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.
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 doses in neonates (including premature neonates weighing <1,000 g), the following methods have reported at some centers: Dose rounding to the nearest whole mg (down or up, as appropriate) and administering with a ≤100 unit insulin syringe (see "Preparation for Administration: Pediatric") (Bauman 2009a; Bauman 2009b; Goldsmith 2015); extra precaution should be taken to ensure accurate dose delivery.
Prophylaxis: Limited data available: SUBQ: 0.75 mg/kg/dose every 12 hours (Giglia 2013; Monagle 2012). Note: May consider titrating dose to achieve a 4 to 6 hours postdose target anti-factor Xa level of 0.1 to 0.3 units/mL (Monagle 2012).
Thrombosis, treatment: Limited data available: 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). Duration of treatment based on thrombosis site, clinical response, and other identified risk factors; usual duration between 6 weeks and 3 months (Monagle 2012):
Initial: SUBQ: 1.5 mg/kg/dose every 12 hours (Monagle 2012); some data suggest that doses higher than those recommended in the Chest guidelines (Monagle 2012) are required in neonates (Malowany 2007; Malowany 2008; Sanchez de Toledo 2010); some centers have used the following initial doses:
Premature neonates: SUBQ: 2 mg/kg/dose every 12 hours.
Full-term neonates: SUBQ: 1.7 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 between second and fourth dose. Studies have suggested that initial dosing and dosage titration from the Chest guidelines do not consistently result in therapeutic anti-factor Xa levels; more aggressive dosing may be necessary (Dinh 2019; McCormick 2015; Monagle 2001; Monagle 2012; Wiltrout 2020).
Previous Chest guidelines (Molinari 2011; Monagle 2001; Monagle 2008) suggested the following dosage adjustments to achieve the target anti-factor Xa range (Duplaga 2001):
Anti-factor Xa |
Dose Titration |
Time to Repeat Anti-factor Xa Levela,c |
---|---|---|
a Based on pharmacokinetic parameters including half-life and steady-state levels. b Trough anti-factor Xa level to ensure continued drug clearance and optimize safety; may consider checking trough anti-factor Xa levels in high-risk patients (eg, patients with changing renal function and/or increased risk of bleeding). Goal trough anti-factor Xa level not defined/reported for twice-daily dosing; trough anti-factor Xa level of 0.1 units/mL has been suggested with once-daily dosing. c Consider more frequent anti-factor Xa monitoring based clinical scenario. Adapted from Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest. 2001;119:344S-370S; Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S. doi:10.1378/chest.11-2308; and Wiltrout K, Lissick J, Raschka M, Nickel A, Watson D. Evaluation of a pediatric enoxaparin dosing protocol and the impact on clinical outcomes. J Pediatr Pharmacol Ther. 2020;25(8):689-696. doi:10.5863/1551-6776-25.8.689. | ||
<0.35 units/mL |
Increase dose by 25% |
4 to 6 hours after second dose |
0.35 to 0.49 units/mL |
Increase dose by 10% |
4 to 6 hours after second dose |
0.5 to 1 unit/mL |
Keep same dosage |
Next day, then 1 week later, then every 1 to 4 weeks (4 to 6 hours after dose) |
1.1 to 1.5 units/mL |
Decrease dose by 20% |
4 to 6 hours after second dose; may consider checking trough level immediately before next dose to confirm drug clearance.b |
1.6 to 2 units/mL |
Hold dose for 3 hours and decrease dose by 30% |
Consider checking trough level immediately before next dose to confirm drug clearanceb, then 4 to 6 hours after second dose. |
>2 units/mL |
Hold all doses until anti-factor Xa is 0.5 units/mL, then decrease dose by 40% |
While level is ≥0.5 units/mL: 12 hours after last dose and every 12 hours until anti-factor Xa <0.5 units/mL. Once enoxaparin restarted: 4 to 6 hours after second dose; may consider more frequent monitoring based on clinical scenario. |
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: Pediatric") (Bauman 2009a; Bauman 2009b); extra precaution should be taken to ensure accurate dose delivery.
