.¹¹⁰¹

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy and bleeding risk as well as other logistics and compliance issues.¹⁰⁰³

Because risk of DVT is increased for several months following hip- or knee-replacement surgery,^{35 36 38} ACCP suggests extended prophylaxis for up to 35 days in patients undergoing major orthopedic surgery; ASH states that extended VTE prophylaxis (generally considered as >3 weeks) may be considered in selected patients undergoing major surgery.^{1003 1101}

Thromboprophylaxis in Other Surgical Settings

Also has been used for VTE prophylaxis in patients undergoing other types of surgery including neurosurgery^{† [off-label]}, cardiac surgery^{† [off-label]}, and vascular surgery^{† [off-label]}.^{1002 1101}

Thromboprophylaxis in Acutely Ill Medical Patients

Prevention of DVT, which may lead to PE, in patients who are at increased risk of thromboembolic complications due to severely restricted mobility during acute illness.^{1 67 71 1001}

Treatment decisions regarding use of VTE prophylaxis in acutely ill hospitalized patients should include assessment of the patient's risk of thromboembolism and risk of bleeding.^{1001 1108}

LMWHs are recommended as one of several options for thromboprophylaxis in acutely ill, hospitalized medical patients (including those in the ICU).^{1001 1108}

ACCP suggests continued thromboprophylaxis for 6–21 days until full mobility is restored or hospital discharge, whichever comes first.¹⁰⁰¹ Extended thromboprophylaxis after hospital discharge may be considered in selected patients.^{1108 1109}

Risk of VTE is particularly high in patients with cancer.^{1001 1102 1103} In acutely ill hospitalized patients with cancer, thromboprophylaxis is generally recommended, with LMWHs suggested over unfractionated heparin.¹¹⁰³ Routine thromboprophylaxis generally not recommended in cancer patients in the outpatient setting who have no additional risk factors for VTE.^{1102 1103}

Thromboprophylaxis in Trauma Patients

LMWHs also have been used for VTE prophylaxis in trauma patients^{† [off-label]}.^{1002 1101}

Treatment and Secondary Prevention of VTE

Inpatient treatment of acute DVT with or without PE when administered in conjunction with warfarin.^{1 28 1005}

Outpatient treatment of acute DVT without PE when administered in conjunction with warfarin.^{1 28 1005}

Although labeled indication includes the use of warfarin in conjunction with enoxaparin for treatment of VTE, other anticoagulants other than warfarin (e.g., direct oral anticoagulants [DOACs]) have been used for long-term anticoagulation following initial treatment with enoxaparin.¹¹⁰⁴

LMWHs are recommended as one of several parenteral anticoagulant options for initial treatment of acute VTE; however, initial treatment with a parenteral anticoagulant may not always be necessary since oral anticoagulant options are available.^{1005 1102 1103 1104}

Continue anticoagulant therapy for at least 3 months, and possibly longer depending on individual clinical situation.^{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 For long-term anticoagulant therapy (secondary prevention), ACCP states DOACs are generally preferred in patients without cancer; in patients with cancer, LMWHs or DOACs are generally suggested over warfarin for long-term anticoagulation.^{1102 1103 1104}

LMWHs also have been used for 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 a central venous access device.¹⁰¹³

Non-ST-Segment-Elevation Acute Coronary Syndromes (NSTE-ACS)

Used in conjunction with aspirin to reduce risk of ischemic complications (death, MI) in patients with NSTE-ACS (unstable angina or non-ST-segment-elevation MI [NSTEMI]).^{1 40 41 42 43 48 53 146 991}

Initial parenteral anticoagulants with established efficacy in patients with NSTE-ACS include enoxaparin, unfractionated heparin, bivalirudin (only in patients managed with an early invasive strategy), and fondaparinux.⁹⁹¹

In patients undergoing PCI, an additional IV dose of enoxaparin may be required based on timing of the last administered sub-Q dose.⁹⁹⁴

ST-Segment-Elevation MI (STEMI)

Used in conjunction with aspirin for treatment of acute STEMI in patients managed medically (with thrombolytic therapy) or with subsequent PCI.^{1 162 164 165 527 994}

