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Enoxaparin

Medically reviewed on Sep 10, 2018

Pronunciation

(ee noks a PA rin)

Index Terms

  • Enoxaparin Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection, as sodium:

Lovenox: 300 mg/3 mL (3 mL) [contains benzyl alcohol, pork (porcine) protein]

Generic: 300 mg/3 mL (3 mL)

Solution, Subcutaneous, as sodium [preservative free]:

Lovenox: 30 mg/0.3 mL (0.3 mL); 40 mg/0.4 mL (0.4 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL); 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL) [contains pork (porcine) protein]

Generic: 30 mg/0.3 mL (0.3 mL); 40 mg/0.4 mL (0.4 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL); 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)

Brand Names: U.S.

  • Lovenox

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Low Molecular Weight Heparin

Pharmacology

Standard heparin consists of components with molecular weights ranging from 4000 to 30,000 daltons with a mean of 16,000 daltons. Heparin acts as an anticoagulant by enhancing the inhibition rate of clotting proteases by antithrombin III impairing normal hemostasis and inhibition of factor Xa. Low molecular weight heparins have a small effect on the activated partial thromboplastin time and strongly inhibit factor Xa. Enoxaparin is derived from porcine heparin that undergoes benzylation followed by alkaline depolymerization. The average molecular weight of enoxaparin is 4500 daltons which is distributed as (≤20%) 2000 daltons (≥68%) 2000 to 8000 daltons, and (≤18%) >8000 daltons. Enoxaparin has a higher ratio of antifactor Xa to antifactor IIa activity than unfractionated heparin.

Distribution

4.3 L (based on antifactor Xa activity)

Metabolism

Hepatic, via desulfation and depolymerization to lower molecular weight molecules with very low biological activity

Excretion

Urine (40% of dose as active and inactive fragments; 10% as active fragments; 8% to 20% of antifactor Xa activity is recovered within 24 hours)

Clearance: Decreased by 30% in patients with CrCl <30 mL/minute

Onset of Action

Peak effect: SubQ: Antifactor Xa and antithrombin (antifactor IIa): 3 to 5 hours

Duration of Action

40 mg dose: Antifactor Xa activity: ~12 hours

Half-Life Elimination

Plasma: 2 to 4 times longer than standard heparin, independent of dose; based on anti-Xa activity: 4.5 to 7 hours

Protein Binding

Does not bind to heparin binding proteins

Special Populations: Renal Function Impairment

AUC increased 65% in patients with severe renal impairment (CrCl <30 mL/minute).

Special Populations: Elderly

The 10-day mean AUC was about 15% higher than the mean day 1 AUC value.

Special Populations: Gender

Apparent clearance and maximum observed activity derived from anti–factor Xa values following subcutaneous dosing were slightly higher in men than in women.

Special Populations Note

Body weight: Mean AUC of anti–Factor Xa activity is marginally higher at steady state in obese healthy patients. Anti–factor Xa exposure was found to be 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg).

Use: Labeled Indications

Acute coronary syndromes: Unstable angina (UA), non-ST-elevation (NSTEMI), and ST-elevation myocardial infarction (STEMI)

DVT prophylaxis: Following hip or knee replacement surgery, abdominal surgery, or in medical patients with severely-restricted mobility during acute illness who are at risk for thromboembolic complications. Note: Patients at risk of thromboembolic complications who undergo abdominal surgery include those with one or more of the following risk factors: >40 years of age, obesity, general anesthesia lasting >30 minutes, malignancy, history of deep vein thrombosis or pulmonary embolism

DVT treatment (acute): Inpatient treatment (patients with or without pulmonary embolism [PE]) and outpatient treatment (patients without PE). Note: In patients with venous thromboembolism (VTE) (ie, DVT or PE) and without cancer, oral anticoagulants are preferred over LMWH (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin). In patients with venous thromboembolism (VTE) (ie, DVT or PE) and cancer, ACCP recommends LMWH over oral anticoagulants for initial and long-term treatment (Kearon 2012; Kearon 2016).