Prophylaxis: Limited data available (Giglia 2013; Monagle 2012): Note: May consider titrating dose to achieve a 4 to 6 hours postdose target anti-factor Xa level of 0.1 to 0.3 units/mL (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). Once-daily dosing in pediatric patients with normal renal function is not feasible due to faster enoxaparin clearance and lower drug exposure in pediatric patients compared to adults (O'Brien 2007). Duration of treatment based on thrombosis site, clinical response, and other identified risk factors; usual duration between 6 weeks and 3 months (Monagle 2012):
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: SUBQ: 1.8 mg/kg/dose every 12 hours.
3 to 12 months: SUBQ: 1.5 mg/kg/dose every 12 hours.
1 to 5 years: SUBQ: 1.2 mg/kg/dose every 12 hours.
6 to 18 years: SUBQ: 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 between second and fourth dose. Studies have suggested that initial dosing and dosage titration from the Chest guidelines do not consistently result in therapeutic anti-factor Xa levels; more aggressive dosing may be necessary (Dinh 2019; McCormick 2015; Monagle 2001; Monagle 2012; Wiltrout 2020).
Previous Chest guidelines (Molinari 2011; Monagle 2001; Monagle 2008) suggested the following dosage adjustments to achieve the target anti-factor Xa range (Duplaga 2001):
Anti-factor Xa |
Dose Titration |
Time to Repeat Anti-factor Xa Levela,c |
---|---|---|
a Based on pharmacokinetic parameters including half-life and steady-state levels. b Trough anti-factor Xa level to ensure continued drug clearance and optimize safety; may consider checking trough anti-factor Xa levels in high-risk patients (eg, patients with changing renal function and/or increased risk of bleeding). Goal trough anti-factor Xa level not defined/reported for twice-daily dosing; trough anti-factor Xa level of 0.1 units/mL has been suggested with once-daily dosing. c Consider more frequent anti-factor Xa monitoring based clinical scenario. Adapted from Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest. 2001;119:344S-370S; Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S. doi:10.1378/chest.11-2308; and Wiltrout K, Lissick J, Raschka M, Nickel A, Watson D. Evaluation of a pediatric enoxaparin dosing protocol and the impact on clinical outcomes. J Pediatr Pharmacol Ther. 2020;25(8):689-696. doi:10.5863/1551-6776-25.8.689. | ||
<0.35 units/mL |
Increase dose by 25% |
4 to 6 hours after second dose |
0.35 to 0.49 units/mL |
Increase dose by 10% |
4 to 6 hours after second dose |
0.5 to 1 unit/mL |
Keep same dosage |
Next day, then 1 week later, then every 1 to 4 weeks (4 to 6 hours after dose) |
1.1 to 1.5 units/mL |
Decrease dose by 20% |
4 to 6 hours after second dose; may consider checking trough level immediately before next dose to confirm drug clearance.b |
1.6 to 2 units/mL |
Hold dose for 3 hours and decrease dose by 30% |
Consider checking trough level immediately before next dose to confirm drug clearanceb, then 4 to 6 hours after second dose. |
>2 units/mL |
Hold all doses until anti-factor Xa is 0.5 units/mL, then decrease dose by 40% |
While level is ≥0.5 units/mL: 12 hours after last dose and every 12 hours until anti-factor Xa <0.5 units/mL. Once enoxaparin restarted: 4 to 6 hours after second dose; may consider more frequent monitoring based on clinical scenario. |
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.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
(For additional information see "Enoxaparin (including biosimilars available in Canada): Drug information")
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.
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 (ACC/AHA [Otto 2021]).
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.
Superficial vein thrombosis, acute symptomatic (off-label use):
Note: For use in patients at increased risk for thromboembolism or with recurrent superficial vein thrombosis.
SUBQ: 40 mg once daily for 45 days (ACCP [Kearon 2012]; Décousus 2003).
