Enoxaprine

Pharmacologic Category

Anticoagulant; Anticoagulant, Low Molecular Weight Heparin

Dosing: Adult

The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.

Note: One mg of enoxaparin is equal to 100 units of anti-factor 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.

Acute symptomatic superficial vein thrombosis (lower extremity; ≥5 cm in length) (off-label use):

SubQ: 40 mg once daily for 45 days (ACCP [Kearon 2012]; Décousus 2003). Risk of recurrence is high if anticoagulation is discontinued earlier than 45 days. Monitor d-dimer at baseline and again at 45 days; if d-dimer remains elevated, a longer course may be necessary (Scovell 2020).

Hemodialysis, intermittent, anticoagulation of circuit (off-label use):

Note: Standard dosing has not been established for intermittent hemodialysis. Recommendations provided below are examples. Refer to institutional protocols. May need to individualize dose based on patient-specific needs.

Injection into arterial line of hemodialysis circuit: 0.5 to 1 mg/kg administered once at the beginning of hemodialysis (Klingel 2004b; Saltissi 1999; Canadian manufacturer’s labeling). Some experts recommend 20 to 40 mg administered once at the beginning of hemodialysis (Al-Arrayed 2002; Kovalik 2020).

Ischemic heart disease:

Acute coronary syndromes:

Non-ST-elevation acute coronary syndromes:

SubQ: 1 mg/kg every 12 hours in conjunction with an appropriate antiplatelet regimen; continue for the duration of hospitalization or until percutaneous coronary intervention (PCI) is performed.

Note: Some experts suggest that enoxaparin, although comparable in efficacy to unfractionated heparin (UFH), does not have a role in patients undergoing an invasive approach due to an increased risk of bleeding; UFH or bivalirudin is preferred (Cutlip 2020a; Ferguson 2004).

ST-elevation myocardial infarction:

Note: Although the manufacturer's labeling includes the use of enoxaparin for patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI, heparin or bivalirudin is preferred. Initial dosing is the same for patients who undergo reperfusion with fibrinolysis or PCI and for patients who do not undergo reperfusion. In patients with STEMI receiving thrombolytics, initiate enoxaparin between 15 minutes before and 30 minutes after fibrinolytic therapy. Use in conjunction with an appropriate antiplatelet regimen (ACCF/AHA [O'Gara 2013]).

Patients <75 years of age: Single IV bolus of 30 mg 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.

Patients ≥75 years of age: Note: No IV bolus is administered. SubQ: 0.75 mg/kg (maximum: 75 mg for the first 2 doses only) every 12 hours.

Duration: Therapy may be continued for up to 8 days (minimum of 48 hours when undergoing reperfusion with fibrinolysis) or until revascularization (ACCF/AHA [O'Gara 2013]).

Percutaneous coronary intervention, adjunctive therapy (off label):

Note: Not generally initiated in patients undergoing elective PCI and not preferred in patients undergoing PCI for acute coronary syndromes (Cutlip 2020b; Lincoff 2020).

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 (ACCF/AHA/SCAI [Levine 2011]).

If PCI occurs 8 to 12 hours after the last SubQ enoxaparin dose in a patient treated with multiple doses of enoxaparin or the patient received only 1 therapeutic SubQ dose (eg, 1 mg/kg): Administer a single IV dose of 0.3 mg/kg (ACCF/AHA/SCAI [Levine 2011]).

If PCI occurs >12 hours after the last SubQ dose: May use an established anticoagulation regimen (eg, full-dose UFH or bivalirudin) (ACCF/AHA/SCAI [Levine 2011]).

Mechanical heart valve (bridging anticoagulation) (off-label use):

Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral or tricuspid valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older generation mechanical aortic valve (AHA/ACC [Nishimura 2017]).

SubQ: 1 mg/kg every 12 hours; adjust dose based on anti-factor Xa monitoring (ACCP [Douketis 2012]). For additional information regarding anti-factor Xa monitoring, refer to the Reference Range field.

Venous thromboembolism prophylaxis:

Bariatric surgery, high venous thromboembolism risk (off-label use):

Note: Optimal dosing strategies have not been established. Dosing regimens based on best available evidence (Birkmeyer 2012; Borkgren-Okonek 2008; Scholten 2002).

BMI ≤50 kg/m2: SubQ: 40 mg every 12 hours initiated at least 2 hours before surgery.

BMI >50 kg/m2: SubQ: 60 mg every 12 hours initiated at least 2 hours before surgery.

Note: Optimal duration of prophylaxis is unknown, but is usually continued until hospital discharge and may be extended for up to 6 weeks postoperatively depending upon venous thromboembolism (VTE) risk. There is no consensus on indications for extended prophylaxis following bariatric surgery (Lim 2019).

