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    Fractionated Heparins (LMWHs)

    BOXED WARNING

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Epidural or spinal hemorrhage and subsequent hematomas can occur in patients receiving enoxaparin while epidural or spinal anesthesia/analgesia or spinal puncture procedures are performed. The bleeding risk for spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with use of postoperative indwelling epidural catheters, in patients with a history of traumatic or repeated epidural or spinal puncture, a history of spinal deformity, a history of spinal surgery, or concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. Although the optimal timing between the administration of enoxaparin and neuraxial procedures is not known, if epidural anesthesia, lumbar puncture, or spinal anesthesia is performed, it is best done when the anticoagulant effect of enoxaparin is low. The manufacturer recommends delaying the placement or removal of epidural catheters for at least 12 hours after administration in patients receiving low doses (30 mg twice daily or 40 mg once daily) and at least 24 hours after administration in patients receiving high doses (0.75 to 1 mg/kg twice daily or 1.5 mg/kg once daily). Patients receiving 0.75 mg/kg or 1 mg/kg twice daily should not receive the second enoxaparin dose in the twice daily regimen to allow a longer delay before catheter placement or removal. In patients with severe renal dysfunction (CrCl less than 30 ml/min), consider delaying the placement or removal of epidural catheters for at least 24 hours after administration in adult patients receiving low doses and 48 hours after administration in adult patients receiving high doses because of slower enoxaparin clearance. Although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, the manufacturer recommends considering delaying subsequent enoxaparin doses for at least 4 hours after catheter removal. If neuraxial procedures are employed, monitor patients frequently for symptoms of neurological impairment such as midline back pain, sensory and motor deficits, and bowel and/or bladder dysfunction. Consider the risk versus benefit of neuraxial intervention in patients anticoagulated or to be anticoagulated. If neurological compromise is noted, urgent treatment is necessary; however, such treatment may not prevent or reverse neurological sequelae. In addition, monitor patients closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. When administered at recommended prophylaxis doses, routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of enoxaparin activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.

    DEA CLASS

    Rx

    DESCRIPTION

    Low molecular weight heparin (LMWH)
    Used for prophylaxis and management of systemic thromboembolism
    More predictable anticoagulant response than unfractionated heparin

    COMMON BRAND NAMES

    Lovenox

    HOW SUPPLIED

    Enoxaparin Sodium (Porcine)/Lovenox Intravenous Inj Sol: 1mL, 100mg
    Enoxaparin Sodium (Porcine)/Lovenox Subcutaneous Inj Sol: 0.3mL, 0.4mL, 0.6mL, 0.8mL, 1mL, 30mg, 40mg, 60mg, 80mg, 100mg, 120mg, 150mg

    DOSAGE & INDICATIONS

    For the treatment of venous thromboembolism (VTE) including acute deep venous thrombosis (DVT) or pulmonary embolism (PE).
    For inpatient treatment of DVT with or without PE.
    Subcutaneous dosage
    Adults

    1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours. Both regimens have been shown to be equivalent to continuous IV heparin in clinical trials. Oral warfarin is typically begun within 72 hours of initiation of enoxaparin; however clinical practice guidelines recommend starting a vitamin K antagonist on day 1 of enoxaparin treatment. Enoxaparin is discontinued when the targeted warfarin INR is achieved and a minimum of 5 days of enoxaparin administration has elapsed. The average duration of enoxaparin treatment is 7 days, with up to 17 days well-tolerated in clinical trials.

    Infants 2 months and older†, Children†, and Adolescents†

    Initially, 1 mg/kg/dose subcutaneously every 12 hours is recommended in clinical practice guidelines; adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose. Alternatively, a higher initial dose of 1.5 mg/kg/dose subcutaneously every 12 hours for infants 3 months and older and 1.2 mg/kg/dose subcutaneously every 12 hours for children 1 to 5 years has been recommended based on a retrospective study including 117 patients 3 months and older. Mean doses required to achieve therapeutic anti-factor Xa concentrations were inversely proportional to age and were 1.48 mg/kg/dose subcutaneously, 1.23 mg/kg/dose subcutaneously, and 1.13 mg/kg/dose subcutaneously every 12 hours in patients 3 to 12 months, 1 to 5 years, and 6 to 18 years of age, respectively.

    Infants younger than 2 months†

    Initially, 1.5 mg/kg/dose subcutaneously every 12 hours is recommended in clinical practice guidelines; adjust the dose to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose. Alternatively, a higher initial dose of 1.8 mg/kg/dose subcutaneously every 12 hours has been recommended based on a retrospective study including 75 patients younger than 3 months of age. Patients treated with a higher initial dose achieved a therapeutic anti-factor Xa level 1 day earlier and required 1 less venipuncture on average than those treated with a standard dose (1.5 mg/kg/dose subcutaneously).

    Neonates†

    Initially, 1.7 mg/kg/dose subcutaneously every 12 hours has been recommended based on several studies indicating that neonates require higher doses than older pediatric patients. A lower initial dose of 1.5 mg/kg/dose subcutaneously every 12 hours is recommended in clinical practice guidelines for all infants younger than 2 months with subsequent dosage adjustments to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.

    Premature Neonates†

    Initially, 2 mg/kg/dose subcutaneously every 12 hours has been recommended based on several studies indicating that premature neonates require higher doses than term neonates. A lower initial dose of 1.5 mg/kg/dose subcutaneously every 12 hours is recommended in clinical practice guidelines for all infants younger than 2 months with subsequent dosage adjustments to maintain an anti-factor Xa concentration of 0.5 to 1 units/mL when drawn 4 to 6 hours after the dose or 0.5 to 0.8 units/mL when drawn 2 to 6 hours after the dose.

    For the outpatient treatment of acute DVT not associated with PE, in conjunction with warfarin.
    Subcutaneous dosage
    Adults

    1 mg/kg/dose subcutaneously every 12 hours. Warfarin therapy should be administered when appropriate (usually within 72 hours of enoxaparin initiation). Continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved. In clinical trials, thromboembolism recurrence with enoxaparin (5.3%) was similar to inpatient treatment with continuous IV heparin (6.7%). Episodes of major bleeding were also similar. Enoxaparin patients spent an average of 1.1 days in the hospital compared to 6.5 days for the heparin group. The average duration of enoxaparin treatment is 7 days, with up to 17 days well-tolerated in clinical trials.

    For the treatment of DVT or PE in pregnant females†.
    Subcutaneous dosage
    Pregnant Females†

    1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose every 24 hours throughout pregnancy. Because enoxaparin requirements may change as pregnancy progresses due to changes in volume of distribution and glomerular filtration rate, twice daily dosing is preferred by some clinicians. However, many clinicians use a once-daily regimen to simplify administration and enhance compliance. Observational studies have not shown an increase in the risk of recurrence with once daily dosing compared to twice daily dosing. Dose adjustments during pregnancy remains controversial. Due to the lack of data demonstrating a correlation with therapeutic anti-Xa concentrations and safety or efficacy, clinical practice guidelines suggest routine monitoring with anti-Xa concentrations is difficult to justify. Enoxaparin should be discontinued 24 hours prior to elective induction of labor or cesarean section. An anticoagulant should be administered for at least 6 weeks postpartum, for a minimum of 3 months of therapy.

    For the treatment of DVT or PE in patients with cancer†.
    Subcutaneous dosage
    Adults

    1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours. The rate of recurrence of VTE in patients with active cancer is high; therefore, extended therapy is recommended unless there is a very high risk of bleeding. Clinical practice guidelines recommend treatment of VTE with low molecular weight heparin (LMWH) for over 3 months if the risk of bleeding is not high. Trials of extended enoxaparin in the treatment of VTE in patients with cancer have not demonstrated a difference in terms of recurrence or major bleeding between extended treatment with enoxaparin vs. warfarin.