Venous thromboembolism prophylaxis:
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 venous thromboembolism (VTE) has diminished (ACCP [Kahn 2012]; ASCO [Key 2020]). Extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; Osataphan 2021; Sharma 2012); however, in high-risk COVID-19 patients who are discharged from the hospital, some experts would consider extended prophylaxis with a direct oral anticoagulant (eg, rivaroxaban) (Cuker 2021).
Bariatric surgery patients at high risk for venous thromboembolism, perioperative (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 VTE risk. There is no consensus on indications for extended prophylaxis following bariatric surgery (Lim 2021).
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: 40 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 2021; 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 venous thromboembolism: 3 months (provided the provoking risk factor is no longer present) (ACCP [Kearon 2016]).
Unprovoked venous thromboembolism: ≥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 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 2022a; 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 2022b).
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.
Venous thromboembolism 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 2022b).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
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)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Inclunox: 40 mg/0.4 mL (0.4 mL)
Noromby: 40 mg/0.4 mL (0.4 mL)
Solution, Injection, as sodium:
Lovenox: 300 mg/3 mL (3 mL) [contains benzyl alcohol]
Redesca: 300 mg/3 mL (3 mL) [contains benzyl alcohol]
Solution, Subcutaneous, as sodium:
Inclunox: 30 mg/0.3 mL (0.3 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL)
Inclunox HP: 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)
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: 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)
Noromby: 30 mg/0.3 mL (0.3 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL)
Noromby HP: 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)
Redesca: 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)
Redesca HP: 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)
Parenteral: For SUBQ use only, do not administer IM or IV. Administer by deep SUBQ injection. In neonates, the thighs are the usual sites for injection (Ting 2021). In adults, it is recommended to alternate between the left or right anterolateral and left or right posterolateral abdominal wall; these injection sites, in addition to the triceps, have also been suggested in children and adolescents with adequate subcutaneous tissue (Ting 2021; manufacturer's labeling). 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).
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 administer into bruised or scarred skin or through clothing. 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.
Store in original container 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.
Prophylaxis for DVT 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 (ie, >40 years of age, obese, general anesthesia >30 minutes, malignancy, history of DVT, or pulmonary embolism); inpatient treatment of DVT (with or without pulmonary embolism); outpatient treatment of DVT without pulmonary embolism; prevention of ischemic complications with acute coronary syndromes, unstable angina, non-ST-elevation (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) (All indications: FDA approved in adults).
Lovenox may be confused with Lasix, Levaquin, Levemir, Lotronex, Protonix
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
Enoxaparin may increase the risk of bleeding (hemorrhage), including severe and potentially fatal major hemorrhage as defined by the International Society on Thrombosis and Hemostasis (Ref). Bleeding is partially reversible with the use of protamine. Although the risk of bleeding is dependent upon many factors, at recommended doses enoxaparin does not significantly affect PT or aPTT; therefore, if monitoring, anti-factor Xa levels must be used (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, anticoagulant; inhibition of factor Xa with less inhibition of factor IIa) (Ref).
Onset: Varied; time to onset of bleeding is unpredictable and affected by many variables. In one study, time to bleeding ranged from after the second dose to after 25 days of therapy (Ref).
Risk factors:
• Dose (Ref)
• Kidney impairment (CrCl <50 mL/minute) (Ref)
• Uncontrolled hypertension (Ref)
• Females (Ref)
• Age >75 years (Ref)
• Obesity (Ref)
• Bridging with warfarin therapy (Ref)
• Concurrent antiplatelet agents (Ref)
• Hepatic impairment (Ref)
• History of GI bleeding (Ref)
• Peptic ulcer disease (Ref)
• Anemia (Ref)
• Congenital or acquired bleeding disorders
• Hemorrhagic stroke or use shortly after brain, spinal, or ophthalmic surgery
• Thrombocytopenia or platelet defects or history of heparin-induced thrombocytopenia
• Hypertensive or diabetic retinopathy
• Patients undergoing invasive procedures
Spinal hematoma or epidural intracranial hemorrhage may occur in patients treated with enoxaparin who are receiving neuraxial anesthesia or undergoing spinal puncture; may result in long-term or permanent paralysis. Spontaneous spinal epidural hematoma (SEH) have also been reported (Ref). Withholding enoxaparin and treating immediately with consideration for spinal cord decompression may improve symptoms but may not be able to entirely prevent or reverse neurologic sequelae (Ref).