Off Label Uses

Mechanical prosthetic heart valve (bridge)

Based on the 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update of the 2014 guideline for the management of patients with valvular heart disease, a low molecular weight heparin (eg, enoxaparin) is reasonable to decrease the risk of thrombotic events in patients who require temporary interruption of oral anticoagulation and have a mechanical mitral heart valve, mechanical aortic heart valve plus additional risk factors for thromboembolism (eg, atrial fibrillation, previous thromboembolism, left ventricular dysfunction, or hypercoagulable condition), older-generation mechanical valves (ball-cage or tilting disc) or in pregnant patients with a mechanical prosthetic heart valve only if anti-Xa levels can be monitored.

Pulmonary embolism (acute)

Based on the 2016 American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, low molecular weight heparin (LMWH) (eg, enoxaparin) is an effective and recommended treatment option for acute pulmonary embolism. However, in patients without cancer, oral anticoagulants are preferred over LMWH (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin). Note: In patients with venous thromboembolism (VTE) (ie, DVT or PE) and cancer, ACCP recommends LMWH over oral anticoagulants for initial and long-term treatment.

Venous thromboembolism (VTE) during pregnancy

Based on the 2012 American College of Chest Physicians (ACCP) guidelines for the management of antithrombotic therapy a low molecular weight heparin (LMWH) (eg, enoxaparin) is effective and recommended for the treatment and prevention of VTE during pregnancy.

Venous thromboembolism prophylaxis in bariatric surgery

Data from one prospective open-label non-randomized trial in patients undergoing Roux-en-Y gastric bypass (RYGB) demonstrated that a BMI-stratified, extended enoxaparin dosing regimen provided effective VTE prophylaxis [Borkgren-Okonek 2008]. In a prior non-randomized open-label trial in patients undergoing primary RYGB or revisional bariatric surgery, the use of enoxaparin demonstrated feasibility and a low incidence of postoperative VTE complications [Scholten 2002]. Additional trials may be necessary to further define the role of enoxaparin in the prevention of VTE with bariatric surgery.

The 2013 AACE/TOS/ASMBS bariatric surgery guidelines recommend, along with early ambulation, both sequential compression devices and subcutaneous LMWH or unfractionated heparin administered within 24 hours after surgery with consideration of extended prophylaxis for those who are at high risk for VTE (eg, history of DVT).

Venous thromboembolism, extended treatment in cancer patients

Based on the 2013 American Society of Clinical Oncology Clinical Practice Guideline Update for venous thromboembolism prophylaxis and treatment in patients with cancer and the 2016 American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, a low molecular weight heparin (eg, enoxaparin) is effective and recommended for initial and long-term anticoagulation for extended treatment (up to 6 months) of established VTE (DVT and/or PE) to reduce the recurrence of VTE in cancer patients.

Additional Off-Label Uses

Prophylaxis and treatment of thromboembolism in children; Anticoagulant bridge therapy during temporary interruption of vitamin K antagonist therapy in patients at high risk for thromboembolism; DVT prophylaxis following moderate-risk general surgery, major gynecologic surgery; Anticoagulant used during percutaneous coronary intervention (PCI)

Contraindications

Known hypersensitivity to enoxaparin (eg, pruritus, urticaria, anaphylactic/anaphylactoid reactions), heparin, pork products, or any component of the formulation (including benzyl alcohol in multiple-dose vials); history of immune mediated heparin-induced thrombocytopenia (HIT) in the past 100 days or in the presence of circulating antibodies; active major bleeding

Canadian labeling: Additional contraindications (not in US labeling): Use of multiple-dose vials in newborns or premature neonates; acute or subacute bacterial endocarditis; major blood clotting disorders; active gastric or duodenal ulcer; hemorrhagic cerebrovascular accident (except if there are systemic emboli); severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; other conditions or diseases involving an increased risk of hemorrhage; injuries to and operations on the brain, spinal cord, eyes, and ears; spinal/epidural anesthesia when repeated dosing of enoxaparin (1 mg/kg every 12 hours or 1.5 mg/kg daily) is required, due to increased risk of bleeding.