Medical patients with acute illness at moderate and high risk for venous thromboembolism:

SubQ: 40 mg once daily; continue for length of hospital stay or until patient is fully ambulatory and risk of VTE has diminished (ACCP [Kahn 2012]; ASCO [Key 2020]). Extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; Sharma 2012). However, in high-risk coronavirus disease 2019 (COVID-19) patients who are discharged from the hospital, some experts would consider extended prophylaxis with a direct oral anticoagulant (rivaroxaban or betrixaban) (Cuker 2020).

Nonmajor orthopedic surgery of lower limb (alternative therapy) (off-label use):

Note: Early ambulation alone is preferred when feasible, but pharmacologic prophylaxis may be considered for patients with higher than usual risk (eg, history of VTE, limited mobility, or undergoing high-risk surgery such as Achilles tendon repair, femoral fracture, tibial plateau fracture, or ligament repair of the knee) (Pai 2020; Samama 2020).

SubQ: 40 mg once daily initiated ≥6 to 10 hours after surgery; continue for the duration of immobilization (Pai 2020; Samama 2020).

Nonorthopedic surgery (off label):

Patients with active cancer:

SubQ: 40 mg started 10 to 12 hours before surgery and 40 mg once daily thereafter (ASCO [Key 2020]).

or

SubQ: 20 mg started 2 to 4 hours before surgery and 40 mg once daily thereafter (ASCO [Key 2020]).

or

SubQ: 40 mg once daily started ~12 to 24 hours after surgery (Bauer 2019; Pai 2019).

Note: The optimal duration of prophylaxis has not been established. It is usually given for a minimum of 7 to 10 days. Extending for up to 4 weeks may be reasonable in those undergoing major abdominal or pelvic surgery (ASCO [Key 2020]).

Patients without active cancer:

Note: For patients with moderate and high risk of VTE and low risk of bleeding:

SubQ: 40 mg once daily, with initial dose given at least 2 hours before abdominal surgery or ~12 hours before other nonorthopedic surgery. Alternatively, may postpone pharmacologic prophylaxis until after surgery (eg, high bleeding risk) when it is safe to initiate (Pai 2019). Continue until fully ambulatory and risk of VTE has diminished (typically up to 10 days) (ACCP [Gould 2012]; Pai 2019).

Pregnancy (off label):

Note: For patients at moderate and high VTE risk during antepartum and postpartum periods. Dose intensity is individualized based on risks of thrombosis and bleeding complications.

Prophylactic dose: SubQ: 40 mg once every 24 hours (ACOG 2018).

Intermediate dose: SubQ: 40 mg every 12 hours (ACOG 2018); however, some experts use an alternative intermediate regimen of 40 mg SubQ once daily, increasing as pregnancy progresses to 1 mg/kg once daily (Bauer 2020a; Malhotra 2020).

Adjusted dose (therapeutic): SubQ: 1 mg/kg every 12 hours; reserved for patients at the highest risk (eg, history of recurrent thrombosis or severe thrombophilia) (ACCP [Bates 2012]; ACOG 2018).

Note: Anticoagulation management prior to delivery is individualized. Options include replacing with UFH at ~36 to 37 weeks' gestation or extending to 38 to 39 weeks' gestation in patients at very low risk of delivery while on enoxaparin (Bauer 2020a). In such patients, discontinue enoxaparin ≥12 hours before delivery (for prophylactic doses) or ≥24 hours before delivery (for higher doses), particularly if neuraxial anesthesia is planned; may restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred (ACOG 2018). Anticoagulation should continue for up to 6 weeks postpartum, but potentially longer (ACCP [Bates 2012]; ACOG 2018; Bauer 2020a).

Total hip arthroplasty or hip fracture surgery:

SubQ: 40 mg once daily or 30 mg every 12 hours, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved (ACCP [Falck-Ytter 2012]; Eriksson 2001; Pai 2020). Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (ACCP [Falck-Ytter 2012]; Bergqvist 1996; Eikelboom 2001; Pai 2020; Sobieraj 2012); some experts suggest a duration at the higher end of range (eg, 30 days) (Pai 2020).

Total knee arthroplasty:

SubQ: 30 mg every 12 hours, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved (ACCP [Falck-Ytter 2012]; Pai 2020). Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (ACCP [Falck-Ytter 2012]; Eikelboom 2001; Pai 2020); some experts suggest a duration at the lower end of the range (eg, 10 to 14 days) (Pai 2020).

Venous thromboembolism treatment:

Note: For timing of initiating oral anticoagulant, see Transitioning between anticoagulants.

Deep vein thrombosis and/or pulmonary embolism (pulmonary embolism is an off-label use): Inpatient treatment: SubQ: 1 mg/kg every 12 hours (preferred) or 1.5 mg/kg once every 24 hours. Note: In select low-risk patients, may consider outpatient treatment using 1 mg/kg every 12 hours for the remainder of the course after first dose administered in hospital or urgent care center (ACCP [Kearon 2016]; Aujesky 2011; Erkens 2010).