ACCF and AHA state that patients with STEMI undergoing thrombolytic therapy should receive an anticoagulant (e.g., unfractionated heparin, enoxaparin, fondaparinux) for ≥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 (>48 hours) is necessary.⁵²⁷

Adjunctive use of LMWHs in patients with acute STEMI 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}

In patients undergoing PCI, an additional IV dose of enoxaparin may be required based on the timing of the last administered sub-Q dose.^{1 994}

Thromboprophylaxis in Acute Ischemic Stroke

LMWHs have been used for thromboprophylaxis in selected patients with acute ischemic stroke^†; those with additional risk factors for VTE are more likely to benefit from such prophylaxis.¹⁰⁰⁹

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

Thromboembolism During Pregnancy

Prevention and treatment of VTE during pregnancy^†.^{1012 1104} LMWHs are recommended by ACCP for this use; there is a potential for other agents to cross the placenta.^{1012 1104} ACCP recommends LMWHs for initial treatment and secondary prevention throughout the remainder of the pregnancy.¹⁰¹² To prevent recurrence, anticoagulation should be continued for ≥6 weeks and for a total duration of ≥3 months.¹⁰¹²

Prevention of thrombotic complications in pregnant women with mechanical heart valves^†.^{138 996} However, cases of valve thrombosis resulting in death (including maternal and fetal deaths) and/or requiring surgical intervention reported with such use.^{1 68 69 70 71 83 97 98 996} (See Patients with Mechanical Prosthetic Heart Valves under Cautions.)

Also has been used in combination with low-dose aspirin for prevention of recurrent pregnancy loss in women with antiphospholipid antibody (APLA) syndrome^†.¹⁰¹²

In general, thromboprophylaxis (e.g., with an LMWH) is suggested during the antepartum period only in pregnant women who have a history of thromboembolism^† and are considered to be at moderate to high risk of recurrent events (e.g., those with a single episode of unprovoked VTE, pregnancy- or estrogen-related venous thromboembolism, history of multiple unprovoked events).¹⁰¹²

Hereditary thrombophilias and a family history of VTE substantially increase risk of pregnancy-related VTE.¹⁰¹² ACCP suggests antepartum and postpartum prophylaxis with an LMWH in some pregnant women with high-risk hereditary thrombophilias (e.g., homozygous genetic mutations for factor V Leiden or prothrombin G20210A)^†.¹⁰¹²

Discontinue LMWH therapy ≥24 hours prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) to avoid an unwanted anticoagulant effect on fetus.^{996 1012}

Cardioversion of Atrial Fibrillation/Flutter

LMWHs have been used for prevention of stroke and systemic embolism in patients with atrial fibrillation or atrial flutter undergoing electrical or pharmacologic cardioversion^†.^{999 1007 1105}

Therapeutic anticoagulation with LMWHs has been used at the time of transesophageal echocardiography (TEE) in patients with atrial fibrillation lasting ≥48 hours or of unknown duration, followed by cardioversion within 24 hours if no thrombus is detected.^{999 1007 1105}

Patients with atrial fibrillation of <48 hours' duration and a high risk of stroke (CHA₂DS₂-VASc score ≥2 for males or ≥3 for females) usually do not require prolonged anticoagulation or TEE prior to cardioversion; LMWHs (in therapeutic dosages) may be used at presentation, followed by immediate cardioversion and long-term anticoagulation in these patients.^{999 1007 1105}

In patients with atrial fibrillation of <48 hours' duration and a low risk of stroke (CHA₂DS₂-VASc score of 0 for males or 1 for females), either therapeutic anticoagulation or no anticoagulation may be considered prior to cardioversion.^{999 1105}

After successful cardioversion in patients with atrial fibrillation of ≥48 hours' duration, therapeutic anticoagulation is recommended for ≥4 weeks.^{999 1007} Patients with atrial fibrillation of <48 hours' duration who have a low risk of stroke generally do not require anticoagulation postcardioversion.^{999 1105} In all situations, 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}

Thromboprophylaxis in Patients with Prosthetic Heart Valves

Has been used to reduce risk of thromboembolism 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 Patients with Mechanical Prosthetic Heart Valves under Cautions.)