Dosing: Adult

Note: One mg of enoxaparin is equal to 100 units of anti-Xa activity (World Health Organization First International Low Molecular Weight Heparin Reference Standard). Weight-based doses (eg, 1 mg/kg) are commonly rounded to the nearest 10 mg; also see institution-specific rounding protocols if available. Most available prefilled syringes are graduated in 10 mg increments.

DVT prophylaxis: SubQ:

Obesity: Note: In morbidly-obese patients (BMI ≥40 kg/m2), increasing the prophylactic dose by 30% may be appropriate for some indications (Nutescu 2009). For bariatric surgery, dose increases may be >30% based on clinical trial data.

Abdominal surgery: 40 mg once daily, with initial dose given 2 hours prior to surgery; continue until risk of DVT has diminished (usually 7 to 10 days).

Hip replacement surgery:

Twice-daily dosing: 30 mg every 12 hours, with initial dose within 12 to 24 hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt 2012).

Once-daily dosing: 40 mg once daily, with initial dose within 9 to 15 hours before surgery, and daily for at least 10 days (or up to 35 days postoperatively) or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt 2012).

Knee replacement surgery: 30 mg every 12 hours, with initial dose within 12 to 24 hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt 2012).

Medical patients with severely restricted mobility during acute illness: 40 mg once daily; continue until risk of DVT has diminished (usually 6 to 11 days). In hospitalized cancer patients, the recommended duration of therapy is length of hospital stay or until fully ambulatory (Lyman 2013; Lyman 2015).

Major surgery in cancer patients (off-label): 20 mg 2 to 4 hours prior to surgery, then 40 mg once daily thereafter or 40 mg 10 to 12 hours prior to surgery, then 40 mg once daily thereafter; treatment durations should be at least 7 to 10 days. Prolonged treatment up to 4 weeks should be considered in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features (eg, limited mobility, obesity, VTE history, comorbid conditions) (Lyman 2013; Lyman 2015).

Bariatric surgery (off-label use): Roux-en-Y gastric bypass: Appropriate dosing strategies have not been clearly defined (Borkgren-Okonek 2008; Scholten 2002):

BMI ≤50 kg/m2: 40 mg every 12 hours

BMI >50 kg/m2: 60 mg every 12 hours

Note: The 2013 AACE/TOS/ASMBS bariatric surgery guidelines recommend, along with early ambulation, both sequential compression devices and subcutaneous LMWH or unfractionated heparin administered within 24 hours after surgery with consideration of extended prophylaxis for those who are at high risk for VTE (eg, history of DVT) (AACE/TOS/ASMBS [Mechanick 2013]).

Prevention of recurrent venous thromboembolism in pregnancy (off-label use): 40 mg once daily. Therapy should continue for 6 weeks postpartum in high-risk women (Bates 2012).

DVT treatment (acute) and pulmonary embolism (acute) (off-label): SubQ: Note: In patients with VTE and without cancer, oral anticoagulants are preferred over LMWH (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin) (Kearon 2012; Kearon 2016). In patients transitioning to warfarin, start warfarin on the first or second treatment day and continue enoxaparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days) (Guyatt 2012).

Inpatient treatment of DVT (with or without pulmonary embolism) and pulmonary embolism: 1 mg/kg/dose every 12 hours or 1.5 mg/kg once daily (Kearon 2012; Kearon 2016)

Outpatient treatment (without pulmonary embolism): 1 mg/kg/dose every 12 hours

Obesity: Use actual body weight to calculate dose; a fixed upper dose limit is not recommended, however, increased monitoring and dosage adjustment based on anti-Xa levels may be warranted; use of twice daily dosing preferred (Nutescu 2009).

Pregnant women (off-label use): 1 mg/kg/dose every 12 hours. Discontinue ≥24 hours prior to the induction of labor or cesarean section. Enoxaparin therapy may be substituted with heparin near term. Continue anticoagulation therapy for ≥6 weeks postpartum (minimum duration of therapy: 3 months). LMWH or heparin therapy is preferred over warfarin during pregnancy (Bates 2012).