    For thrombosis prophylaxis.
    NOTE: Mechanical methods of prophylaxis should be used in patients who are at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis.
    For arterial thromboembolism prophylaxis† in patients after prosthetic heart valves† surgery.
    Subcutaneous dosage
    Adults

    1 mg/kg subcutaneously every 12 hours. Guidelines recommend LMWH in combination with oral anticoagulants until the INR is within the therapeutic range for 2 consecutive days.

    For venous thromboembolism (VTE) prophylaxis including deep venous thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis.
    Subcutaneous dosage
    Moderate risk Adults undergoing general surgery (e.g., minor procedure, with additional risk factors; non-major surgery for patients 40 to 60 years with no risk factors; major surgery in patients younger than 40 years with no risk factors†)

    Guidelines suggest a dose of 3,400 anti-factor Xa International Units or less of LMWH subcutaneously once daily (equivalent to 34 mg or less per day of subcutaneous enoxaparin); 20 mg subcutaneously once daily is the dose most studied during 'low-dose' enoxaparin DVT/PE prophylaxis studies. Higher doses of 40 to 60 mg/day subcutaneously are associated with an increased risk of bleeding and the risk of bleeding may outweigh the benefit in this at moderate-risk population. Previous guidelines have suggested starting the LMWH 1 to 2 hours before surgery, followed by once daily postoperatively.

    Higher risk Adults, patients undergoing abdominal surgery, or Geriatric undergoing general surgery (e.g., non-major surgery in patients older than 60 years or with additional risk factors; major surgery in patients older than 40 years or with additional risk factors)

    Guidelines suggest a dose more than 3,400 anti-factor Xa International Units subcutaneously once daily (equivalent to more than 34 mg subcutaneously once daily of enoxaparin); 30 mg subcutaneously every 12 hours or 40 mg subcutaneously once daily are the doses most studied during enoxaparin DVT/PE prophylaxis studies. Previous guidelines have suggested starting enoxaparin, when given in a dose of 30 mg subcutaneously every 12 hours, 8 to 12 hours preoperatively; or when given as 40 mg subcutaneously once daily, starting 1 to 2 hours preoperatively. Subsequent doses, provided hemostasis has been established, are administered beginning 24 hours after the initial preoperative dose and continued for 7 to 10 days. Continue prophylaxis throughout the period of postoperative care until the risk of DVT has diminished. In cancer surgery patients, prophylaxis for 2 to 3 weeks after surgery reduces the risk of symptomatic DVT. In all higher-risk general surgery patients, the use of mechanical prophylaxis with elastic stockings (ES) or intermittent pneumatic compression (IPC) is recommended initially. In very high-risk general surgery patients with multiple risk factors, combination of pharmacologic and mechanical (i.e., ES or IPC) prophylaxis is recommended.

    Adults after orthopedic hip replacement surgery

    40 mg subcutaneously once daily or 30 mg subcutaneously every 12 hours. Guidelines recommend LMWH as the preferred agent for antithrombotic prophylaxis for patients undergoing total hip replacement surgery. Prophylaxis should start 12 hours or more preoperatively or postoperatively and continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.

    Adults after orthopedic knee replacement surgery

    30 mg subcutaneously every 12 hours. Guidelines recommend LMWH as the preferred agent for antithrombotic prophylaxis for patients undergoing total knee replacement surgery. Prophylaxis should start 12 hours or more preoperatively or postoperatively and continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.

    Adults after orthopedic hip fracture surgery†

    40 mg subcutaneously once daily or 30 mg subcutaneously every 12 hours. Guidelines recommend LMWH as the preferred antithrombotic prophylactic agent for patients undergoing hip fracture surgery. Prophylaxis should start 12 hours or more preoperatively or postoperatively and continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.

    General medical Adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe respiratory disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and inflammatory bowel disease)

    40 mg subcutaneously once daily for 14 days or less. In a phase 3 trial, treatment with enoxaparin resulted in a significantly lower incidence of DVT when compared with placebo (4.4% vs. 11.9%) after 14 days of treatment. The reduced incidence was maintained at 3 months of follow-up. There were no significant differences in adverse reactions between the treatment group and placebo except for ecchymosis at the injection site. Additionally, enoxaparin 40 mg subcutaneously once daily was associated with a significant decrease in the incidence of VTE as compared to enoxaparin 20 mg subcutaneously once daily, or placebo (incidence of DVT was 5.5% for enoxaparin 40 mg, 15% for enoxaparin 20 mg, and 14.9% for placebo; RR of enoxaparin 40 mg vs. placebo 0.37, 95% CI 0.22 to 0.63, p less than 0.001).

    Female Adults undergoing major gynecologic surgery for benign disease, no additional risk factors†

    Guidelines recommend 3,400 anti-factor Xa International Units or less of LMWH subcutaneously once daily (equivalent to 34 mg or less per day of subcutaneous enoxaparin). Continue prophylaxis until hospital discharge. Previous guidelines have suggested enoxaparin 20 mg subcutaneously 1 to 2 hours prior to surgery, then once daily.

    Female Adults undergoing extensive gynecologic surgery for malignancy†

    Guidelines recommend more than 3,400 anti-factor Xa International Units of LMWH subcutaneously once daily (equivalent to more than 34 mg subcutaneously once daily of enoxaparin). For most patients, continue prophylaxis until hospital discharge; however, in patients that are considered to be at high risk (i.e., older than 60 years of age or a history of VTE), continue prophylaxis through hospitalization and for 2 to 4 weeks after discharge. Previous guidelines have suggested a dose of enoxaparin 40 mg subcutaneously 1 to 2 hours before surgery then once daily or 30 mg subcutaneously every 12 hours starting 8 to 12 hours before surgery.

    Adults undergoing laparoscopic surgery†

    20 or 40 mg subcutaneously once daily in patients that have additional risk factors for VTE. In a study, enoxaparin was started the night before surgery and continued daily through hospital admission. Patients with risk factors for VTE or weight more than 80 kg received the higher dose of 40 mg.

    Adults undergoing vascular surgery†

    40 mg subcutaneously once daily in patients that have additional risk factors for VTE.

    Adults undergoing major open urologic procedure (including high-risk)†

    20 mg subcutaneously 1 to 2 hours prior to surgery then once daily for patients at moderate risk for VTE. For patients at highest risk, 40 mg subcutaneously 1 to 2 hours before surgery then once daily or 30 mg subcutaneously every 12 hours starting 8 to 12 hours before surgery in combination with elastic stockings (ES) with or without intermittent pneumatic compression (IPC). The optimal duration of prophylaxis is not known.

    Adults undergoing neurosurgery†

    40 mg subcutaneously once daily beginning 24 hours after surgery and in combination with compression stockings, provided hemostasis has been established and no contraindications to LMWH use exist. The use of enoxaparin must be balanced with clinically important risk of intracranial bleeding; some clinicians obtain a CT scan prior to initiating LMWH to rule out an intracranial bleed. Limited data suggests that the combination of LMWH with stockings may be more effective than stockings alone in preventing VTE.

    Adults undergoing elective spinal cord surgery†

    20 or 40 mg subcutaneously once daily beginning postoperatively in patients that have additional risk factors for VTE. The optimal duration of prophylaxis is unknown. In patients with multiple risk factors, the use of LMWH in combination with elastic stockings (ES) or intermittent pneumatic compression (IPC) is recommended.

    Adults with trauma†

    30 mg subcutaneously every 12 hours usually within 36 hours of the injury, provided hemostasis has been established and no contraindications to LMWH exist. Continue VTE prophylaxis throughout hospitalization and inpatient rehabilitation. Continue prophylaxis in patients who have impaired mobility after recovery.