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 for thromboembolism).^{996 1004}

Has been used for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves^†.^{138 996 1012} (See Thromboembolism During Pregnancy under Uses.)

Bridging Anticoagulation

Has been used for bridging anticoagulation^† during temporary interruption of long-term oral anticoagulant therapy in selected patients with VTE, atrial fibrillation, or mechanical prosthetic heart valves undergoing surgery or other invasive procedures; use and type of bridging anticoagulation depend on patient's risk of developing thromboembolism without anticoagulant therapy.¹⁰⁰⁴

Bridging anticoagulation has been associated with 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}

Enoxaparin Dosage and Administration

General

Patient Monitoring

• Since coagulation parameters such as PT or aPTT are insensitive for monitoring enoxaparin activity, routine monitoring of coagulation parameters generally not required.¹

• Monitoring of anti-factor Xa levels may be helpful in high-risk groups, such as pregnant patients, patients with renal impairment, patients at extremes of weight, or if abnormal coagulation parameters or bleeding occurs during treatment.^{1 128 135}

• If LMWHs are used for anticoagulation in children, the American College of Chest Physicians (ACCP) suggests that dosage 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 sub-Q administration.¹⁰¹³

• In patients with NSTE-ACS, adhere precisely to intervals recommended between doses to minimize the risk of bleeding.¹ If a closure device is used, may remove sheath immediately after PCI.¹ Otherwise, if a manual compression method is used, remove vascular access sheath 6 hours following the last dose of enoxaparin sodium.¹ If continuing enoxaparin therapy, administer the next scheduled dose no sooner than 6–8 hours after sheath removal.¹ Observe procedure site for signs of bleeding or hematoma formation.¹

Administration

Administer by deep sub-Q injection for most indications; do not give IM.¹

Single doses also administered by direct IV injection in certain situations.¹ (See STEMI and also see NSTE-ACS under Dosage and Administration.)

When using multiple-dose vials, withdraw dose using a tuberculin or equivalent syringe.¹

Do not mix with other injections or infusions.¹

IV Administration

May be administered by direct IV injection.¹ Use multiple-dose vial for IV administration.¹

To avoid mixing IV enoxaparin with other drugs, flush IV line with a sufficient amount of 0.9% sodium chloride injection or 5% dextrose injection prior to and following IV administration of enoxaparin.¹

Sub-Q Administration

Administer with patient in the supine position.¹

To avoid loss of drug when using the prefilled syringes, do not expel air from syringe prior to injection.¹

For prescribed doses less than a full syringe volume, eject excess volume until only the prescribed dose remains.¹

Inject drug sub-Q into the left and right anterolateral and left and right posterolateral abdominal wall.¹

Insert the entire length of the needle into a skin fold created by the thumb and forefinger; hold the skin fold until the needle is withdrawn.¹

Alternate injection sites frequently.¹

To minimize bruising, do not massage injection sites after injection.¹

Dosage

Available as enoxaparin sodium; dosage expressed in terms of the salt.¹

Dosages for enoxaparin sodium or other LMWHs and heparin cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis.¹

Available as enoxaparin sodium.¹ Enoxaparin sodium has an approximate anti-factor Xa activity of 100 units/mg using the WHO First International Low Molecular Weight Heparin Reference Standard.¹

Adults

Prevention of VTE

General/Abdominal Surgery

Sub-Q

40 mg once daily initiated 2 hours prior to surgery.¹

Usual duration of therapy is 7–10 days, although up to 12 days of treatment has been well tolerated in clinical trials.^{1 71}

Extended VTE prophylaxis (generally considered as >3 weeks) may be considered in selected patients undergoing major general surgery.¹¹⁰¹ Extended prophylaxis (for up to 4 weeks) recommended by ACCP in patients undergoing abdominal or pelvic surgery for cancer.¹⁰⁰²

Hip-Replacement Surgery

Sub-Q

30 mg every 12 hours initiated 12–24 hours after surgery, provided hemostasis has been established.¹