Duration of therapy: Based on the cause of VTE, risk of recurrence and risk of bleeding. Refer to guidelines for specific recommendations.

Percutaneous coronary intervention (PCI), adjunctive therapy (off-label dosing) (ACCF/AHA/SCAI [Levine, 2011]): IV:

If patient undergoing PCI has been treated with multiple doses of enoxaparin and PCI occurs within 8 hours after the last SubQ enoxaparin dose: No additional enoxaparin is needed.

If PCI occurs 8 to 12 hours after the last SubQ enoxaparin dose or the patient received only 1 therapeutic SubQ dose (eg, 1 mg/kg): Administer a single IV dose of 0.3 mg/kg.

If PCI occurs >12 hours after the last SubQ dose: May use an established anticoagulation regimen (eg, full-dose unfractionated heparin or bivalirudin).

If patient has not received prior anticoagulant therapy: 0.5 to 0.75 mg/kg IV bolus dose

ST-elevation MI (STEMI):

Patients <75 years of age: Initial: 30 mg IV single bolus plus 1 mg/kg (maximum: 100 mg for the first 2 doses only) SubQ every 12 hours. The first SubQ dose should be administered with the IV bolus. Maintenance: After first 2 doses, administer 1 mg/kg SubQ every 12 hours.

Patients ≥75 years of age: Initial: SubQ: 0.75 mg/kg every 12 hours (Note: No IV bolus is administered in this population); a maximum dose of 75 mg is recommended for the first 2 doses. Maintenance: After first 2 doses, administer 0.75 mg/kg SubQ every 12 hours

Obesity: Use weight-based dosing; a maximum dose of 100 mg is recommended for the first 2 doses (Nutescu 2009)

Additional notes on STEMI treatment: Therapy may be continued for up to 8 days or until revascularization. Unless contraindicated, all patients should receive aspirin (indefinitely) and clopidogrel (ACCF/AHA [O'Gara 2013]). In patients with STEMI receiving thrombolytics, initiate enoxaparin dosing between 15 minutes before and 30 minutes after fibrinolytic therapy.

Mechanical prosthetic heart valve (aortic or mitral position) to bridge anticoagulation (off-label use): SubQ: 1 mg/kg every 12 hours (ACCP [Douketis, 2012]). Note: If used in pregnant patients, target anti-Xa level of 0.8 to 1.2 units/mL, 4 to 6 hours postdose (AHA/ACC [Nishimura 2014]).

Unstable angina or non-ST-elevation MI (NSTEMI) (also referred to as NSTE-ACS): SubQ: 1 mg/kg every 12 hours in conjunction with oral aspirin therapy; continue for the duration of hospitalization or until PCI is performed; in select patients, an initial 30 mg IV loading dose has been used (ACC/AHA [Amsterdam 2014]).

Obesity: Use actual body weight to calculate dose; a fixed upper dose limit is not recommended (Nutescu 2009)

Conversion:

Conversion from IV unfractionated heparin (UFH) infusion to SubQ enoxaparin (Nutescu 2007): Calculate specific dose for enoxaparin based on indication, discontinue UFH and begin enoxaparin within 1 hour.

Conversion from SubQ enoxaparin (therapeutically dosed) to IV UFH infusion (Nutescu 2007): Note: The following recommendations are based on use of therapeutic doses of enoxaparin (eg, 1 mg/kg every 12 hours). If converting from a prophylactic enoxaparin dose (eg, 30 mg twice daily) to a therapeutic IV UFH dose, there should not be any delay in starting the IV UFH infusion and may include an UFH bolus/loading dose, when indicated.