    Adults with acute spinal cord injury†

    30 mg subcutaneously every 12 hours or 40 mg subcutaneously once daily, provided hemostasis has been established and no contraindications to LMWH use exist. Continue the LMWH throughout hospitalization and the rehabilitation phase.

    Adults with acute ischemic stroke and impaired mobility†

    40 mg subcutaneously once daily, if not contraindicated. For a patient with contraindications to antithrombotic therapy, guidelines recommend intermittent pneumatic compression (IPC) devices or elastic stockings (ES).

    Adults considered to be at high-risk for VTE that are undergoing flights more than 6 hours in duration†

    40 mg subcutaneously for 1 dose 2 to 4 hours before travel, although a higher dose of 1 mg/kg subcutaneously for 1 dose has also been used.

    Infants, Children, and Adolescents 2 months to 17 years†

    0.5 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL. Following the initial 3-month therapy for the first central venous catheter-related DVT, prophylactic doses of LMWH are recommended until the catheter is removed.

    Neonates and Infants younger than 2 months†

    0.75 mg/kg subcutaneously every 12 hours; adjust dose to maintain an anti-factor Xa concentration of 0.1 to 0.3 International Units/mL. Following the initial 3-month therapy for the first central venous catheter-related DVT, prophylactic doses of LMWH are recommended until the catheter is removed.

    For deep venous thrombosis (DVT) prophylaxis in pregnant females.
    NOTE: In all pregnant women with a history of DVT, the use of graduated elastic stockings (ES) is recommended both antenatally and postpartum.
    Subcutaneous dosage
    Pregnant females with a history of DVT with a transient risk factor; no current risk factors

    Surveillance and postpartum anticoagulation are recommended. If the previous event is pregnancy or estrogen-related, or there are additional risk factors (e.g., obesity), antenatal anticoagulation prophylaxis is recommended.

    Pregnant females with an episode of idiopathic DVT; no current long-term anticoagulation

    40 mg subcutaneously once daily; anticoagulation should be continued postpartum. Maintain anti-factor Xa concentration of 0.2 to 0.6 International Units/mL.

    Pregnant females, no prior DVT; thrombophilia (confirmed laboratory abnormality); no current long-term anticoagulation

    40 mg subcutaneously once daily or surveillance is recommended; anticoagulation should be given postpartum. Maintain anti-factor Xa concentration of 0.2 to 0.6 International Units/mL. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions, 40 mg subcutaneously once daily is recommended. In a study of 61 women at high risk for thromboembolism, enoxaparin was initiated in the first trimester and continued throughout pregnancy. Anti-factor Xa concentrations were monitored. No increased bleeding risk was observed, and no embolic complications occurred during the pregnancies. Fetal and neonatal outcomes were normal. Decreased bone density was reported in 34% of the women after delivery, but could not be directly attributed to the use of enoxaparin from this study.

    Pregnant females with a single episode of DVT and thrombophilia (confirmed laboratory abnormality) or a strong family history of thrombosis; no current long-term anticoagulation

    40 mg subcutaneously once daily or every 12 hours is recommended; anticoagulation should be continued postpartum. In women that are antithrombin-deficient, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions, 40 mg subcutaneously every 12 hours is recommended.

    Pregnant females with 2 or more episodes of DVT and/or long-term anticoagulation (e.g., single episode of DVT, idiopathic or associated with thrombophilia)

    1 mg/kg subcutaneously every 12 hours with resumption of long-term anticoagulation postpartum.

    For thrombosis prophylaxis in pregnant patients with prosthetic heart valves†.
    Subcutaneous dosage
    Pregnant females

    1 mg/kg subcutaneously twice daily with anti-factor Xa concentrations monitored and maintained at 1 to 1.2 International Units/mL. Enoxaparin can be administered either throughout pregnancy, or alternately, from weeks 6 to 12, followed by warfarin (INR 2.5 to 3.5) until the middle of the third trimester, and then enoxaparin for the remainder of the pregnancy. Prospective randomized controlled trials have not been completed in this population, and treatment failures with the use of LMWH have been reported. Patients should be treated and monitored aggressively with dose adjustments throughout pregnancy reflective of changes in the patient's weight or as indicated by anti-factor Xa concentrations. In women who are at especially high risk, the addition of aspirin 75 to 162 mg/day PO is recommended. Earlier guidelines recommend similar courses of action; however, the goal anti-factor Xa concentration was 0.7 to 1.2 International Units/mL.

    For thrombosis prophylaxis and/or for pulmonary embolism prophylaxis in patients at increased risk after sustaining an acute MI (e.g., ST segment elevation MI, severe LV dysfunction, CHF, history of systemic or pulmonary embolism, 2D echo evidence of mural thrombus, or atrial fibrillation).
    Subcutaneous dosage
    Adults

    40 mg subcutaneously once daily for up to 3 months as an alternative to IV heparin for continuation of anticoagulation beyond 48 hours of an AMI. All acute MI patients should receive at least LMWH or low-dose heparin until the patient is ambulatory for prevention of DVT.

    For arterial thromboembolism prophylaxis† in patients with atrial fibrillation who are undergoing elective cardioversion.
    Subcutaneous dosage
    Adults

    1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg subcutaneously once daily at presentation for patients without contraindications. For patients with atrial fibrillation of known duration less than 48 hours, cardioversion can be performed without anticoagulation.

    For thrombosis prophylaxis in patients with obesity†.
    Subcutaneous dosage
    Adults

    0.5 mg/kg subcutaneously once or twice daily. Anti-factor Xa concentrations may be monitored with dosage adjustments considered to achieve an anti-factor Xa concentration of 0.2 to 0.5 International Units/mL. Although previous guidelines recommended weight-based dosing for VTE prophylaxis in obese patients, current guidelines do not provide specific dosing recommendations but suggest an increased dose may be required. Among obese, medically ill patients (n = 28, BMI 35 mg/m2 or more), the mean anti-factor Xa concentration after 1 to 2 doses of enoxaparin 0.5 mg/kg subcutaneously once daily was 0.25 International Units/mL (range 0.08 to 0.59 International Units/mL). Another small prospective study of obese, medically ill patients (n = 31, BMI 40 kg/m2 or more) compared enoxaparin 40 mg, 0.4 mg/kg, and 0.5 mg/kg subcutaneously once daily for 3 days or less in most patients. Patients receiving 0.5 mg/kg once daily achieved goal anti-factor Xa concentrations more often (p less than 0.001). Further, 82% of patients in the 40 mg group had anti-factor Xa concentrations below goal compared to 36% and 13% in the 0.4 mg/kg and 0.5 mg/kg groups, respectively (p less than 0.001). There were no observed bleeding or thrombosis complications. A retrospective study evaluated enoxaparin 0.5 mg/kg subcutaneously twice daily in obese surgical ICU patients (n = 23, mean BMI = 46.4 mg/m2). Among these patients, 91% achieved goal anti-factor Xa concentrations with a mean concentration of 0.34 International Units/mL (range 0.2 to 0.59 International Units/mL) after the third or fourth dose. Subsequent dose adjustments of +/- 10 mg were allowed based on anti-factor Xa results. DVT and minor bleeding were each reported in 1 patient.

    For the treatment of cerebral thromboembolism† (e.g., cerebral venous sinus thrombosis†).
    Subcutaneous dosage
    Adults

    The ACCP guidelines recommend treatment with enoxaparin during the acute phase, even in the presence of hemorrhagic infarction. Then, treat with a vitamin k antagonist for 3—6 months. A specific dose of enoxaparin has not been suggested.