Alternatively, may consider dosage of 40 mg once daily, initiated approximately 12 hours before surgery.¹

Because of risk of bleeding, ACCP recommends that LMWHs be initiated at least 12 hours preoperatively or at least 12 hours postoperatively in patients undergoing major orthopedic surgery.¹⁰⁰³

Continue prophylaxis throughout the postoperative period, generally for 7–10 days, until risk of DVT has diminished; manufacturer states that up to 14 days of thromboprophylaxis was well tolerated in clinical trials.¹

Following the initial phase of thromboprophylaxis during the acute postoperative period, manufacturer recommends continued prophylaxis with 40 mg once daily for 3 weeks.¹⁵⁰

ACCP recommends a minimum of 10–14 days of thromboprophylaxis, and suggests extending prophylaxis for up to 35 days on an outpatient basis.¹⁰⁰³ ASH guidelines state that extended VTE prophylaxis (generally considered as >3 weeks) may be considered in selected patients undergoing major surgery.¹¹⁰¹

Knee-Replacement Surgery

Sub-Q

30 mg every 12 hours initiated 12–24 hours after surgery, provided hemostasis has been established.¹

Because of risk of bleeding, ACCP recommends that LMWHs be initiated at least 12 hours preoperatively or 12 hours postoperatively in patients undergoing major orthopedic surgery.¹⁰⁰³

Continue prophylaxis throughout the postoperative period, generally for 7–10 days, until risk of DVT has diminished; manufacturer states that up to 14 days of thromboprophylaxis was well tolerated in clinical trials.¹

ACCP recommends a minimum of 10–14 days of thromboprophylaxis, and suggests extending prophylaxis for up to 35 days on an outpatient basis.¹⁰⁰³ ASH guidelines state that extended VTE prophylaxis (generally considered as >3 weeks) may be considered in selected patients undergoing major surgery.¹¹⁰¹

Acutely Ill Medical Patients

Sub-Q

40 mg once daily.¹ Usual duration of therapy is 6–11 days; well tolerated for up to 14 days in clinical trials.¹

ACCP suggests against the use of extended thromboprophylaxis beyond the period of patient immobilization or acute hospital stay in acutely ill medical patients.¹⁰⁰¹ However, extended thromboprophylaxis has been used in selected patients after hospital discharge.^{1108 1109}

Treatment of VTE

Sub-Q

Outpatient treatment in patients with uncomplicated DVT without PE: 1 mg/kg every 12 hours.^{1 29}

Inpatient (hospital) treatment in patients with DVT with or without PE: 1 mg/kg every 12 hours or 1.5 mg/kg once daily at the same time every day.¹

Manufacturer states average duration of therapy is 7 days.¹ 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), presence of cancer, and patient's risk of bleeding.^{1005 1104}

Transitioning from Enoxaparin to Oral Anticoagulants

Patients transitioning to warfarin for long-term anticoagulant therapy: initiate warfarin when appropriate (usually within 72 hours of enoxaparin initiation) and continue for a minimum of 5 days and until a therapeutic INR (2–3) has been achieved.¹ Discontinue enoxaparin after this period of overlap with warfarin,²⁹ generally after 7 days of enoxaparin treatment.¹

Patients transitioning to dabigatran for long-term anticoagulant therapy: Administer enoxaparin for 5–10 days.¹⁶⁸ Discontinue enoxaparin and initiate dabigatran 0–2 hours prior to the time of next scheduled dose of enoxaparin.¹⁶⁸

Patients transitioning to edoxaban for long-term anticoagulant therapy: Administer enoxaparin for 5–10 days.¹⁶⁹ Discontinue enoxaparin and initiate edoxaban at the time of the next scheduled dose of enoxaparin.¹⁶⁹

Patients transitioning to apixaban for long-term anticoagulant therapy: Discontinue enoxaparin and initiate apixaban at the time of the next scheduled dose of enoxaparin.¹⁷⁰

Patients transitioning to rivaroxaban for long-term anticoagulant therapy: Discontinue enoxaparin and initiate rivaroxaban 0–2 hours prior to the time of the next scheduled dose of enoxaparin.¹⁷¹