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and depends on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preference.

Provoked VTE: 3 months (provided the provoking risk factor is no longer present) (ACCP [Kearon 2016]).

Unprovoked PE or DVT (proximal or isolated distal): ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ISTH [Baglin 2012]).

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Venous thromboembolism treatment in patients with active cancer:

Months 1 to 6: SubQ: Initial: 1 mg/kg every 12 hours or 1.5 mg/kg once daily for 5 to 10 days followed by long-term anticoagulation for a total duration of 3 to 6 months. Note: Twice-daily dosing may be more efficacious than once-daily dosing based on post hoc data (ASCO [Key 2020]; Bauer 2020b).

Maintenance beyond 6 months: ACCP and ASCO guidelines for VTE prophylaxis/treatment recommend considering continuing anticoagulation beyond 6 months in select patients due to the persistent high risk of recurrence in those with active cancer; consider risk versus benefit of bleeding and recurrence (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ASCO [Key 2020]).

Venous thromboembolism treatment in pregnancy:

SubQ: 1 mg/kg every 12 hours (ACCP [Bates 2012]); ACOG 2018). Some experts suggest anti-factor Xa monitoring for dose adjustment (ACCP [Bates 2012]). For additional information regarding anti-factor Xa monitoring, refer to the Reference Range field.

Note: Anticoagulation management prior to delivery is individualized. Options include replacing with UFH at ~36 to 37 weeks' gestation or extending to 38 to 39 weeks' gestation in patients at very low risk of delivery while on enoxaparin (Bauer 2020a). In such patients, discontinue enoxaparin ≥24 hours before delivery, particularly if neuraxial anesthesia is planned; may restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred (ACOG 2018). Optimal duration of anticoagulation is unknown. In general, total duration (antepartum plus postpartum) should be at least 3 to 6 months with at least 6 weeks postpartum (ACOG 2018; Malhotra 2020).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:

Transitioning from another anticoagulant to enoxaparin:

Transitioning from therapeutic IV UFH infusion to therapeutic-dose enoxaparin: Discontinue UFH and begin enoxaparin within 1 hour. Note: If aPTT is not in therapeutic range at the time UFH is discontinued, consult local protocol (Nutescu 2007).

Transitioning from enoxaparin to another anticoagulant:

Transitioning from therapeutic-dose enoxaparin to therapeutic IV UFH infusion: Start IV UFH (rate based on indication) 1 to 2 hours before the next dose of enoxaparin would have been due. Note: Omit IV UFH loading dose (Nutescu 2007).

Transitioning from prophylactic enoxaparin to therapeutic IV UFH: UFH should be started without delay. A UFH bolus/loading dose may be used if indicated.

Transitioning from therapeutic-dose enoxaparin to warfarin: Start warfarin and continue enoxaparin until INR is within therapeutic range (Hull 2019a; Wittkowsky 2018). Note: For the treatment of VTE, overlap enoxaparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is usually 4 to 5 days) (ACCP [Ageno 2012]; Hull 2019b).

Transitioning from therapeutic-dose enoxaparin to a direct oral anticoagulant: Note: In treatment of VTE, some direct oral anticoagulants (dabigatran, edoxaban) require 5 days of parenteral anticoagulation prior to transitioning.

General transition recommendation: Start direct oral anticoagulant (DOAC) within 2 hours prior to the next scheduled dose of enoxaparin.

VTE initial treatment transition (alternative recommendation): For acute VTE, some experts start DOAC within 6 to 12 hours after the last dose of a twice-daily low-molecular-weight heparin (LMWH) regimen or within 12 to 24 hours after a once-daily LMWH regimen (Hull 2019b).

* See Dosage and Administration in AHFS Essentials for additional information.

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 elderly patients. Careful attention should be paid to elderly patients, particularly those <45 kg. Note: Dosage alteration/adjustment may be required.

Dosing: Renal Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: In patients with kidney impairment anti-factor Xa levels may be used to monitor anticoagulant effects.

CrCl >50 mL/minute: No dose adjustment necessary.

CrCl 30 to 50 mL/minute: No dose adjustment necessary.

Note: Bleeding risk may be increased when standard treatment doses are used (eg, treatment of venous thromboembolism) (DeCarolis 2012); monitor closely for evidence of bleeding. Empiric dose reduction strategies have been proposed (Green 2005; Hulot 2005; Kruse 2004) but lack robust evidence.

CrCl <30 mL/minute:

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

Venous thromboembolism treatment: SubQ: 1 mg/kg once daily.

ST-elevation myocardial infarction:

<75 years of age: 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.

Non-ST-elevation acute coronary syndromes: SubQ: 1 mg/kg once daily.