    Children and Infants >= 2 months

    The ACCP guidelines recommend treatment with LMWH initially, followed by warfarin or continued treatment with enoxaparin for 3 months, even if a localized hemorrhagic infarct is present. In a small, pilot study, children with sinovenous thrombosis were randomized to unfractionated heparin (n = 10), enoxaparin (n = 12), or no treatment (n = 8). In children >= 2 months of age the initial dose of enoxaparin was 1 mg/kg subcutaneously every 12 hours adjusted to maintain a goal anti-factor Xa concentration of 0.5—1 anti-factor Xa International Units/mL. The majority of patients received warfarin after the initial treatment; however, 4 patients received enoxaparin for the entire treatment period of 3 months. Recurrent thrombosis was not reported in patients taking enoxaparin or heparin; however, 1 patient in the heparin group experienced clinically silent bleeding. Three patients that did not receive an anticoagulant died versus zero patients that did receive anticoagulant therapy.

    Infants < 2 months

    The ACCP guidelines recommend LMWH for 3 months as long as the there is no large ischemic infarct or an intracranial hemorrhage. In a small, pilot study, children with sinovenous thrombosis were randomized to unfractionated heparin (n = 10), enoxaparin (n = 12), or no treatment (n = 8). In children < 2 months of age the initial dose of enoxaparin was 1.5 mg/kg subcutaneously every 12 hours adjusted to maintain a goal anti-factor Xa concentration of 0.5—1 anti-factor Xa International Units/ml. The majority of patients received warfarin after the initial treatment; however, 4 patients received enoxaparin for the entire treatment period of 3 months. Recurrent thrombosis was not reported in patients taking enoxaparin or heparin; however, 1 patient in the heparin group experienced clinically silent bleeding. Three patients that did not receive an anticoagulant died versus zero patients that did receive anticoagulant therapy.

    For coronary artery thrombosis prophylaxis and the prevention of ischemic complications in patients with acute coronary syndrome (ACS), including patients undergoing percutaneous coronary intervention (PCI)†.
    NOTE: Adhere precisely to the intervals recommended between enoxaparin doses to minimize the risk of bleeding following the vascular instrumentation during the treatment of angina that is unstable, non-Q-wave myocardial infarction, and acute ST-segment elevation myocardial infarction. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, remove the sheath 6 hours after the last enoxaparin dose. If enoxaparin is to be continued, the next scheduled dose should be given no sooner than 6—8 hours after sheath removal. Observe the procedure site for signs of bleeding or of hematoma formation.
    For patients with acute myocardial infarction with ST-segment elevation (ST-segment elevation myocardial infarction or STEMI).
    NOTE: In the pivotal clinical study, the enoxaparin treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.
    Intravenous and Subcutaneous dosage
    Adults and Geriatric < 75 years of age

    30 mg IV bolus plus 1 mg/kg subcutaneous followed by 1 mg/kg subcutaneous every 12 hours (maximum of 100 mg for the first 2 doses only, followed by 1 mg/kg for the remaining doses). If enoxaparin is administered with a fibrin-specific or non-fibrin specific thrombolytic, give enoxaparin between 15 minutes before and 30 minutes after initiation of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and need 75—325 mg ASA once daily unless contraindicated. If a patient is managed with PCI, no additional enoxaparin dosing is needed if the last SC dose was less than 8 hours before balloon inflation. If the last subcutaneous dose was given more than 8 hours before balloon inflation, give an enoxaparin IV bolus of 0.3 mg/kg. The 2004 ACCP guidelines recommend enoxaparin be used when tenecteplase is used as the fibrinolytic and only when patients are <= 75 years of age with preserved renal function (serum creatinine of <= 2.5 mg/dL in males and <= 2 mg/dL in females).

    Geriatric 75 years of age or older

    0.75 mg/kg subcutaneous every 12 hours (maximum 75 mg for the first 2 doses only, followed by 0.75 mg/kg dosing for the remaining doses). If enoxaparin is administered with a fibrin-specific or non-fibrin specific thrombolytic, give enoxaparin between 15 minutes before and 30 minutes after initiation of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and need 75—325 mg ASA once daily unless contraindicated. If a patient is managed with PCI, no additional enoxaparin dosing is needed if the last subcutaneous dose was less than 8 hours before balloon inflation. If the last subcutaneous dose was given more than 8 hours before balloon inflation, give an enoxaparin IV bolus of 0.3 mg/kg.

    For patients with unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or non-Q-wave myocardial infarction.
    Intravenous and Subcutaneous dosage
    Adults

    The ACCP guidelines recommend enoxaparin 1 mg/kg subcutaneous every 12 hours over unfractionated heparin (UFH), including in those patients that receive an upstream GPIIb/IIIa inhibitor as initial therapy for ACS. Per the manufacturer, enoxaparin should be administered for at least 2 days in this setting and until stabilization (usual duration is 2—8 days); administer enoxaparin in combination with 100—325 mg of aspirin PO/day. In patients that receive LMWH as the upstream anticoagulant, it is recommended that the LMWH be continued during PCI. In patients with NSTE ACS, the evidence supports an aggressive and early invasive strategy (e.g., PCI); extended treatment with prophylactic doses of LMWH (studies with dalteparin up to 90 days in duration have been conducted) may provide additional benefit in patients managed medically versus those undergoing invasive procedures. Additionally, in those patients where invasive strategies are planned but delayed, the continued use of LMWH until the procedure is performed is recommended. In patients scheduled to undergo PCI who have been receiving enoxaparin, additional anticoagulant therapy is dependent on the timing of the last dose of enoxaparin. If the last dose of enoxaparin has been administered <= 8 hours prior to PCI, no additional anticoagulant therapy should be administered. If the last dose of enoxaparin has been administered 8—12 hours prior to PCI, a dose of enoxaparin 0.3 mg/kg IV should be administered at the time of PCI, or standard anticoagulation with heparin can be administered during PCI. If the last dose of enoxaparin has been administered > 12 hours before PCI, conventional anticoagulation therapy should be administered during PCI. To minimize the risk of bleeding following vascular instrumentation during the treatment of unstable angina, the vascular access sheath should remain in place for 6—8 hours following a dose of enoxaparin (i.e., next scheduled dose of enoxaparin should be given no sooner than 6—8 hours after sheath removal). In 2 of the trials examining the use of enoxaparin in NSTEMI ACS, the ESSENCE trial and the TIMI-11B trial , twice daily enoxaparin is significantly more effective than UFH intravenous infusions in decreasing the combined endpoint of death, myocardial infarction, or recurrent angina/urgent revascularization. The results of the initial phases of the ESSENCE and TIMI 11B trials show a similar rate of major bleeding for enoxaparin versus UFH; however, enoxaparin is associated with a higher incidence of minor bleeding.

    For the prevention of pregnancy loss and/or thrombosis in patients with antiphospholipid antibody syndrome† (APLA).
    In pregnant women with APLA and >= 2 early pregnancy losses, >= 1 late pregnancy loss, preeclampsia, intrauterine growth restriction (IUGR), or abruption.
    Subcutaneous dosage
    Pregnant females

    Antepartum aspirin and enoxaparin 40 mg subcutaneous once daily. Maintain anti-factor Xa level of 0.2 to 0.6 International Units/mL.

    In pregnant women with congenital thrombophilic defects and recurrent miscarriages, a miscarriage during or after the second trimester, severe or recurrent preeclampsia, or abruption.
    Subcutaneous dosage
    Pregnant females

    40 mg subcutaneous once daily plus antepartum, low-dose aspirin therapy is recommended. Maintain anti-factor Xa level of 0.2 to 0.6 International Units/mL. Give anticoagulants postpartum.

    In pregnant women with APLA and a history of venous thrombosis, with current long-term anticoagulation.
    Subcutaneous dosage
    Pregnant females

    1 mg/kg subcutaneous every 12 hours is recommended. Resume long-term oral anticoagulation therapy postpartum.