Discontinue enoxaparin, calculate specific dose for IV UFH infusion based on indication, omit UFH bolus/loading dose:

Converting from SubQ enoxaparin dosed every 12 hours: Start IV UFH infusion 10 to 11 hours after last dose of enoxaparin

Converting from SubQ enoxaparin dosed every 24 hours: Start IV UFH infusion 22 to 23 hours after last dose of enoxaparin

Venous thromboembolism, extended treatment in cancer patients (off-label use): SubQ:

Months 1 to 6: Initial: 1 mg/kg/dose every 12 hours or 1.5 mg/kg once daily for 5 to 10 days; continue for up to 6 months for maintenance therapy. Note: Twice-daily dosing may be more efficacious than once-daily dosing based on post hoc data. Warfarin may be used for maintenance therapy; however, meta-analyses and randomized control trials have validated the superiority of LMWH over warfarin. If warfarin is to be used for maintenance therapy, overlap enoxaparin with warfarin for a minimum of 5 to 7 days and continue until INR in therapeutic range for at least 48 hours (Lyman 2013; Lyman 2015).

Maintenance beyond 6 months: ACCP and ASCO guidelines for VTE prophylaxis/treatment recommend considering continuing anticoagulation beyond 6 months in selected patients due to the persistent high risk of recurrence in those with active cancer; consider risk vs. benefit of bleeding and recurrence (Kearon 2012; Kearon 2016; Lyman 2013; Lyman 2015).

Dosing: Geriatric

SubQ: Refer to adult dosing. Increased incidence of bleeding with doses of 1.5 mg/kg/day or 1 mg/kg every 12 hours; injection-associated bleeding and serious adverse reactions are also increased in the elderly. Careful attention should be paid to elderly patients, particularly those <45 kg. Note: Dosage alteration/adjustment may be required.

Dosing: Pediatric

Note: One mg of enoxaparin is equal to 100 units of anti-Xa activity (World Health Organization First International Low Molecular Weight Heparin Reference Standard).

Thromboembolism (off-label use; Monagle 2012): SubQ:

Infants <2 months: Initial:

Prophylaxis: 0.75 mg/kg every 12 hours

Treatment: 1.5 mg/kg every 12 hours

Infants >2 months and Children ≤18 years: Initial:

Prophylaxis: 0.5 mg/kg every 12 hours

Treatment: 1 mg/kg every 12 hours

Maintenance: See Dosage Titration table:

Enoxaparin Pediatric Dosage Titration1

Anti-Xa Result

Dose Titration

Time to Repeat Anti-Xa

Measurement

1Nomogram to be used for treatment dosing.

Modified from Duplaga BA, et al, “Dosing and Monitoring of Low-Molecular-Weight Heparins in Special Populations,” Pharmacotherapy, 2001, 21(2):218-34; Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest, 2001;119:344S-370S.

<0.35 units/mL

Increase dose by 25%

4 h after next dose

0.35-0.49 units/mL

Increase dose by 10%

4 h after next dose

0.5-1 unit/mL

Keep same dosage

Next day, then 1 wk later, then monthly (4 h after dose)

1.1-1.5 units/mL

Decrease dose by 20%

Before next dose

1.6-2 units/mL

Hold dose for 3 h and decrease dose by 30%

Before next dose, then 4 h after next dose

>2 units/mL

Hold all doses until anti-Xa is 0.5 units/mL, then decrease dose by 40%

Before next dose and every 12 h until anti-Xa <0.5 units/mL

Table has been converted to the following text.

Enoxaparin Pediatric Dosage Titration1

Anti-Xa <0.35 units/mL:

Increase dose by 25%; repeat anti-Xa level 4 hours after next dose

Anti-Xa 0.35-0.49 units/mL:

Increase dose by 10%; repeat anti-Xa level 4 hours after next dose

Anti-Xa 0.5-1 unit/mL:

Keep same dosage; repeat anti-Xa level next day, then1 week later, then monthly (4 hours after dose)

Anti-Xa 1.1-1.5 units/mL:

Decrease dose by 20%; repeat anti-Xa level before next dose

Anti-Xa 1.6-2 units/mL:

Hold dose for 3 hours and decrease dose by 30%; repeat anti-Xa level before next dose, then 4 hours after next dose

Anti-Xa >2 units/mL:

Hold all doses until anti-Xa is 0.5 units/mL, then decrease dose by 40%; repeat anti-Xa level before next dose and every 12 hours until anti-Xa <0.5 units/mL

1Nomogram to be used for treatment dosing

Modified from Duplaga BA, et al, “Dosing and Monitoring of Low-Molecular-Weight Heparins in Special Populations,” Pharmacotherapy, 2001, 21(2):218-34.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No specific adjustment recommended (per manufacturer); monitor closely for bleeding.