Hemodialysis, intermittent (thrice weekly) (systemic anticoagulation): SubQ: Not dialyzable (Klingel 2004a): Avoid use if possible, as there may be accumulation of active heparin metabolites that are undetected by anti-factor Xa assays (Brophy 2006). Serious bleeding complications have been reported with use in patients who are dialysis dependent or have severe kidney failure (Tsai 2009). Note that some retrospective studies suggest that enoxaparin may be used for deep vein thrombosis prophylaxis in dialysis patients with no increase in bleeding risk (Chan 2013; Green 2017).

Peritoneal dialysis: SubQ: Not dialyzable (Brophy 2006). Avoid use if possible. In one pharmacokinetic trial, peritoneal dialysis subjects exhibited a greater anti-factor Xa 12-hour concentration compared to healthy volunteers and hemodialysis patients.

CRRT or PIRRT (systemic anticoagulation): SubQ: Avoid use if possible. Significant clearance unlikely (Singer 1994; expert opinion). If used, monitor closely for bleeding and utilize anti-factor Xa monitoring (expert opinion).

Dosing: Hepatic Impairment: Adult

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

Dosing: Obesity: Adult

The recommendations for dosing in obese patients are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Note: Potentially reduced absorption following SubQ dosing in obese patients can result in variable exposure. In addition, due to the uncertainty of weight-based dosing metrics, dose adjustment using anti-factor Xa monitoring is recommended, where available (expert opinion).

ST-elevation myocardial infarction: SubQ: Use actual body weight-based dosing, refer to adult dosing; a maximum dose of 100 mg is recommended for the first 2 doses (Nutescu 2009).

Non-ST-elevation acute coronary syndromes: SubQ: Outcome data is limited; clinical expert opinion recommends the use of venous thromboembolism treatment dosing. Actual body weight dosing may result in increased risk of bleeding, especially in patients >150 kg (Spinler 2009).

Venous thromboembolism prophylaxis: Note: For bariatric surgery recommendations, see "Dosing: Adult: Venous Thromboembolism Prophylaxis, Bariatric Surgery, High Venous Thromboembolism Risk."

SubQ: BMI ≥40 kg/m2: Initial: 40 mg twice daily (Scholten 2002). Some experts suggest 60 mg twice daily in patients with more extreme forms of obesity (BMI >47 kg/m2) (Borkgren-Okonek 2008; Simone 2008). Alternatively, a weight-based approach can be used: 0.5 mg/kg twice daily (based on actual body weight) (Bickford 2013; Ludwig 2011; Parikh 2015; Stephenson 2016). Note: Wide variability exits in the reported dosing range and target anti-factor Xa level; recommendations are based on a summary of the literature and expert opinion.

Venous thromboembolism treatment: SubQ: Initial: 1 mg/kg every 12 hours (based on actual body weight); dosing range: 0.7 to 1 mg/kg every 12 hours (Lalama 2015; Lee 2020; Maclachlan 2019; Sebaaly 2018; Thompson-Moore 2015; Witt 2018); for BMI ≥50 kg/m2, recommended to use the lower end of the dosing range; doses below this range may be indicated in patients with extreme BMI (~114 kg/m2) (Heitlage 2017); recommend anti-factor Xa monitoring in select patients (eg, high risk of bleeding and/or ≥150 kg) (ACCP [Garcia 2012]; expert opinion).

Note: Minimal data exist for initial doses that exceed 150 mg every 12 hours as most studies either utilized dose-capping strategies or did not include a substantial number of patients weighing >150 kg (Sebaaly 2018). Pharmacokinetic studies have demonstrated supratherapeutic anti-factor Xa levels with standard dosing (1 mg/kg every 12 hours) in patients with a BMI ≥40 kg/m2 (Curry 2019; Sebaaly 2018; Thompson-Moore 2015; van Oosterom 2019).

Dosing: Pediatric

Note: Enoxaparin has ~100 anti-factor Xa units/mg enoxaparin (World Health Organization First International Low Molecular Weight Heparin Reference Standard). In order to improve accurate measurement and avoid dilution of enoxaparin pediatric enoxaparin doses, the following methods have reported at some centers: Dose rounding to the nearest whole mg (down or up, as appropriate) and administering with ≤100 unit insulin syringe (see Preparation for Administration) (Bauman 2009a; Bauman 2009b); extra precaution should be taken to ensure accurate dose delivery.