    In pregnant women with antiphospholipid antibodies and no previous venous thrombosis and no pregnancy losses.
    Subcutaneous dosage
    Pregnant females

    40 mg subcutaneous once daily is recommended. Low-dose aspirin may be used in combination with enoxaparin. Maintain anti-factor Xa level of 0.2 to 0.6 International Units/mL.

    For periprocedural anticoagulation† (bridge therapy) in patients with atrial fibrillation, mechanical heart valve, or venous thrombosis who require an interruption in oral anticoagulant therapy.
    For patients taking direct-acting oral anticoagulants (DOACs) who require multiple procedures and/or are unable to tolerate oral medications post-procedure.
    Subcutaneous dosage
    Adults

    40 mg subcutaneously once daily or 30 mg subcutaneously twice daily may be sufficient. DOACs have short half-lives; hence, alternative anticoagulation during temporary interruption is not needed in the majority of situations.

    For patients taking warfarin at moderate or high risk for thromboembolism and with no significant bleed risk.
    Subcutaneous dosage
    Adults

    1 mg/kg/dose subcutaneously twice daily or 1.5 mg/kg/dose subcutaneously once daily. Alternatively, 30 mg subcutaneously twice daily or 40 mg subcutaneously once daily (low-dose prophylactic regimen) or 40 mg subcutaneously twice daily (intermediate-dose regimen) has been used. Stop warfarin approximately 5 days prior to procedure and initiate LMWH 24 hours or more after the first missed dose of warfarin. Guidelines recommend starting LMWH when INR is less than 2 in those with nonvalvular atrial fibrillation, or if INR is not measured, after omitting 2 to 3 doses of warfarin. Administer the last dose of LMWH approximately 24 hours before procedure, potentially longer in those with renal dysfunction. If necessary, residual anticoagulation can be assessed by checking antifactor Xa concentrations. In most cases, warfarin can be restarted in the first 12 to 24 hours after the procedure at the patient’s usual therapeutic dose; post-procedural bridging can be considered in patients with moderate or high risk of stroke or thromboembolic events.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Enoxaparin has a narrow therapeutic index, specific for the patient population and indication. The maximum dosage is individualized based on anti-factor Xa concentrations and assessment of efficacy and safety parameters.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Adults
    The following initial dosage adjustments have been recommended. While some have recommended monitoring anti-factor Xa serum concentrations, others do not recommend using serum concentrations to guide dosage adjustment in patients with a CrCl less than 30 mL/minute. Instead, the recommendation is to use the manufacturer renal dose adjustment or switch to an alternative anticoagulant with lower renal clearance. Although no dosage adjustment is recommended for mild to moderate renal impairment, observe these patients frequently for signs and symptoms of bleeding.
    CrCl 30 mL/minute or more: No dosage adjustment needed.
    CrCl less than 30 mL/minute:
    Thrombosis prophylaxis in abdominal or hip or knee replacement surgery or acute medical illness: 30 mg subcutaneously once daily
    Prophylaxis of ischemic complications of unstable angina or non-Q-wave myocardial infarction plus aspirin: 1 mg/kg subcutaneously once daily
    Treatment of deep vein thrombosis with or without pulmonary embolism plus warfarin: 1 mg/kg subcutaneously once daily
    Treatment of acute ST-segment elevation myocardial infarction in patients younger than 75 years plus aspirin: 30 mg IV bolus plus 1 mg/kg subcutaneously then 1 mg/kg subcutaneously once daily
    Treatment of acute ST-segment elevation myocardial infarction in patients 75 years and older plus aspirin: 1 mg/kg subcutaneously once daily
     
    Pediatric patients
    The following initial dosage adjustments have been recommended for pediatric patients. Adjust dose further based on anti-factor Xa concentrations. Although no dosage adjustment is recommended for mild to moderate renal impairment, observe these patients frequently for signs and symptoms of bleeding.
    CrCl 30 mL/minute/1.73 m2 or more: No dosage adjustment needed.
    CrCl 10 to 29 mL/minute/1.73 m2: Reduce initial dose by 30%.
    CrCl less than 10 mL/minute//1.73 m2: Reduce initial dose by 50% and administer every 24 hours.
     
    Intermittent hemodialysis and Peritoneal dialysis
    Reduce the initial dose by 50%.
     
    Continuous renal replacement therapy (CRRT)
    Reduce the initial dose by 30% (assuming a dialysis dose of 2,000 mL/minute/1.73 m2).

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    Administered via subcutaneous or intravenous administration. Do not administer intramuscularly.
    Evaluate all patients for a bleeding disorder prior to administration, unless the medication is needed urgently.
    If withdrawing from the multi-dose vial, utilize a tuberculin or equivalent graduated syringe to ensure proper measurement of the required dose. Do not mix with other injections or parenteral fluids.
    Enoxaparin cannot be used interchangeably (unit for unit) with heparin sodium or other low molecular weight heparins.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Storage: Discard the multi-dose vial 28 days after the first use.
     
    Preparation and stability of enoxaparin 20 mg/mL dilution for parenteral administration:
    NOTE: Enoxaparin is not FDA-approved to be prepared as a 20 mg/mL dilution. Prepare in a sterile environment, using aseptic technique.
    Add the contents of 4 enoxaparin 60 mg/0.6 mL syringes and 9.6 mL preservative-free Sterile Water for Injection to a sterile glass vial.
    Storage: The dilution may be stored for up to 4 weeks in the glass vial at room temperature (22 to 26 degrees C) or up to 2 weeks in tuberculin syringes with rubber stoppers at room temperature or under refrigeration (2 to 6 degrees C) without significant loss of anti-Xa activity.
    The cited stability study was conducted in a class 100 environment and did not test microbiologic properties.
     
    Preparation and stability of enoxaparin 8 mg/mL dilution for SUBCUTANEOUS administration:
    NOTE: Enoxaparin is not FDA-approved to be prepared as an 8 mg/mL dilution. Prepare in a sterile environment, using aseptic technique.
    It has been suggested that an enoxaparin dilution of 8 mg/mL be used in smaller patients receiving single doses less than 8 mg/dose to ensure adequate dosing and titration. Clinicians should be aware of when to switch to a more concentrated dilution, so the patient does not receive a subcutaneous injection volume more than 1 mL/dose.
    Add the contents of 1 enoxaparin 40 mg/0.4 mL syringe and 4.6 mL Sterile Water for Injection to a 10 mL sterile vial.
    Storage: The dilution may be stored for up to 14 days in polypropylene syringes under refrigeration at 2 to 6 degrees C.

    Intravenous Administration

    Use the multiple-dose vial for intravenous injection. Use a tuberculin or equivalent graduated syringe to ensure proper measurement of the required dose.
    Administer via IV bolus through an intravenous line. Do not mix or coadminister with other drugs. To avoid the possible mixing with other drugs, flush the IV access port with a sufficient amount of saline or dextrose solution before and after enoxaparin administration.
    May be safely administered with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

    Subcutaneous Administration

    Patients should be in a supine position.
    Administer by deep subcutaneous injection. Inject into the left and right anterolateral or posterolateral abdominal wall. Using the thumb and forefinger, you must lift up a fold of skin while giving the injection.
    Insert the entire length of the needle vertically at a 90 degree angle.
    Alternate the injection site with each injection. Do not rub the injection site after administration.
    To avoid loss of drug when using the 30 mg or 40 mg prefilled syringes, do not expel the air bubble from the syringe before subcutaneous injection.
    Prefilled syringes for the 30 mg and 40 mg doses are not graduated. Do not use these syringes to administer partial doses.
    When using the prefilled syringes, after injection, a safety system to prevent inadvertent needle sticks can be activated by firmly pressing down on the plunger rod. An audible click will be heard once the protective sleeve is in place. Dispose of the syringe in a sharps container. The safety system can only be activated once the syringe is empty. Do not activate the safety system until the syringe is away from the skin.