CrCl <30 mL/minute:

DVT prophylaxis in abdominal surgery, hip replacement, knee replacement, or in medical patients during acute illness: SubQ: 30 mg once daily. Note: The Canadian labeling recommends 20 to 30 mg once daily (based on risk/benefit assessment) for prophylaxis in abdominal or colorectal surgery or in medical patients during acute illness.

DVT treatment: SubQ: 1 mg/kg once daily

STEMI:

<75 years: Initial: IV: 30 mg as a single dose with the first dose of the SubQ maintenance regimen administered at the same time as the IV bolus; Maintenance: SubQ: 1 mg/kg once daily. Note: Canadian labeling recommends a maximum dose of 100 mg for the first SubQ dose.

≥75 years of age: Omit IV bolus; Maintenance: SubQ: 1 mg/kg once daily. Note: Canadian labeling recommends a maximum dose of 100 mg for the first SubQ dose.

Unstable angina, NSTEMI: SubQ: 1 mg/kg once daily

Dialysis: Enoxaparin has not been FDA approved for use in dialysis patients. Its elimination is primarily via the renal route. Serious bleeding complications have been reported with use in patients who are dialysis dependent or have severe renal failure. LMWH administration at fixed doses without monitoring has greater unpredictable anticoagulant effects in patients with chronic kidney disease. If used, dosages should be reduced and anti-Xa levels frequently monitored, as accumulation may occur with repeated doses. Many clinicians would not use enoxaparin in this population especially without timely anti-Xa levels.

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016]). Supplemental dose is not necessary.

Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Administration

Note: Enoxaparin is available in 100 mg/mL and 150 mg/mL concentrations.

SubQ: Administer by deep SubQ injection alternating between the left or right anterolateral and left or right posterolateral abdominal wall. Do not mix with other infusions or injections. In order to minimize bruising, do not rub injection site. To avoid loss of drug from the 30 mg and 40 mg prefilled syringes, do not expel the air bubble from the syringe prior to injection.

IV: STEMI and PCI only: The US labeling recommends using the multiple-dose vial to prepare IV doses. The Canadian labeling recommends either the multiple-dose vial or a prefilled syringe. Do not mix or coadminister with other medications; may be administered with NS or D5W. Flush IV access site with a sufficient amount of NS or D5W prior to and following IV bolus administration. When used prior to percutaneous coronary intervention or as part of treatment for ST-elevation myocardial infarction (STEMI), a single dose may be administered IV except when the patient is ≥75 years of age and is experiencing STEMI then only administer by SubQ injection.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Do not store multiple-dose vials for >28 days after first use.

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the adverse/toxic effect of Heparins (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Aliskiren: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Aliskiren. Monitor therapy

Angiotensin II Receptor Blockers: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Antithrombin: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Canagliflozin: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Canagliflozin. Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Eplerenone: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Palifermin: Heparins (Low Molecular Weight) may increase the serum concentration of Palifermin. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Monitor therapy

Potassium Salts: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts. Monitor therapy

Potassium-Sparing Diuretics: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Adverse Reactions

As with all anticoagulants, bleeding is the major adverse effect of enoxaparin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables. At the recommended doses, single injections of enoxaparin do not significantly influence platelet aggregation or affect global clotting time (ie, PT or aPTT).