Mechanism: SEH due to neuraxial anesthesia or spinal puncture is related to trauma in the presence of impaired hemostasis with enoxaparin (Ref). Spontaneous SEH may be due to venous rupture and hemorrhage secondary to sudden increase in thoracic and/or abdominal pressure (Ref).
Onset: SEH in patients treated with enoxaparin who received neuraxial anesthesia or spinal puncture: Rapid; several studies reported onset within 2 to 3 days after initiation (Ref). In cases of spontaneous SEH, onset of symptoms occurred within 1 dose to 1 week of enoxaparin therapy (Ref).
Risk factors:
• Use of indwelling epidural catheters (Ref)
• Concurrent administration of other drugs that affect hemostasis (eg, aspirin, nonsteroidal anti-inflammatory drugs, platelet inhibitors, other anticoagulants) (Ref)
• History of traumatic or repeated epidural or spinal punctures (Ref)
• History of spinal deformity or surgery (Ref)
• If optimal timing between administration of enoxaparin and neuraxial procedures is unknown
• Older patients (Ref)
• Females (Ref)
• Congenital coagulation deficiencies (Ref)
• Underlying vascular lesions (Ref)
• Risk factors for spontaneous SEH: Conditions causing increased intra-abdominal pressure (eg, coughing, Valsalva maneuver, weight-lifting) (Ref)
Heparin-induced thrombocytopenia (HIT) and thrombosis in heparin-induced thrombocytopenia (HITT) have occurred, with some cases complicated by organ infarction, limb ischemia, and/or death. Low platelet counts from acute HIT are reversible upon enoxaparin discontinuation and initiation of appropriate interventions (Ref).
Mechanism: Immunologic. Caused by IgG antibodies binding to heparin and platelet-factor 4 (PF4) complexes, leading to platelet activation, consumption, and subsequent thrombosis (Ref).
Onset: Varied; depends on heparin exposure in the past 30 days. Usually occurs 5 to 14 days after exposure in heparin-naive patients (5 to 7 days with enoxaparin), or <1 day after repeat exposure in patients who received heparin in the past 30 days (Ref).
Risk factors:
• Duration of therapy (>5 days) (Ref)
• Patient population (surgical and trauma patients at highest risk versus medical and obstetrical patients) (Ref)
• Females (Ref)
• Dose (treatment dosing is a higher risk than prophylactic dosing) (Ref)
• Higher with unfractionated heparin compared to low-molecular weight heparin (eg, enoxaparin) (Ref)
The following adverse reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Hematologic & oncologic: Anemia (≤16%) (table 1) , hemorrhage (4% to 13%)
Drug (Enoxaparin) |
Comparator (Heparin) |
Placebo |
Dose |
Indication |
Number of Patients (Enoxaparin) |
Number of Patients (Heparin) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|---|
3% |
3% |
N/A |
40 mg daily |
Abdominal or colorectal surgery |
1,228 |
1,234 |
N/A |
N/A |
16% |
5% |
7% |
40 mg daily |
Hip or knee replacement surgery |
288 |
766 |
115 |
Peri-operative period |
2% |
5% |
7% |
30 mg q12h |
Hip or knee replacement surgery |
1,080 |
766 |
115 |
N/A |
<2% |
5% |
7% |
40 mg daily |
Hip or knee replacement surgery |
131 |
766 |
115 |
Extended prophylaxis period |
Drug (Enoxaparin) |
Comparator (Heparin) |
Placebo |
Dose |
Indication |
Number of Patients (Enoxaparin) |
Number of Patients (Heparin) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|---|
7% |
6% |
N/A |
40 mg daily |
Abdominal or colorectal surgery |
1,128 |
1,234 |
N/A |
N/A |
13% |
4% |
3% |
40 mg daily |
Hip or knee replacement surgery |
288 |
766 |
115 |
Peri-operative period |