    STORAGE

    Lovenox:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Benzyl alcohol hypersensitivity, heparin hypersensitivity, porcine protein hypersensitivity

    Enoxaparin is contraindicated in patients with porcine protein hypersensitivity and enoxaparin or heparin hypersensitivity. Multiple-dose vials of enoxaparin contain benzyl alcohol (1.5%) as a preservative; administration of this formulation of enoxaparin is contraindicated in patients with benzyl alcohol hypersensitivity.

    Heparin-induced thrombocytopenia (HIT), thrombocytopenia

    Enoxaparin is contraindicated for use in patients with a history of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies. If more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present, use enoxaparin only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.[29732] Although LMWHs are less likely to trigger the formation of HIT antibodies than unfractionated heparin (UFH), LMWHs are just as effective as UFH at triggering platelet activation by HIT antibodies (i.e., LMWHs have essentially 100% in vitro cross-reactivity).[25334] Circulating antibodies may last for several years, and HIT may still occur if more than 100 days have passed or if no circulating antibodies are present. Monitor the platelet count in patients receiving enoxaparin. Any degree of thrombocytopenia should be closely monitored and, if the platelet count drops below 100,000/mm3, discontinue enoxaparin. Enoxaparin may also cause HIT with thrombosis (HITTS), which may result in organ infarction, limb ischemia, or death.[29732]

    Aneurysm, bleeding, coagulopathy, diabetic retinopathy, diverticulitis, endocarditis, GI bleeding, hemophilia, hepatic disease, hypertension, idiopathic thrombocytopenic purpura (ITP), inflammatory bowel disease, peptic ulcer disease, renal disease, stroke, surgery

    Bleeding is the major risk associated with use of enoxaparin. Enoxaparin is contraindicated in patients with active major bleeding, such as GI bleeding. Before initiating therapy, rule out coagulopathy. Avoid use of enoxaparin in patients with severe bleeding disorders, such as hemophilia or immune thrombocytopenic purpura (ITP). Use enoxaparin with caution in any disease state in which there is an increased risk of hemorrhage, such as acute infective endocarditis, dissecting aneurysm, peptic ulcer disease, recent GI bleeding, non-hemorrhagic stroke, diverticulitis, inflammatory bowel disease, decreased platelets, abnormal vaginal bleeding, severe hepatic disease or renal disease, uncontrolled hypertension, hypertensive or diabetic retinopathy, recent brain, spinal or ophthalmological surgery, and in patients with a bleeding diathesis. Adhere precisely to the intervals recommended between enoxaparin doses to minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction, and acute ST-segment elevation myocardial infarction. It is important to achieve hemostasis at the puncture site after percutaneous coronary intervention. If a closure device is used, the sheath can be removed immediately. If a manual compression method is used, remove the sheath 6 hours after the last enoxaparin dose. If enoxaparin treatment is to be continued, give the next scheduled dose no sooner than 6 to 8 hours after sheath removal. Observe the procedure site for signs of bleeding or of hematoma formation. In addition, patients should be closely monitored for bleeding after tube drainage of the stomach or small intestine. Patients should be monitored closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. The risk of enoxaparin-associated bleeding and serious adverse reactions increases with age. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. When administered at recommended prophylaxis doses, routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of enoxaparin activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.[29732]

    Intramuscular injections

    Intramuscular injections should not be administered to patients receiving enoxaparin. IM injections may cause bleeding, bruising, or hematoma formation in patients who are anticoagulated.

    Prosthetic heart valves

    Enoxaparin has not been adequately studied for thromboprophylaxis in patients with prosthetic heart valves, including pregnant women, and has not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and/or fetal death. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Regardless, the ACCP recommends the use of LMWHs for thromboprophylaxis in patients with prosthetic heart valves after prosthetic valve insertion or when vitamin K antagonists must be discontinued.

    Pregnancy

    Benzyl alcohol can cross the placenta, thus multiple-dose vials of enoxaparin (contain 1.5% benzyl alcohol) should be used with caution during pregnancy, and only if clearly needed. It is recommended to use preservative-free enoxaparin when possible in pregnant women. No well-controlled studies exist in pregnant women. Enoxaparin was found to cross the placenta in animal studies. The rate of major congenital anomalies in a retrospective, cohort study involving 693 live births was 2.5%; similar to estimated background risk in the general population. Sixty-three women experienced 72 hemorrhagic events; 11 were classified as serious. In addition, there were 14 neonatal, hemorrhagic cases. Several reports have described the use of enoxaparin during pregnancy without fetal or maternal complications.[25683] There have been reports of congenital anomalies including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defect, when women received enoxaparin during pregnancy. A cause and effect relationship has not been established nor has the incidence been shown to be higher than in the general population. Fetal death has been reported with post-marketing use of enoxaparin in pregnant women; causality for these cases has not been determined. Pregnant women, similar to other patient populations, receiving anticoagulants, including enoxaparin, are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving enoxaparin should be carefully monitored, especially women with lupus anticoagulant or antiphospholipid antibody syndrome who have a history of fetal loss. According to the manufacturer, it is not known if dosage adjustment or anti-factor Xa monitoring is needed during general pregnancy (in pregnant women without prosthetic valves). Pregnant women and women of child-bearing potential should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. In addition, one case of hyperlipidemia with hypertriglyceridemia in a diabetic pregnant woman receiving enoxaparin has been reported; causality is uncertain. In a clinical study of pregnant women with prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. There are post-marketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. These events resulted in maternal death or surgical interventions. Enoxaparin has not been adequately studied for thromboprophylaxis in pregnant women with prosthetic heart valves; however, the 2004 ACCP guidelines do recommend using LMWH in pregnant women with prosthetic heart valves requiring anticoagulation therapy.[32598] Pregnant women with prosthetic heart valves may be at higher risk for thromboembolism, and have a higher rate of fetal loss from stillbirth, spontaneous abortion, and premature delivery. Frequent monitoring of peak and trough anti-factor Xa levels, and follow up enoxaparin dosage adjustments may be needed for patients with mechanical valves, especially pregnant women. Compared with unfractionated heparin, low molecular weight heparins (LMWHs) may have advantages in pregnant women because they cause less heparin-induced thrombocytopenia and may be less likely to produce osteoporosis; the 2004 ACCP guidelines indicate that because of these reasons, LMWH are the preferred drugs for the treatment of acute venous thromboembolism (VTE) in pregnancy. The treatment of acute venous thromboembolism in pregnancy requires weight-adjusted dosing, but optimal dose regimens have not been established; however, because the half-life of enoxaparin is decreased in pregnancy, twice daily dosing is preferred for acute VTE treatment.[32598] Teratogenic effects have not been demonstrated in animals.[25683]

    Breast-feeding

    According to the manufacturer, it is unknown if enoxaparin is excreted into breast milk. The manufacturer recommends caution when using enoxaparin in women who are breast-feeding. However, because of the relatively high molecular weight of enoxaparin, excretion is expected to be minimal. Also, because of inactivation by the GI tract on oral ingestion, any potential risk to a nursing infant posed by enoxaparin should be negligible. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Anticoagulant therapy, thrombolytic therapy

    Enoxaparin should be used with caution in patients receiving other anticoagulant therapy (e.g., warfarin), thrombolytic therapy (e.g., alteplase, reteplase, streptokinase), and/or platelet inhibitors (e.g., aspirin, ticlopidine), or NSAIDs, due to the potential increased risk of bleeding. If coadministration of these agents with enoxaparin continues, patients should be closely monitored.