NSTE-ACS

Sub-Q

1 mg/kg every 12 hours in conjunction with aspirin therapy (100–325 mg once daily).¹

Initiate as soon as possible after hospital admission.⁹⁹¹ Administer for a minimum of 2 days and continue until clinical stabilization.^{1 41 42}

Usual duration of treatment is 2–8 days, although up to 12.5 days of treatment has been well tolerated in clinical trials.^{1 41 42}

Patients undergoing PCI who have not received prior anticoagulant therapy: ACCF/AHA/SCAI state that it is reasonable to administer enoxaparin sodium (e.g., 0.5–0.75 mg/kg by direct IV injection) at the time of PCI^†.⁹⁹⁴

Patients in whom sub-Q 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) sub-Q doses of enoxaparin sodium have been given or if the last sub-Q 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), adhere strictly to dosage intervals and observe precautions in removing vascular access sheath.¹ Administer next dose of enoxaparin sodium no sooner than 6–8 hours after removal of vascular access sheath;¹ ACCF/AHA/SCAI suggest removal of femoral sheath when ACT falls to <150–180 seconds or aPTT falls to <50 seconds.⁹⁹⁴ Monitor vascular access sites carefully for signs of bleeding or hematoma formation after removal of vascular sheath and during enoxaparin treatment.¹

STEMI

IV, then Sub-Q

Patients <75 years of age: 30 mg by direct IV injection. Follow with 1 mg/kg sub-Q every 12 hours (maximum 100 mg per dose for each of the first 2 sub-Q doses, then 1 mg/kg per dose thereafter);¹ give first sub-Q dose immediately after direct IV dose.¹

Patients ≥75 years of age: 0.75 mg/kg sub-Q every 12 hours (maximum dose 75 mg for each of the first 2 doses only, then 0.75 mg/kg per dose thereafter); do not administer an initial IV dose.¹

When used with thrombolytic therapy, initiate enoxaparin therapy 15 minutes before to 30 minutes after initiation of thrombolytic therapy.¹

Manufacturer states optimal duration not known but likely >8 days; enoxaparin therapy was continued for 8 days or until hospital discharge in clinical trials.¹

Use in conjunction with aspirin therapy (75–325 mg once daily) unless contraindicated.¹

Patients undergoing PCI: If last sub-Q dose of enoxaparin sodium was administered ≥8 hours before PCI, manufacturer recommends an additional 0.3-mg/kg dose by direct IV injection during PCI.^{1 166 167}

To minimize possibility of bleeding associated with vascular (e.g., vascular access sheath) instrumentation (e.g., PCI), adhere strictly to dosage intervals and observe precautions in removing vascular access sheath.¹ Administer next dose of enoxaparin sodium no sooner than 6–8 hours after removal of vascular access sheath.¹ ACCF/AHA/SCAI suggest removal of femoral sheath after PCI when ACT falls to <150–180 seconds or aPTT falls to <50 seconds.⁹⁹⁴ Monitor vascular access sites carefully for signs of bleeding or hematoma formation after removal of vascular sheath and during enoxaparin treatment.¹

Treatment and Prevention of Thromboembolism During Pregnancy†

Sub-Q

Treatment of acute VTE: 1 mg/kg every 12 hours for the remainder of pregnancy; continue anticoagulation for ≥6 weeks postpartum (minimum total duration of 3 months).¹⁰¹²

Postpartum prophylaxis in pregnant women with prior VTE: Prophylactic (40 mg once daily) or intermediate (40 mg every 12 hours) dosage suggested.¹⁰¹²

Pregnant women receiving long-term warfarin therapy: If the decision is made to switch to an LMWH-based strategy, dose-adjusted LMWH is recommended; the LMWH may be administered throughout all 3 trimesters or, alternatively, administered during the first trimester, followed by warfarin during the second and third trimesters.⁹⁹⁶ Administer the LMWH at least 2 times daily with close monitoring of anti-factor Xa levels.⁹⁹⁶

Primary prevention of VTE in pregnant women with high-risk thrombophilias: Prophylactic (40 mg once daily) or intermediate (40 mg every 12 hours) dosage suggested.¹⁰¹²

Pregnant women with mechanical heart valves: If an LMWH is used, twice-daily administration recommended because of altered pharmacokinetics in pregnant women, with adjustment of enoxaparin sodium dosage to maintain anti-factor Xa levels of 0.8–1.2 units/mL 4 hours after dosing.⁹⁹⁶ Resume usual long-term anticoagulation postpartum.¹⁰¹² (See Patients with Mechanical Heart Valves under Cautions.)