5% |
4% |
3% |
40 mg daily |
Hip or knee replacement surgery |
131 |
766 |
115 |
Extended prophylaxis period |
4% |
4% |
3% |
30 mg q12h |
Hip or knee replacement surgery |
1,080 |
766 |
115 |
N/A |
1% to 10%:
Cardiovascular: Peripheral edema (6%)
Dermatologic: Ecchymoses (3%)
Gastrointestinal: Nausea (3%)
Genitourinary: Hematuria (≤2%)
Hematologic & oncologic: Major hemorrhage (≤4%; includes cases of intracranial [up to 0.8%], retroperitoneal, or intraocular hemorrhage; incidence varies with indication/population) (table 2) , thrombocytopenia (≤3%) (table 3)
Drug (Enoxaparin) |
Comparator (Heparin) |
Placebo |
Dose |
Indication |
Number of Patients (Enoxaparin) |
Number of Patients (Heparin) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|---|
4% |
3% |
N/A |
40 mg daily |
Abdominal surgery |
555 |
560 |
N/A |
N/A |
2% |
1% |
N/A |
Initial 30 mg IV bolus followed by 1 mg/kg q12h SubQ |
Acute ST-segment elevation myocardial infarction |
10,176 |
10,151 |
N/A |
N/A |
4% |
3% |
N/A |
40 mg daily |
Colorectal surgery |
673 |
674 |
N/A |
N/A |
2% |
2% |
N/A |
1.5 mg/kg daily |
Deep vein thrombosis with or without pulmonary embolism treatment |
298 |
554 |
N/A |
N/A |
2% |
2% |
N/A |
1 mg/kg q12h |
Deep vein thrombosis with or without pulmonary embolism treatment |
559 |
554 |
N/A |
N/A |
2% |
N/A |
N/A |
40 mg daily |
Hip replacement surgery with extended prophylaxis |
288 |
N/A |
N/A |
Peri-operative period |
0% |
N/A |
N/A |
40 mg daily |
Hip replacement surgery with extended prophylaxis |
221 |
N/A |
N/A |
Extended prophylaxis period |
4% |
6% |
N/A |
30 mg q12h |
Hip replacement surgery without extended prophylaxis |
786 |
541 |
N/A |
N/A |
1% |
1% |
N/A |
30 mg q12h |
Knee replacement surgery without extended prophylaxis |
294 |
225 |
N/A |
N/A |
<1% |
N/A |
<1% |
40 mg daily |
Severely restricted mobility during acute illness |
360 |
N/A |
362 |
N/A |
1% |
1% |
N/A |
1 mg/kg q12h |
Unstable angina and non–Q-wave myocardial infarction |
1,578 |
1,529 |
N/A |
N/A |
Drug (Enoxaparin) |
Comparator (Heparin) |
Placebo |
Dose |
Indication |
Number of Patients (Enoxaparin) |
Number of Patients (Heparin) |
Number of Patients (Placebo) |
Comments |
---|---|---|---|---|---|---|---|---|
2% |
N/A |
N/A |
N/A |
Acute ST-segment elevation myocardial infarction |
N/A |
N/A |
N/A |
N/A |
0.1% |
0.2% |
0.4% |
N/A |
N/A |
N/A |
N/A |
N/A |
Platelet counts <50,000/mm3 |
1% |
1% |
0.7% |
N/A |
N/A |
N/A |
N/A |
N/A |
Platelet counts between 100,000/mm3 and 50,000/mm3 |
3% |
N/A |
3% |
40 mg daily |
Severely restricted mobility during acute illness |
360 |
N/A |
362 |
N/A |
Hepatic: Increased serum alanine aminotransferase (>3 x ULN: 6%), increased serum aspartate aminotransferase (>3 x ULN: 6%)
Local: Bleeding at injection site (3% to 5%), hematoma at injection site (9%), pain at injection site (2%)
Nervous system: Confusion (2%)
Miscellaneous: Fever (5% to 8%)
<1%:
Cardiovascular: Atrial fibrillation, cardiac failure
Respiratory: Pneumonia, pulmonary edema
Frequency not defined: Local: Bruising at injection site, erythema at injection site, irritation at injection site
Postmarketing:
Cardiovascular: Hypersensitivity angiitis, thrombosis (prosthetic value [in pregnant females; McLintock 2009] or associated with enoxaparin-induced thrombocytopenia; can cause limb ischemia or organ infarction [Singh 2020])
Dermatologic: Alopecia (Wang 2006), maculopapular rash (Kim 2003), pruritus (MacLaughlin 2002), skin necrosis (Abou Issa 2015; Coelho 2016), urticaria (Abou Issa 2015; Villanueva 2012), vesicobullous rash (Miguel-Gomez 2016; Villanueva 2012)