>10%: Hematologic & oncologic: Anemia (≤16%), hemorrhage (4% to 13%)

1% to 10%:

Cardiovascular: Peripheral edema (6%)

Central nervous system: Confusion (2%)

Gastrointestinal: Nausea (3%)

Hematologic & oncologic: Major hemorrhage (<1% to 4%; includes cases of intracranial [up to 0.8%], retroperitoneal, or intraocular hemorrhage; incidence varies with indication/population), ecchymoses (3%), thrombocytopenia (1% to 2%)

Hepatic: Increased serum ALT (>3 x ULN: 6%), increased serum AST (>3 x ULN: 6%)

Local: Hematoma at injection site (9%), bleeding at injection site (3% to 5%), pain at injection site (2%)

Renal: Hematuria (≤2%)

Miscellaneous: Fever (≤8%)

<1%, postmarketing, and/or case reports: Acute posthemorrhagic anemia, alopecia, anaphylactoid reaction, anaphylaxis, atrial fibrillation, bruising at injection site, eosinophilia, epidural hematoma (spinal; after neuroaxial anesthesia or spinal puncture; risk may be increased with indwelling epidural catheter or concomitant use of other drugs affecting hemostasis), erythema at injection site, headache, hepatic injury (hepatocellular and cholestatic), hyperkalemia, hyperlipidemia (very rare), hypersensitivity angiitis, hypersensitivity reaction, hypertriglyceridemia, injection site reactions (including nodules, inflammation, oozing), irritation at injection site, osteoporosis (following long-term therapy), pneumonia, pruritus, pulmonary edema, purpura, shock, skin necrosis, thrombocythemia, thrombosis in heparin-induced thrombocytopenia, thrombosis (prosthetic value [in pregnant females] or associated with enoxaparin-induced thrombocytopenia; can cause limb ischemia or organ infarction), urticaria, vesicobullous rash

ALERT: U.S. Boxed Warning

Spinal/Epidural hematoma:

Epidural or spinal hematomas may occur in patients who are anticoagulated with LMWHs or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures.

Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, and other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; and a history of spinal deformity or spinal surgery. Optimal timing between the administration of enoxaparin and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmic surgery; in patients treated concomitantly with platelet inhibitors; recent GI bleeding or ulceration; renal dysfunction and hemorrhage; thrombocytopenia or platelet defects or history of heparin-induced thrombocytopenia; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Discontinue if bleeding occurs. Protamine may be considered as a partial reversal agent in overdose situations (consult Protamine monograph for dosing recommendations). To minimize risk of bleeding following PCI, achieve hemostasis at the puncture site after PCI. If a closure device is used, sheath can be removed immediately. If manual compression is used, remove sheath 6 hours after the last IV/SubQ dose of enoxaparin. Do not administer further doses until 6 to 8 hours after sheath removal; observe for signs of bleeding/hematoma formation.

• Hyperkalemia: Monitor for hyperkalemia; can cause hyperkalemia possibly by suppressing aldosterone production. Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, renal dysfunction, concomitant use of potassium-sparing diuretics or potassium supplements, hematoma in body tissues).

.• Thrombocytopenia: Thrombocytopenia can occur. Cases of enoxaparin-induced thrombocytopenia with thrombosis, some complicated by organ infarction, limb ischemia, or death, have been observed; monitor platelet count closely. Use with extreme caution or avoid in patients with history of HIT (Warkentin 2001); use is contraindicated in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies. In patients with a history of HIT, use only if >100 days have elapsed since the prior HIT episode and no circulating antibodies are present (HIT may still occur in these patients; assess risk vs benefit and use only after non-heparin alternative treatments are considered). Discontinue therapy and consider alternative treatment if platelets are <100,000/mm3 and/or thrombosis develops. Use caution in patients with congenital or drug-induced thrombocytopenia or platelet defects.

Disease-related concerns:

• Prosthetic heart valves: Cannot be recommended for long-term thromboprophylaxis in patients with prosthetic heart valves (especially pregnant women) due to insufficient evidence.

• Renal impairment: Use with caution in patients with renal failure; dosage adjustment needed if CrCl <30 mL/minute.

Special populations:

• Elderly: Use with caution in the elderly; delayed elimination may occur. Dosage alteration/adjustment may be required (eg, omission of IV bolus in acute STEMI in patients ≥75 years of age).

• Low weight patients: Risk of bleeding may be increased in women <45 kg and in men <57 kg.