Consider use of a shorter-acting anticoagulant as delivery approaches.¹ To avoid an unwanted anticoagulant effect on the fetus during delivery, discontinue LMWH ≥24 hours prior (or ≥12 hours prior if using prophylactic-dose LMWH) to induction of labor or cesarean section.¹⁰¹² Pregnant women with mechanical heart valves who are on LMWH should switch to unfractionated heparin ≥36 hours prior to planned delivery.⁹⁹⁶

Cardioversion of Atrial Fibrillation/Flutter†

Sub-Q

For prevention of stroke and systemic embolism in patients undergoing cardioversion for atrial fibrillation or atrial flutter^†, use of full VTE treatment dosages recommended.¹⁰⁰⁷

Bridging Anticoagulation†

Sub-Q

In patients receiving bridging anticoagulation during temporary interruption of oral anticoagulant therapy for surgery or other invasive procedures, ACCP suggests administering last preoperative dose of enoxaparin approximately 24 hours prior to surgery.¹⁰⁰⁴

Administer postoperative anticoagulation with caution and only when hemostasis achieved because of the potential for bleeding at surgical site.¹⁰⁰⁴ In patients undergoing procedures associated with high risk of bleeding, ACCP suggests delaying the resumption of therapeutic-dose enoxaparin until 48–72 hours after surgery when adequate hemostasis achieved.¹⁰⁰⁴

Special Populations

Hepatic Impairment

No special population dosage recommendations at this time.¹

Renal Impairment

Use with caution in renally impaired patients.^{1 3 128} No dosage adjustments necessary in patients with mild (Cl_cr 50–80 mL/minute) or moderate (Cl_cr 30–50 mL/minute) renal impairment.¹

Adjust dosage for patients with severe renal impairment (Cl_cr <30 mL/minute).^{1 1000} (See Table 1.)

Geriatric Patients

Use with caution; careful attention to dosing intervals and concomitant medications (particularly antiplatelet drugs) advised.¹

Manufacturer states that no dosage adjustment necessary in geriatric patients for uses other than STEMI unless renal function is impaired.¹ (See Renal Impairment under Dosage and Administration.)

Low-Weight Patients

Carefully monitor for signs and symptoms of bleeding in patients with low body weight (women <45 kg or men <57 kg).^{1 71}

Obese Patients

Safety and efficacy of thromboprophylactic doses in patients with body mass index (BMI) >30 kg/m² not established; closely monitor for signs and symptoms of thromboembolism in such patients.¹ ASH suggests using actual body weight for dosing in patients with acute VTE and not monitoring anti-factor Xa concentrations to guide dosage.¹¹⁰⁶

Cautions for Enoxaparin

Contraindications

• Active major bleeding.¹

• Immune-mediated heparin-induced thrombocytopenia within 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

Spinal/Epidural Hematomas

Epidural or spinal hematoma reported with concurrent use of anticoagulants (e.g., LMWHs, heparinoids) and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.^{1 161 163} Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.^{1 161} (See Boxed Warning.)

Prior to performing a spinal or epidural procedure, determine whether a patient is receiving anticoagulants.¹⁶¹

Carefully consider the timing of spinal catheter placement and removal in relation to anticoagulant use, considering both dosage and pharmacokinetic properties (e.g., elimination half-life) of the anticoagulant.^{1 161}

Insertion or removal of catheter is best performed when the anticoagulant effect of enoxaparin is minimal (e.g., ≥12 hours after a low dose [30 mg once or twice daily or 40 mg once daily] or ≥24 hours after a high dose [0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily]).^{1 161} In patients receiving a twice-daily treatment dosage (0.75 or 1 mg/kg twice daily), omit second dose to allow for a longer delay between doses.¹ Consider doubling these recommended time delays in patients with renal impairment.¹