Endocrine & metabolic: Hyperkalemia (Scalese 2016), hyperlipidemia (very rare) (Resic 2010; Tomsu 1998), hypertriglyceridemia (Resic 2010; Tomsu 1998)
Hematologic & oncologic: Acute posthemorrhagic anemia (Bala 2017), purpuric disease (Li 2019), spinal hematoma (rare: <1%) (Heppner 2004), thrombocythemia (Meenpidiyil 2020), thrombosis in heparin-induced thrombocytopenia
Hepatic: Hepatotoxicity (hepatocellular and cholestatic; including increased serum alkaline phosphatase) (Baker 2009; Mehershahi 2020])
Hypersensitivity: Anaphylactic shock, anaphylaxis (Anders 2013; Leguisamo 2015), angioedema (Smith 2004), nonimmune anaphylaxis (MacLaughlin 2002), type IV hypersensitivity reaction (Cabanas 1998)
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Ronceray 2012)
Local: Injection site reaction (including nodules, inflammation, oozing)
Nervous system: Epidural intracranial hemorrhage (rare: <1%) (Wysowski 1998), headache
Neuromuscular & skeletal: Osteoporosis (following long-term therapy) (Wawrzyska 2003)
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.
Concerns related to adverse effects:
• Bleeding: 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: May rarely 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: Use with extreme caution or avoid in patients with history of HIT (Warkentin 2001). 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.
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 may be required. In pediatric patients with renal impairment, more frequent monitoring is recommended (Bahabri 2021).
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.
• 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: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 CrCl <30 mL/minute.
None known.
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
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
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
Kanamycin: 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
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. 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
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: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. 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
Patients undergoing assisted reproduction therapy (ART) may be at increased risk for thrombosis. Venous thromboembolism prophylaxis is not routinely recommended for patients undergoing ART; however, prophylactic doses of low-molecular-weight heparin (LMWH) are recommended for patients who develop severe ovarian hyperstimulation syndrome (ACCP [Bates 2012]; ASH [Bates 2018]; SOGC [Shmorgun 2017]). In addition, prophylactic doses of LMWH are recommended in patients undergoing ART who have a positive antiphospholipid antibody test but are not diagnosed with antiphospholipid syndrome (APS), as well as patients diagnosed with obstetric APS. Therapeutic doses of LMWH are recommended in patients undergoing ART diagnosed with thrombotic APS (ACR [Sammaritano 2020]).
Low-molecular-weight heparin (LMWH) does not cross the placenta (ACOG 2018).
An increased risk of fetal bleeding or teratogenic effects have not been reported (ACCP [Bates 2012]).
Due to pregnancy-induced physiologic changes, some pharmacokinetic properties of LMWH may be altered; dosing adjustment may be required. Prophylactic doses of LMWH may also need modifying in pregnant patients at extremes of body weight (ACOG 2018).