• Obesity: Safety and efficacy of prophylactic dosing of enoxaparin has not been established in patients who are obese (>30 kg/m2) nor is there a consensus regarding dosage adjustments; monitor closely for signs/symptoms of thromboembolism. Anti-Xa levels are increased to appropriate levels when enoxaparin is dosed on actual body weight in obese patients weighing up to 144 kg (Sanderink 2002). Monitoring of anti-Xa levels 4 hours after the dose may be warranted. The American College of Chest Physicians Practice Guidelines suggest consulting with a pharmacist regarding dosing in bariatric surgery patients and other obese patients who may require higher doses of LMWH (ACCP [Gould 2012]).

• Surgical patients: In patients receiving bridging anticoagulation with therapeutic dose enoxaparin, the American College of Chest Physicians suggests that the last preoperative dose of enoxaparin be administered ~24 hours prior to surgery (ACCP [Douketis 2012]).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and should not be used in pregnant women. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”); the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Administration: Do not administer intramuscularly.

• Conversion to other products: Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.

• Neuraxial anesthesia: [US Boxed Warning]: Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; and a history of spinal deformity or spinal surgery. Optimal timing between the administration of enoxaparin and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Delay placement or removal of catheter for at least 12 hours after administration of low-dose enoxaparin (eg, 30 to 60 mg/day) and at least 24 hours after high-dose enoxaparin (eg, 0.75 to 1 mg/kg twice daily or 1.5 mg/kg once daily); risk of neuraxial hematoma may still exist since antifactor Xa levels are still detectable at these time points. Patients receiving twice daily high-dose enoxaparin should have the second dose withheld to allow a longer time period prior to catheter placement or removal. Upon removal of catheter, consider withholding enoxaparin for at least 4 hours. Consider doubling these times in patients with creatinine clearance <30 mL/minute. If anticoagulation is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia/analgesia, or spinal anesthesia/analgesia monitor frequently for signs and symptoms of neurological impairment (midline back pain, sensory and motor deficits, bowel or bladder dysfunction). If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered although it may not prevent or reverse neurological sequelae.

Monitoring Parameters

Platelets, occult blood, anti-Xa levels, serum creatinine; monitoring of PT and/or aPTT is not necessary. Routine monitoring of anti-Xa levels is not required, but has been utilized in patients with obesity and/or renal insufficiency. For patients > 144 kg, if anti-Xa monitoring is available, adjusting dose based on anti-Xa levels is recommended; if anti-Xa monitoring is unavailable, reduce dose if bleeding occurs (Garcia 2012; Nutescu 2009). Monitor obese patients closely for signs/symptoms of thromboembolism. Monitoring anti-Xa levels is recommended in pregnant women receiving therapeutic doses of enoxaparin or when receiving enoxaparin for the prevention of thromboembolism with mechanical heart valves (Guyatt 2012).

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Low molecular weight heparin (LMWH) does not cross the placenta; increased risks of fetal bleeding or teratogenic effects have not been reported (Bates 2012).

LMWH is recommended over unfractionated heparin for the treatment of acute venous thromboembolism (VTE) in pregnant women. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant women with certain risk factors (eg, homozygous factor V Leiden, antiphospholipid antibody syndrome with ≥3 previous pregnancy losses). Prophylaxis is not routinely recommended for women undergoing assisted reproduction therapy; however, LMWH therapy is recommended for women who develop severe ovarian hyperstimulation syndrome. LMWH should be discontinued at least 24 hours prior to induction of labor or a planned cesarean delivery. For women undergoing cesarean section and who have additional risk factors for developing VTE, the prophylactic use of LMWH may be considered (Bates 2012).

LMWH may also be used in women with mechanical heart valves (consult current guidelines for details) (Bates 2012; Nishimura 2014). Women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (Bates 2012). Monitoring antifactor Xa levels is recommended (Bates 2012; Nishimura 2014).

Multiple-dose vials contain benzyl alcohol (avoid in pregnant women due to association with gasping syndrome in premature infants); use of preservative-free formulations is recommended.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, injection site irritation, or diarrhea. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), back pain, numbness or tingling feeling, muscle weakness, paralysis, urinary incontinence, fecal incontinence, severe dizziness, passing out, confusion, severe headache, or severe loss of strength (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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