Consider delaying subsequent dose of enoxaparin for ≥4 hours after catheter removal based on patient's risk of bleeding versus thrombosis.^{1 161}

Frequently monitor for signs of neurologic impairment (e.g., midline back pain, numbness or weakness in lower limbs, bowel or bladder dysfunction).¹ If spinal hematoma suspected, diagnose and treat immediately; consider spinal cord decompression even though it may not prevent or reverse neurologic sequelae.¹

Bleeding

Risk of serious, potentially fatal bleeding.¹ Search for bleeding site if an unexplained decrease in hematocrit or BP occurs.¹

Use with extreme caution in patients with increased risk of hemorrhage.¹ Such patients include those with bacterial endocarditis; congenital or acquired bleeding disorders; active ulceration and angiodysplastic GI disease; hemorrhagic stroke; or recent brain, spinal, or ophthalmologic surgery.¹

Increased risk for hemorrhage in patients treated concomitantly with platelet inhibitors.¹

Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension, or a history of recent GI ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage.¹

Periodic CBCs, including platelet counts, and stool occult blood tests recommended.¹ If abnormal coagulation parameters or bleeding occurs, may consider use of anti-factor Xa levels to monitor anticoagulant effects of enoxaparin.¹

Carefully monitor patients with low body weight or renal impairment for signs and symptoms of bleeding.¹

Protamine sulfate may be used to neutralize the anticoagulant effect of enoxaparin if bleeding occurs.¹ Because fatal reactions resembling anaphylaxis have been reported with protamine sulfate administration, use only when resuscitation techniques and treatment for anaphylactic shock are readily available.¹

To minimize risk of bleeding during percutaneous revascularization procedures, adhere precisely to recommended dosing intervals.¹ Ensure hemostasis at puncture site after PCI; observe for signs of bleeding or hematoma formation.¹ If arterial closure device used, may remove sheath immediately; if manual compression used, remove sheath 6 hours after last dose of enoxaparin.¹ Administer next scheduled dose no sooner than 6–8 hours after sheath removal.¹

Thrombocytopenia

Cases of HIT and HITTS reported, including complications such as organ infarction, limb ischemia, or death.¹ Use with extreme caution in patients with history of HIT/HITTS; use only if ≥100 days since prior episode and absence of circulating antiplatelet antibodies.¹ Monitor thrombocytopenia of any degree closely.¹ If platelet count <100,000/mm³, discontinue enoxaparin.¹ Consider use of nonheparin anticoagulants in patients with history of HIT/HITTS since recurrence possible.¹ (See Contraindications under Cautions.)

Interchangeability with Other Heparins

Do not use enoxaparin sodium 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 (See Dosage under Dosage and Administration.)

Patients with Mechanical Prosthetic Heart Valves

Valve thrombosis resulting in death and/or requiring surgical intervention reported during prophylaxis in some patients with mechanical prosthetic heart valves, including pregnant women.^{1 68 69 70 71 82 83 85 87 90} Women with mechanical prosthetic heart valves are at higher risk for thromboembolism during pregnancy.^{1 85} If enoxaparin is used in pregnant women with mechanical prosthetic heart valves, monitor peak and trough anti-factor Xa concentrations frequently and adjust dosage if necessary to maintain anti-factor Xa levels of 0.7–1.2 units/mL 4 hours after dosing.^{1 71 82 83 93}

Specific Populations

Pregnancy

Crosses placenta in animals, but not in humans.^{1 1107} No evidence of teratogenicity or fetotoxicity.¹ ACOG considers use of LMWHs generally safe in pregnancy.¹¹⁰⁷ Because benzyl alcohol may cross the placenta, enoxaparin in multiple-dose vials containing benzyl alcohol should be used with caution and only if clearly needed in pregnant women.¹

Maternal and neonatal hemorrhage reported; potentially fatal.¹

Use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves may result in valve thrombosis.¹ (See Patients with Mechanical Prosthetic Heart Valves under Cautions.) Frequent monitoring of peak and trough levels of anti-factor Xa required.¹

Monitor pregnant women carefully for evidence of bleeding or excessive anticoagulation.¹ As delivery approaches, consider use of a shorter-acting anticoagulant.¹ (See Boxed Warning.)