    Dialysis, renal failure, renal impairment

    Use enoxaparin cautiously in patients with renal impairment (CrCl less than 30 mL/min) or renal failure. These patients may have delayed elimination of enoxaparin. A linear relationship between anti-factor Xa plasma clearance and creatinine clearance at steady-state has been observed, indicating reduced enoxaparin clearance and increased anticoagulant exposure in patients with renal impairment. In patients receiving hemodialysis (dialysis), the AUC appears to be 2-fold higher than the control population. Patients with renal impairment should be observed carefully for signs and symptoms of bleeding. Although no dosage adjustment is recommended in patients with mild to moderate renal impairment, severe renal impairment requires dosage adjustment and cautious monitoring. Monitoring of anti-Xa activity is prudent during enoxaparin therapy in patients with renal impairment, especially in patients receiving chronic therapy. Patients with renal impairment should be observed carefully for signs and symptoms of bleeding during enoxaparin therapy. In addition, hyperkalemia has been associated with enoxaparin treatment in patients with renal failure.

    Geriatric

    When treating geriatric patients, careful attention to enoxaparin dosing intervals and concomitant medications (especially antiplatelet medications) is advised. The risk of enoxaparin-associated bleeding increased with age. Serious adverse events increased with age for patients receiving enoxaparin. Monitoring of geriatric patients with low body weight (less than 45 kg) and those predisposed to decreased renal function should be considered. The incidence of bleeding complications is higher in geriatric patients as compared to younger adult patients when enoxaparin is given at doses of 1.5 mg/kg once daily or 1 mg/kg every 12 hours. In addition, an increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight females (less than 45 kg) and low-weight males (less than 57 kg); the increase is greater in low-weight females. Geriatric and low-weight patients should be observed carefully for signs and symptoms of bleeding. Furthermore, because of the increased risk of bleeding, when using for the acute treatment of ST-segment elevation myocardial infarction (STEMI), elderly patients should receive a reduced dosage of enoxaparin. According to the Beers Criteria, the dose of enoxaparin should be reduced in geriatric patients with a creatinine clearance (CrCl) less than 30 mL/minute due to an increased risk of bleeding.

    Obesity

    Obesity places patients at higher risk for thromboembolism. The safety and efficacy of enoxaparin in obese patients (BMI greater than 30 kg/m2) have not been established, and a consensus regarding dose adjustments in these patients is not available.[29732] Although monitoring of low molecular weight heparin (LMWH) in adults is typically not necessary, some authorities suggest monitoring be done in obese patients. A negative correlation exists between total body weight and anti-Xa concentrations when enoxaparin is used in fixed doses for thromboprophylaxis in obese patients. However, when administered in doses based on total body weight up to 144 kg, anti-Xa activity appears to increase to appropriate therapeutic concentrations.[51288] Carefully monitor obese patients for signs and symptoms of thromboembolism during treatment with enoxaparin.[29732]

    Infants, neonates

    Benzyl alcohol, which is used as a preservative in multiple-dose vials of enoxaparin, can cause a gasping syndrome in neonates and low birth weight infants; avoid the use of this formulation in these populations. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.[29732]

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Epidural or spinal hemorrhage and subsequent hematomas can occur in patients receiving enoxaparin while epidural or spinal anesthesia/analgesia or spinal puncture procedures are performed. The bleeding risk for spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with use of postoperative indwelling epidural catheters, in patients with a history of traumatic or repeated epidural or spinal puncture, a history of spinal deformity, a history of spinal surgery, or concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants. Although the optimal timing between the administration of enoxaparin and neuraxial procedures is not known, if epidural anesthesia, lumbar puncture, or spinal anesthesia is performed, it is best done when the anticoagulant effect of enoxaparin is low. The manufacturer recommends delaying the placement or removal of epidural catheters for at least 12 hours after administration in patients receiving low doses (30 mg twice daily or 40 mg once daily) and at least 24 hours after administration in patients receiving high doses (0.75 to 1 mg/kg twice daily or 1.5 mg/kg once daily). Patients receiving 0.75 mg/kg or 1 mg/kg twice daily should not receive the second enoxaparin dose in the twice daily regimen to allow a longer delay before catheter placement or removal. In patients with severe renal dysfunction (CrCl less than 30 ml/min), consider delaying the placement or removal of epidural catheters for at least 24 hours after administration in adult patients receiving low doses and 48 hours after administration in adult patients receiving high doses because of slower enoxaparin clearance. Although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, the manufacturer recommends considering delaying subsequent enoxaparin doses for at least 4 hours after catheter removal. If neuraxial procedures are employed, monitor patients frequently for symptoms of neurological impairment such as midline back pain, sensory and motor deficits, and bowel and/or bladder dysfunction. Consider the risk versus benefit of neuraxial intervention in patients anticoagulated or to be anticoagulated. If neurological compromise is noted, urgent treatment is necessary; however, such treatment may not prevent or reverse neurological sequelae. In addition, monitor patients closely for a fall in hematocrit and/or a fall in blood pressure, hematuria, hematemesis, and other signs or symptoms of bleeding. To minimize bleeding risk, periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. When administered at recommended prophylaxis doses, routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are relatively insensitive measures of enoxaparin activity and, therefore, unsuitable for monitoring. Monitor anti-factor Xa concentrations to assess the anticoagulant effect of enoxaparin.

    ADVERSE REACTIONS

    Severe

    bleeding / Early / 0-13.0
    heart failure / Delayed / 1.0-1.0
    intracranial bleeding / Delayed / 0.8-0.8
    pulmonary edema / Early / 0.7-0.7
    atrial fibrillation / Early / 0.7-0.7
    retroperitoneal bleeding / Delayed / Incidence not known
    spinal hematoma / Delayed / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 0-16.0
    hematoma / Early / 0-9.0
    elevated hepatic enzymes / Delayed / 5.9-6.1
    peripheral edema / Delayed / 3.0-6.0
    dyspnea / Early / 3.3-3.3
    thrombocytopenia / Delayed / 0.1-2.8
    confusion / Early / 2.2-2.2
    hematuria / Delayed / 0-2.0
    edema / Delayed / 2.0-2.0
    bullous rash / Early / Incidence not known
    erythema / Early / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known