The risk of venous thromboembolism (VTE) is increased in pregnant patients especially during the third trimester and first week postpartum. LMWH is recommended over unfractionated heparin for the treatment of acute VTE in pregnant patients. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant patients with certain risk factors (eg, homozygous factor V Leiden, antiphospholipid antibody syndrome with ≥3 previous pregnancy losses) (ACCP [Bates 2012]; ACOG 2018; ASH [Bates 2018]; ESC [Regitz-Zagrosek 2018]). Consult current recommendations for appropriate use in pregnancy.
LMWH may be used prior to cesarean delivery in patients with additional risk factors for developing VTE. Risk factors may include a personal history of DVT or PE, inherited thrombophilia, or patients with class III obesity (SMFM 2020).
LMWH may also be used in pregnant patients with mechanical heart valves. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered. Patients with mechanical heart valves have an increased risk of adverse fetal and maternal outcomes (including valve thrombosis) and these risks are greater without appropriate anticoagulation. Increased monitoring of anti-factor Xa levels is required; frequent dose titration may be needed to maintain adequate therapeutic anti-factor Xa concentrations during pregnancy (consult current recommendations for details) (ACC/AHA [Otto 2021]; ESC [Regitz-Zagrosek 2018]).
LMWH is recommended for pregnant patients hospitalized with severe COVID-19, taking into consideration risk factors for bleeding, including threatened delivery. Prophylactic doses are recommended during hospitalization if there are no contraindications to use. Patients prescribed antithrombotic therapy prior to a COVID-19 diagnosis should continue their therapy (NIH 2021).
Multiple-dose vials contain benzyl alcohol (avoid in pregnant patients due to association with gasping syndrome in premature infants); use of preservative-free formulations is recommended.
CBC with platelets, stool occult blood tests, serum creatinine and potassium; anti-factor Xa activity in select patients (eg, neonates, infants, children, obese patients, and patients with significant renal impairment, active bleeding, or abnormal coagulation parameters); Note: Routine monitoring of PT and APTT is not warranted since PT and APTT are relatively insensitive measures of low molecular weight heparin activity; consider monitoring bone density in infants and children with long-term use.
Neonates, Infants, Children, and Adolescents:
Treatment:
Peak anti-factor Xa level: 0.5 to 1.0 units/mL, measured 4 to 6 hours after SUBQ administration (Monagle 2012).
Trough anti-factor Xa Level: Goal anti-factor Xa trough level not defined/reported for twice-daily dosing; anti-factor Xa trough level of 0.1 units/mL has been suggested with once-daily dosing. Note: Monitoring of trough levels and once-daily dosing are not routinely recommended in pediatric patients with normal renal function (Monagle 2012).
Prophylaxis:
Peak anti-factor Xa level: 0.1 to 0.3 units/mL, measured 4 to 6 hours after SUBQ administration (Monagle 2012).
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.
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
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).
Solution (Enoxaparin Sodium Injection)
300 mg/3 mL (per mL): $12.80 - $28.17
Solution (Enoxaparin Sodium Subcutaneous)
30 mg/0.3 mL (per 0.3 mL): $3.61 - $24.35
40 mg/0.4 mL (per 0.4 mL): $4.81 - $32.47
60 mg/0.6 mL (per 0.6 mL): $7.22 - $48.77
80 mg/0.8 mL (per 0.8 mL): $9.64 - $65.03
100 mg/mL (per mL): $12.05 - $81.28
120 mg/0.8 mL (per 0.8 mL): $21.60 - $97.57
150 mg/mL (per mL): $27.00 - $121.97
Solution (Lovenox Injection)
300 mg/3 mL (per mL): $25.66
Solution (Lovenox Subcutaneous)
30 mg/0.3 mL (per 0.3 mL): $7.70
40 mg/0.4 mL (per 0.4 mL): $10.25
60 mg/0.6 mL (per 0.6 mL): $15.39
80 mg/0.8 mL (per 0.8 mL): $20.51
100 mg/mL (per mL): $25.64
120 mg/0.8 mL (per 0.8 mL): $30.77
150 mg/mL (per mL): $38.46
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.