Prophylaxis: Limited data available (Giglia 2013; Monagle 2012):

Infants 1 to <2 months: SubQ: 0.75 mg/kg/dose every 12 hours

Infants ≥2 months, Children, and Adolescents: SubQ: 0.5 mg/kg/dose every 12 hours

Thrombosis; treatment: Note: Preliminary data from 213 pediatric patients evaluating 1,061 anti-factor Xa levels suggests that pediatric dose titration in patients <2 years of age may be affected by assay methodology (Greene 2014); SubQ:

Initial:

Chest/AHA guidelines (Giglia 2013; Monagle 2012)

Infants 1 to <2 months: SubQ: 1.5 mg/kg/dose every 12 hours

Infants ≥2 months, Children, and Adolescents: SubQ: 1 mg/kg/dose every 12 hours

Alternate dosing: Some data suggest that initial doses higher than those recommended in the Chest guidelines (Monagle 2012) are required in pediatric patients (especially in young infants or critically ill) (Bauman 2009; Malowany 2007; Malowany 2008; Schloemer 2014). Some centers have used the following:

1 to <3 months: 1.8 mg/kg/dose every 12 hours

3 to 12 months: 1.5 mg/kg/dose every 12 hours

1 to 5 years: 1.2 mg/kg/dose every 12 hours

6 to 18 years: 1.1 mg/kg/dose every 12 hours

Dosing adjustment, thrombosis treatment: Titrate dose to achieve a 4 to 6 hours postdose target anti-factor Xa level of 0.5 to 1 units/mL (Monagle 2012); based on pharmacokinetic parameters, steady-state levels are typically reached after the third or fourth dose. Duration of treatment based on thrombosis site, clinical response, and other identified risk factors; usual duration between 6 weeks and 3 months (Monagle 2012). A prospective study of 177 courses of enoxaparin in pediatric patients (146 treatment courses) reported considerable variation in maintenance dosage requirements (Dix 2000).

Previous CHEST guidelines (Molinari 2011; Monagle 2001; Monagle 2008) suggested the following dosage adjustments to achieve the target anti-factor Xa range (Duplaga 2001).

Enoxaparin Dosage Titration

Antifactor Xa

Dose Titration

Time to Repeat Antifactor Xa Level

Modified from 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

antifactor Xa is 0.5 units/mL,

then decrease dose by 40%

Before next dose and

every 12 h until

antifactor Xa <0.5 units/mL

Dosing: Renal Impairment: Pediatric

There are no pediatric specific recommendations; use with caution and monitor patient closely; based on experience in adult patients, dosage adjustment suggested in some instances.

Dialysis: Enoxaparin has not been FDA approved for use in dialysis patients (pediatric or adult). Its elimination is primarily via the renal route. Serious bleeding complications have been reported with use in adult 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: Pediatric

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

Calculations

• 4T score
• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Modified Wells Score for DVT
• Pulmonary Embolism Wells Score

Use: Labeled Indications

Acute coronary syndromes: Unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction.

Deep vein thrombosis treatment (acute): Inpatient treatment (patients with or without pulmonary embolism [PE]) and outpatient treatment (patients without PE).

Venous thromboembolism 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.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

​Acute symptomatic superficial vein thrombosis (lower extremity; ≥5 cm in length)Level of Evidence [A, G]

Data from a randomized, double-blind, placebo-controlled trial support the use of enoxaparin in the treatment of this condition Ref.

Based on the American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy for venous thromboembolism (VTE) disease, enoxaparin is effective and recommended for use in patients with acute symptomatic superficial vein thrombosis (≥5 cm in length) of the legs.

​Hemodialysis, intermittent, anticoagulation of circuitLevel of Evidence [C]

Data from a limited number of clinical trials suggest that enoxaparin may be beneficial for anticoagulation of the dialysis circuit during intermittent hemodialysis procedures Ref.

​Mechanical heart valve (bridging anticoagulation)Level of Evidence [G]

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 (LMWH) (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), or older-generation mechanical valves (ball-cage or tilting disc); or in pregnant patients with a mechanical prosthetic heart valve only if anti-factor Xa levels can be monitored.

​Pulmonary embolism (acute)Level of Evidence [G]

Based on the 2016 American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease, LMWH (eg, enoxaparin) is an effective and recommended treatment option for acute pulmonary embolism (PE). 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 VTE (ie, deep vein thrombosis [DVT] or PE) and cancer, ACCP recommends LMWH over oral anticoagulants for initial and long-term treatment.

​Venous thromboembolism prophylaxis, bariatric surgery (high venous thromboembolism risk)Level of Evidence [C, G]

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

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

​Venous thromboembolism prophylaxis, nonmajor orthopedic surgery of lower limbLevel of Evidence [B]

Data from a parallel-group, randomized, double-blind, noninferiority trial support the use of enoxaparin for VTE prophylaxis following nonmajor orthopedic surgery of the lower limb in patients at increased risk for developing VTE (eg, history of VTE, immobility, high-risk surgery) Ref. Although enoxaparin appears to be less effective than rivaroxaban based on the results of this study, some experts still consider LMWH to be a reasonable option for VTE prophylaxis Ref.

​Venous thromboembolism prophylaxis, nonorthopedic surgeryLevel of Evidence [G]

Based on the 2012 ACCP guideline for prevention of venous thromboembolism in nonorthopedic surgical patients, LMWH (eg, enoxaparin) is an effective and recommend option for pharmacologic prophylaxis to decrease the perioperative risk of thrombotic events.