    Mild

    fever / Early / 5.0-8.0
    ecchymosis / Delayed / 0-3.0
    nausea / Early / 2.5-3.0
    diarrhea / Early / 2.2-2.2
    pruritus / Rapid / Incidence not known
    vesicular rash / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    headache / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    Alteplase: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Antithrombin III: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving low molecular weight heparins (LMWHs) concomitantly. The anticoagulant effect of LMWHs is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the LMWH dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA; Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with enoxaparin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Caplacizumab: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dabigatran: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Dalteparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with enoxaparin. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk of bleeding.
    Danaparoid: (Severe) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with enoxaparin. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk of bleeding.
    Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Moderate) Any agent which may enhance the risk of hemorrhage (e.g., enoxaparin) should generally be discontinued before initiating desirudin therapy. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Diclofenac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
    Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Esomeprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Etodolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Famotidine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Flurbiprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue enoxaparin before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Hydrocodone; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as enoxaparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Indomethacin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-n3: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ketoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lepirudin: (Major) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Meclofenamate Sodium: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone: (Major) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. Consider an alternative to mifepristone in these circumstances. When mifepristone is used chronically for other conditions, such as Cushing's disease, an interaction with low-molecular weight heparins is not expected; however, follow usual cautions and monitor as per standard of care.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Sumatriptan: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
    Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like enoxaparin, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Palifermin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
    Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with pentosan. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk of bleeding.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Pimozide: (Major) Concurrent use of pimozide with CYP1A2 inhibitors such as enoxacin should be avoided if possible. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Piperacillin: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piroxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Based on the mechanism of actions of prasugrel and unfractionated heparin or low-molecular weight heparins (LMWHs), patients receiving these medications in combination may be at increased risk of bleeding. The concurrent use of prasugrel and a single 100 unit/kg intravenous dose of heparin did not disrupt coagulation or the inhibition of platelet aggregation; however, the bleeding time increased compared with monotherapy of either medication. Use caution when administering prasugrel with medications that may increase the risk of bleeding, such as unfractionated heparin or LMWH.
    Reteplase, r-PA: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with enoxaparin; the safety of concomitant use has not been studied. If enoxaparin is used during therapeutic transition periods, closely observe patients, and promptly evaluate any signs or symptoms of blood loss. In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetic parameters of rivaroxaban.
    Rofecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
    Selective serotonin reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like low molecular weight heparins. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like enoxaparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with anticoagulants, including low-molecular weight heparins (LMWHs), especially if used within the 3 weeks prior to the procedure.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Spironolactone: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Streptokinase: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Tenecteplase: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Thrombolytic Agents: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Ticagrelor: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such low-molecular weight heparins (LMWHs). No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticlopidine: (Moderate) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
    Tinzaparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with enoxaparin. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk of bleeding.
    Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
    Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Tolmetin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Urokinase: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other agents known to increase the risk of bleeding such as thrombolytic agents (e.g. alteplase, reteplase, streptokinase). Monitor clinical and laboratory response closely during concurrent use.
    Valdecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
    Warfarin: (Moderate) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    Benzyl alcohol can cross the placenta, thus multiple-dose vials of enoxaparin (contain 1.5% benzyl alcohol) should be used with caution during pregnancy, and only if clearly needed. It is recommended to use preservative-free enoxaparin when possible in pregnant women. No well-controlled studies exist in pregnant women. Enoxaparin was found to cross the placenta in animal studies. The rate of major congenital anomalies in a retrospective, cohort study involving 693 live births was 2.5%; similar to estimated background risk in the general population. Sixty-three women experienced 72 hemorrhagic events; 11 were classified as serious. In addition, there were 14 neonatal, hemorrhagic cases. Several reports have described the use of enoxaparin during pregnancy without fetal or maternal complications.[25683] There have been reports of congenital anomalies including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defect, when women received enoxaparin during pregnancy. A cause and effect relationship has not been established nor has the incidence been shown to be higher than in the general population. Fetal death has been reported with post-marketing use of enoxaparin in pregnant women; causality for these cases has not been determined. Pregnant women, similar to other patient populations, receiving anticoagulants, including enoxaparin, are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving enoxaparin should be carefully monitored, especially women with lupus anticoagulant or antiphospholipid antibody syndrome who have a history of fetal loss. According to the manufacturer, it is not known if dosage adjustment or anti-factor Xa monitoring is needed during general pregnancy (in pregnant women without prosthetic valves). Pregnant women and women of child-bearing potential should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. In addition, one case of hyperlipidemia with hypertriglyceridemia in a diabetic pregnant woman receiving enoxaparin has been reported; causality is uncertain. In a clinical study of pregnant women with prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. There are post-marketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. These events resulted in maternal death or surgical interventions. Enoxaparin has not been adequately studied for thromboprophylaxis in pregnant women with prosthetic heart valves; however, the 2004 ACCP guidelines do recommend using LMWH in pregnant women with prosthetic heart valves requiring anticoagulation therapy.[32598] Pregnant women with prosthetic heart valves may be at higher risk for thromboembolism, and have a higher rate of fetal loss from stillbirth, spontaneous abortion, and premature delivery. Frequent monitoring of peak and trough anti-factor Xa levels, and follow up enoxaparin dosage adjustments may be needed for patients with mechanical valves, especially pregnant women. Compared with unfractionated heparin, low molecular weight heparins (LMWHs) may have advantages in pregnant women because they cause less heparin-induced thrombocytopenia and may be less likely to produce osteoporosis; the 2004 ACCP guidelines indicate that because of these reasons, LMWH are the preferred drugs for the treatment of acute venous thromboembolism (VTE) in pregnancy. The treatment of acute venous thromboembolism in pregnancy requires weight-adjusted dosing, but optimal dose regimens have not been established; however, because the half-life of enoxaparin is decreased in pregnancy, twice daily dosing is preferred for acute VTE treatment.[32598] Teratogenic effects have not been demonstrated in animals.[25683]

    According to the manufacturer, it is unknown if enoxaparin is excreted into breast milk. The manufacturer recommends caution when using enoxaparin in women who are breast-feeding. However, because of the relatively high molecular weight of enoxaparin, excretion is expected to be minimal. Also, because of inactivation by the GI tract on oral ingestion, any potential risk to a nursing infant posed by enoxaparin should be negligible. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Enoxaparin exerts its antithrombotic activity by binding to and accelerating the activity of antithrombin III (AT III). The interaction with antithrombin is mediated by a unique pentasaccharide sequence distributed along the heparin chains. Only 15% to 25% of the chains of enoxaparin contain this pentasaccharide sequence, compared with about one-third of the chains of unfractionated heparin (UFH). By activating antithrombin, coagulation factor Xa and factor IIa (thrombin) are inhibited. Enoxaparin and other low molecular weight heparins (LMWHs) are more selective inhibitors of factor Xa than UFH. Although any pentasaccharide chain can inhibit factor Xa, only those at least 18 saccharide units long can inactivate thrombin, since a long chain is required to form a ternary complex between heparin, antithrombin, and thrombin. Although most of the chains of UFH are at least 18 saccharide units long, less than 50% of those of enoxaparin and other LMWHs are of adequate length to bind both antithrombin and thrombin (factor IIa). Therefore, the anti-factor Xa:anti-factor IIa inhibitory ratio of enoxaparin is 2 to 4:1, compared to 1:1 for UFH. Ultimately, thrombin inhibition prevents the formation of fibrin clots. At recommended doses, enoxaparin does not significantly affect platelet activity, prothrombin time (PT) or activated partial thromboplastin time (aPTT).

    PHARMACOKINETICS

    Enoxaparin is administered by subcutaneous or intravenous (IV) injection. Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. A significant route of elimination for enoxaparin is renal, which appears to be dose-independent. After IV radiolabeled enoxaparin, 40% of total radioactivity and 8% to 20% of anti-Factor Xa is recovered in the urine within 24 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intravenous Route

    A 30 mg IV bolus immediately followed by 1 mg/kg subcutaneously every 12 hours provides initial peak anti-factor Xa concentrations of 1.16 International Units/mL and average exposure corresponding to 84% of steady-state concentrations. After IV dosing, the total body clearance of enoxaparin in adults is 26 mL/minute. Results of a small (n = 7) retrospective study in critically ill pediatric patients indicates the peak anti-factor Xa concentrations may occur sooner after IV dosing (1 to 2 hours) vs. subcutaneously dosing (4 to 6 hours).

    Subcutaneous Route

    Based on anti-factor Xa activity, mean absolute bioavailability in adults after 1.5 mg/kg subcutaneously is approximately 100%. Peak plasma anti-factor Xa activity occurs 3 to 5 hours after subcutaneous injection. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy adult volunteers, steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen in adults, steady-state is reached from day 4 with mean exposure about 65% higher than after a single dose and mean peak and trough serum concentrations of about 1.2 and 0.52 International Units/mL, respectively. Based on enoxaparin pharmacokinetics, this difference in steady-state is expected, and is within the therapeutic range. The elimination half-life of enoxaparin in adults based on anti-factor Xa activity is 4.5 hours after a single subcutaneous dose, and may increase to 7 hours after repeated dosing. Following a 40 mg subcutaneous dose of enoxaparin in adults, significant anti-factor Xa activity persists in plasma for about 12 hours; the apparent clearance of subcutaneous enoxaparin is 15 mL/minute.