Lactation

Not known whether enoxaparin is distributed into breast milk; limited distribution into rat milk.¹ Not known whether enoxaparin affects breast-fed child or milk production.¹ ACOG considers use of LMWHs compatible with lactation.^{1 1107} ACCP recommends that LMWHs be continued in nursing women who are already receiving such therapy.¹⁰¹²

Pediatric Use

Manufacturer states safety and efficacy not established.¹

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) has been associated with toxicity (e.g., “gasping syndrome” and fatal reactions) in neonates;^{1 80 81} each mL of enoxaparin sodium injection in multiple-dose vials contains 15 mg of benzyl alcohol as a preservative.¹

Geriatric Use

Use with caution.¹ No substantial differences in efficacy relative to younger adults.¹ Possible increased risk of bleeding complications.¹ Pay careful attention to dosing intervals and concomitant medications (especially antiplatelet medications).¹ Consider monitoring (i.e., with anti-factor Xa assay) geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function.¹

Renal Impairment

Use with caution; carefully monitor for manifestations of bleeding.¹ Monitor anti-factor Xa concentrations in patients with appreciable renal impairment.¹ Hyperkalemia reported in patients with renal failure receiving enoxaparin.¹

Decreased clearance.¹ Dosage adjustments necessary in patients with severe renal impairment. ^{1 128} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Anemia, ecchymosis, thrombocytopenia, elevation of serum aminotransferase concentrations, fever, nausea, diarrhea, peripheral edema, dyspnea, injection site pain, confusion.¹

Drug Interactions

Drugs Affecting Hemostasis

Potential pharmacodynamic interaction with concomitant use of anticoagulants, platelet-aggregation inhibitors, or other drugs affecting hemostasis (increased risk of bleeding complications).¹ Use with caution.¹

Specific Drugs

Enoxaparin Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability of approximately 100% (based on anti-factor Xa activity) when given sub-Q in healthy individuals.¹

Onset

Maximum anti-factor Xa and antithrombin (anti-factor II_a) activities occur 3–5 hours after administration.¹

Direct IV injection of 30 mg immediately followed by 1 mg/kg dose sub-Q resulted in postinjection aPTT of 50 seconds.¹

Duration

Substantial anti-factor Xa activity persists in plasma for about 12 hours following administration (40 mg once daily).¹

Average aPTT prolongation on day 1 about 16% higher than on day 4.¹

Distribution

Extent

About 4.3 L (based on anti-factor Xa activity).¹

Enoxaparin does not appear to cross the placenta; not known whether the drug is distributed into milk.¹

Elimination

Metabolism

Metabolized, principally in the liver via desulfation and/or depolymerization, to less active metabolites.¹

Elimination Route

40% of dose is excreted in urine.¹

Half-life

4.5 hours after single sub-Q dose, approximately 7 hours after multiple dosing (based on anti-factor Xa activity).¹

Special Populations

Clearance reduced in patients with renal impairment.¹ In patients with severe renal impairment (Cl_cr <30 mL/minute), anti-factor Xa exposure (represented by AUC) was increased by approximately 65%.¹

Possible delayed elimination and increased exposure in geriatric patients.^{1 3}

Stability

Storage

Parenteral

Solution for Injection

25°C (may be exposed to 15–30°C).¹

Do not store multiple-dose vials for >28 days after first use.¹

Compatibility

Parenteral

Solution Compatibility1

Actions

• An LMWH with antithrombotic properties.^{1 2 3 4}

• Has less effect than unfractionated heparin on thrombin at a given level of anti-factor Xa activity.^{1 2}

• Prolongs some global clotting function tests (i.e., thrombin time, aPTT) by up to 1.8 times the control value.¹ At a sub-Q dosage of 1 mg/kg every 12 hours in a large clinical trial, aPTT was ≤45 seconds in most treated patients.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.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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