Level of Evidence Definitions

​Level of Evidence Scale

Class and Related Monographs

Low Molecular Weight Heparins

Clinical Practice Guidelines

Atrial Fibrillation:

AHA/ACC/HRS, "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," January 2019

AHA/ACC/HRS, "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation," March 2014

“Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report," July 2018

Canadian Cardiovascular Society, "2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation," 2016

Critical Care:

“Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016,” March 2017

Non-ST-Elevation Acute Coronary Syndromes:

AHA/ACC, "2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes,” September 2014

Percutaneous Coronary Intervention:

"2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention,” November 2011

Pulmonary Embolism:

“British Thoracic Society Guideline for the Initial Management of Pulmonary Embolism" June 2018

"Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement from the American Heart Association,” March, 2011

ST-Elevation Myocardial Infarction:

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” December 2012

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

AHA/ACC, "2017 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease," 2017

Venous thromboembolism:

ACCP, “Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report,” February 2016

AHA/ASA, "Diagnosis and Management of Cerebral Venous Thrombosis," April 2011

AHA, "The Postthrombotic Syndrome: Evidence-Based Prevention, Diagnosis, and Treatment Strategies,” October 2014

ASCO, "American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update," 2013

ASCO, "American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update," 2014

ASH, “American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism,” December 2018

ASCO, “Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update,” August 2019

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

Administration: Injectable Detail

pH: 5.5 to 7.5

Administration: Subcutaneous

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

Administration: Pediatric

Parenteral: For SubQ use only, do not administer IM or IV. Administer by deep SubQ injection; in adults it is recommended to alternate between the left or right anterolateral and left or right posterolateral abdominal wall; do not rub injection site after SubQ administration as bruising may occur. When administering 30 mg or 40 mg SubQ from a commercially prefilled syringe, do not expel the air bubble from the syringe prior to injection (in order to avoid loss of drug).

Storage/Stability

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.

Preparation for Administration: Pediatric

Parenteral: SubQ: Some centers dispense neonatal and pediatric doses in a ≤100 unit insulin syringe for greater delivery accuracy and to avoid errors associated with dilutions. Each 1 unit on a 30, 50, or 100 unit graduated insulin syringe is 0.01 mL; using a 100 mg/mL enoxaparin injection, each "1 unit" on the insulin syringe would provide 1 mg of enoxaparin (Bauman 2009a).

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat or prevent blood clots.

• It is used to lower the number of heart attacks in patients who have unstable angina or mild heart attacks.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach

• Injection site irritation

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Nerve problems like back pain, numbness or tingling, muscle weakness, paralysis, or loss of bladder or bowel control

• Bleeding like throwing up blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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.

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Pinpoint red spots on the skin

• Shortness of breath

• Swelling of arms or legs

• Dizziness

• Passing out

• Confusion

• Severe headache

• Feeling very tired or weak

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

​Sound-alike/look-alike issues:

​High alert medication:

​National Patient Safety Goals:

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.

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 HIT and heparin-induced thrombocytopenia with thrombosis (HITTS), 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 impairment; 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); monitor closely for signs/symptoms of thromboembolism. Monitoring of anti-factor 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 anti-factor 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 and/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.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

No specific dosage adjustment recommendations for most indications, however, total clearance is lower and elimination is delayed in patients with renal failure. Adjustment may be necessary if renal impairment is present. In the treatment of STEMI, a lower dosage (0.75 mg/kg every 12 hours) and omission of the IV bolus, are recommended in patients ≥75 years of age.

In clinical trials, the efficacy of enoxaparin injection in elderly (≥65 years) was similar to that seen in younger patients (<65 years). The risk of enoxaparin injection associated bleeding increased with age. Serious adverse events increased with age for patients receiving enoxaparin injections. Other clinical experience has not revealed additional differences in the safety of enoxaparin injection between elderly and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Monitoring of elderly patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.

Reproductive Considerations

Venous thromboembolism (VTE) prophylaxis is not routinely recommended for women undergoing assisted reproduction therapy; however, LMWH therapy is recommended for women who develop severe ovarian hyperstimulation syndrome (Bates 2012).

Pregnancy Considerations

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 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). For women undergoing cesarean section and who have additional risk factors for developing VTE, the prophylactic use of LMWH may be considered (Bates 2012). Consult current recommendations for appropriate use in pregnant women.

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 anti-factor 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.

Breast-Feeding Considerations

It is not known if enoxaparin is present in breast milk. Small amounts of another LMWH have been detected in breast milk; however, because they have a low oral bioavailability, LMWHs are unlikely to cause adverse events in a breastfeeding infant. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. However, antithrombotic guidelines state that use of LMWH may be continued in breastfeeding women (Bates 2012).

Briggs' Drugs in Pregnancy & Lactation

• Enoxaparin

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

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Low Molecular Weight Heparin Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open 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. Risk C: Monitor therapy

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

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

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

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

Antithrombin: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: 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. Risk X: Avoid combination

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

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Risk C: 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. Risk X: Avoid combination

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

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: 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. Risk X: Avoid combination

Eplerenone: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone. Risk C: 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. Risk D: Consider therapy modification

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

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Risk D: 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. Risk C: Monitor therapy

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

Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

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

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

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

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

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: 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. Risk X: Avoid combination

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

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

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

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

Potassium Salts: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts. Risk C: 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. Risk C: 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. Risk D: 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. Risk C: 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. Risk X: Avoid combination

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

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

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

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

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

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

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

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

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

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Test Interactions

May cause falsely-elevated free thyrotropin and free triiodothyronine levels when assays involving prolonged incubation periods are used. Thyroid-stimulating hormone and standard competitive free thyroid hormone assays are not usually affected (Burch 2019).

Monitoring Parameters

Platelet count, hemoglobin, hematocrit, fecal occult blood, signs and symptoms of bleeding, anti-factor Xa levels (as appropriate), and serum creatinine at baseline and during therapy; monitoring of PT and/or aPTT is not necessary. Routine monitoring of anti-factor Xa activity is not required but has been utilized in patients with obesity and/or renal insufficiency.

For patients >144 kg, if anti-factor Xa monitoring is available, adjusting dose based on anti-factor Xa activity is recommended; if anti-factor Xa monitoring is unavailable, reduce dose if bleeding occurs (Garcia 2012; Nutescu 2009). Monitor obese patients closely for signs/symptoms of thromboembolism.

Monitoring anti-factor Xa activity is recommended in pregnant women receiving therapeutic doses of enoxaparin or when receiving enoxaparin for the prevention of thromboembolism with mechanical heart valves (ACCP [Guyatt 2012]).

Reference Range

The following therapeutic ranges for anti-factor Xa activity have been suggested but have not been validated in a controlled trial. Anti-factor Xa activity should be measured 4 to 6 hours after dosing, beginning after the third or fourth dose when steady state has been achieved (ACCP [Garcia 2012]; ACOG 2018; AHA/ACC [Nishimura 2014]; Nutescu 2009).

Mechanical heart valve (bridging anticoagulation):

Anti-factor Xa activity target:

Non-pregnant patients: Monitoring anti-factor Xa activity is not necessary. However, some experts recommend monitoring, if possible, and targeting a range of 0.5 to 1 units/mL (ESC/EACTS [Baumgartner 2017]).

Pregnant patients: 0.8 to 1.2 units/mL (AHA/ACC [Nishimura 2014]). Some experts recommend higher anti-factor Xa targets (eg, 1 to 1.2 units/mL) for mechanical mitral valves and lower targets (0.8 to 1 units/mL) for mechanical aortic valves (Nelson-Piercy 2019). Note: Target trough anti-factor Xa activity should be ≥0.6 units/mL (Goland 2014).

Venous thromboembolism treatment (pulmonary embolism and/or deep vein thrombosis):

Anti-factor Xa activity target:

Once-daily dosing: 1 to 2 units/mL; if there is concern for accumulation (eg, renal impairment) a trough measurement (target <0.5 units/mL) may be useful (ACCP [Garcia 2012]; Nutescu 2009).

Twice-daily dosing: 0.6 to 1 units/mL Note: Twice-daily dosing is recommended in pregnant patients (ACCP [Garcia 2012]; ACOG 2018).

Venous thromboembolism prophylaxis in pregnant women: 0.2 to 0.6 units/mL (ACCP [Bates 2012]).

Advanced Practitioners Physical Assessment/Monitoring

Obtain CBC including platelets, renal function tests, and stool occult blood tests. Screen for known allergy to pork products. Screen for known or suspected history of heparin-induced thrombocytopenia (HIT). Monitor patient’s weight prior to treatment and periodically throughout. In patients with severe renal impairment, abnormal coagulation parameters, bleeding or who are pregnant, consider obtaining anti-Xa levels 4 to 6 hours after administration. For patients >144 kg, obtain anti-Xa levels and adjust dose accordingly. Continue medication therapy 6 weeks postpartum. Assess for signs and symptoms of bleeding, neurological impairment, and thrombocytopenia with/without thrombosis. Consider protamine administration in patients that experience serious bleeding. Evaluate risks vs benefits of continuing/discontinuing therapy in patients who may require neuraxial anesthesia, indwelling epidural catheter, or spinal tap. Allow sufficient time between discontinuation/restarting of medication and beginning/finishing neuraxial anesthesia, spinal tap, and cesarean section, and/or delivery. Instruct patients that premature discontinuation increases the risk of thrombotic events.

Nursing Physical Assessment/Monitoring

Verify no known allergy to pork products. Check ordered labs and report any abnormalities. Obtain weight; dosing is weight based. Monitor patient for signs and symptoms of bleeding (bruising or bleeding that is not normal, changes in menstrual periods like lots of bleeding, spotting, or bleeding between cycles, nosebleeds that won’t stop, bowel movements that are red or black like tar, throwing up blood or liquid that looks like coffee grounds) and neurological impairment (midline back pain, sensory defects, motor defects, bowel dysfunction, and bladder dysfunction). Educate patients on bleeding precautions including avoiding invasive procedures, activities that could cause injuries, and how to handle bleeding emergencies. Monitor for signs and symptoms of thrombocytopenia after therapy initiation. Instruct patient on proper subcutaneous self-injection technique if applicable. Advise patient to tell all doctors and dentists about use of an anticoagulant.

Dosage Forms: US

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:

Generic: 30 mg/0.3 mL (0.3 mL); 80 mg/0.8 mL (0.8 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)

Dosage Forms: Canada

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]

Solution, Subcutaneous, as sodium:

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)

Lovenox HP: 150 mg/mL (0.8 mL, 1 mL)

Anatomic Therapeutic Chemical (ATC) Classification

• B01AB05

Generic Available (US)

Yes

Pricing: US

Solution (Enoxaparin Sodium Injection)

300 mg/3 mL (per mL): $12.80 - $89.21

Solution (Enoxaparin Sodium Subcutaneous)

30 mg/0.3 mL (per 0.3 mL): $3.61 - $26.76

40 mg/0.4 mL (per 0.4 mL): $4.81 - $35.68

60 mg/0.6 mL (per 0.6 mL): $7.22 - $53.59

80 mg/0.8 mL (per 0.8 mL): $9.64 - $71.45

100 mg/mL (per mL): $12.05 - $89.31

120 mg/0.8 mL (per 0.8 mL): $21.60 - $107.21

150 mg/mL (per mL): $27.00 - $134.01

Solution (Lovenox Injection)

300 mg/3 mL (per mL): $99.23

Solution (Lovenox Subcutaneous)

30 mg/0.3 mL (per 0.3 mL): $29.77

40 mg/0.4 mL (per 0.4 mL): $39.69

60 mg/0.6 mL (per 0.6 mL): $59.61

80 mg/0.8 mL (per 0.8 mL): $79.48

100 mg/mL (per mL): $99.34

120 mg/0.8 mL (per 0.8 mL): $119.25

150 mg/mL (per mL): $149.07

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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 anti-factor Xa to anti-factor IIa activity than unfractionated heparin.

Pharmacodynamics/Kinetics

Onset of action: Peak effect: SubQ: Anti-factor Xa and antithrombin (anti-factor IIa): 3 to 5 hours

Duration: 40 mg dose: Anti-factor Xa activity: ~12 hours

Distribution: 4.3 L (based on anti-factor Xa activity)

Protein binding: Does not bind to heparin binding proteins

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

Bioavailability: Adults: SubQ: ~100%

Half-life elimination, plasma: 2 to 4 times longer than standard heparin, independent of dose; based on anti-factor Xa activity: 4.5 to 7 hours

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

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

Pharmacodynamics/Kinetics: Additional Considerations

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

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

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

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).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Bleeding is the major adverse effect of enoxaparin. See Effects on Bleeding.

Effects on Bleeding

As with all anticoagulants, bleeding is the major adverse effect of enoxaparin. Hemorrhage may occur at virtually any site. Routine coagulation tests, such as prothrombin time (PT) and aPTT, are relatively insensitive measures of enoxaparin injection activity and, therefore, unsuitable for monitoring. Moderate thrombocytopenia occurred at a rate of ~1%. Medical consult is suggested.

Related Information

• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Dosing Considerations for the Critically Ill Patient With Morbid Obesity

Index Terms

Enoxaparin Sodium

FDA Approval Date

March 29, 1993

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Brand Names: International

Bolentax (CR, DO, GT, HN, NI, PA, SV); Clenox (CO, PE); Clexane (AE, AR, AU, BB, BE, BF, BG, BH, BJ, BM, BS, CH, CI, CL, CN, CO, CR, CU, CY, CZ, DE, DO, EC, EE, ES, ET, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, IE, IL, IN, IT, JM, JO, JP, KE, KR, KW, LK, LR, LT, LU, LV, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, NL, NZ, PA, PE, PH, PK, PL, PR, PY, QA, RO, RU, SA, SC, SD, SG, SI, SK, SL, SN, SV, TH, TN, TR, TT, TW, TZ, UA, UG, UY, VE, VN, ZM, ZW); Clexane Forte (AU, IL, SG); Cutenox (LK); Dilutol (EC, VN); Enoclex (PH); Enoxane (PH); Flenox (UA); Klexane (DK, FI, IS, NO, SE); Lomoh-40 (PH); Lomoh-60 (PH); Lovenox (AT, FR, ID, LB, PT); Olxarin (PH)

Last Updated 10/14/20