Enoxaparin

Enoxaparin is an anticoagulant agent belonging to low molecular weight Heparin.

Enoxaparin is a low molecular weight heparin used for the prophylaxis of deep vein thrombosis and ischemic complications of unstable angina and non-Q-wave myocardial infarction.

Rapidly and almost completely absorbed. The bioavailability is approximately 100%. The peak plasma concentrations are about 1-5 hours. The volume of distribution of anti-Factor Xa activity is about 4.3 L. Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg SC once a day dose. Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.

Enoxaparin shows common side effects like Upset stomach, fever, irritation or burning at site of injection.

Enoxaparin is available in the form Injectable Solution.

Enoxaparin is available in India, US, UK, Singapore, Canada, China, Japan, France, Italy, and Australia.

Enoxaparin belonging to the low molecular weight Heparin, acts as an anticoagulant agent.

Enoxaparin binds to antithrombin III, a serine protease inhibitor, forming a complex that irreversibly inactivates factor Xa, which is frequently used to monitor anticoagulation in the clinical setting. Following factor Xa inactivation, enoxaparin is released and binds to other anti-thrombin molecules. Factor IIa (thrombin) is directly inhibited by enoxaparin, however with less potency than unfractionated heparin (UFH). Due to the cascade of effects resulting from enoxaparin binding, thrombin is unable to convert fibrinogen to fibrin and form a clot, preventing thromboembolic events.

The data of onset of action of Enoxaparin is not available.

The duration of Action of Enoxaparin is approximately >12 hours.

The Tmax was found to be approximately 3-5 hours of following the administration of Enoxaparin.

Enoxaparin is available in the form of Injectable solution.

Enoxaparin Injection is given subcutaneously usually once daily or every 12 hours.

Enoxaparin is a low molecular weight heparin used for the prophylaxis of deep vein thrombosis and ischemic complications of unstable angina and non-Q-wave myocardial infarction.

Enoxaparin is an anticoagulant agent belonging to low molecular weight Heparin.

Enoxaparin is a low molecular weight heparin with anticoagulant property. It acts by enhancing the inhibition rate of activated clotting factors including thrombin and factor Xa through its action on antithrombin III.

Enoxaparin is approved for use in the following clinical indications

Enoxaparin is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

Enoxaparin is indicated for:

Enoxaparin, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).

Although not approved, there have been certain off-label indications. These include

Prophylaxis and Treatment of Thrombosis in Pediatrics

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

Subcutaneously: 40 mg once daily; continue for length of hospital stay or until patient is fully ambulatory and risk of venous thromboembolism (VTE) has diminished. Extended prophylaxis beyond acute hospital stay is not routinely recommended; however, in high-risk COVID-19 patients who are discharged from the hospital, some experts would consider extended prophylaxis with a direct oral anticoagulant (eg, rivaroxaban).

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

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

Subcutaneously: 40 mg once daily initiated ≥6 to 10 hours after surgery; continue for the duration of immobilization.

Subcutaneously: 40 mg started 10 to 12 hours before surgery and 40 mg once daily thereafter.

or

Subcutaneously: 40 mg started 2 to 4 hours before surgery and 40 mg once daily thereafter.

or

Subcutaneously: 40 mg once daily started ~12 to 24 hours after surgery.

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

Prophylactic dose: Subcutaneously: 40 mg once every 24 hours.

Intermediate dose: Subcutaneously: 40 mg every 12 hours; however, some experts use an alternative intermediate regimen of 40 mg Subcutaneously once daily, increasing as pregnancy progresses to 1 mg/kg once daily.

Adjusted dose (therapeutic): Subcutaneously: 1 mg/kg every 12 hours; reserved for patients at the highest risk (eg, history of recurrent thrombosis or severe thrombophilia).

Subcutaneously: 40 mg once daily or 30 mg every 12 hours, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved. Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration at the higher end of range (eg, 30 days).

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

Patients ≤65 years of age, ≥50 kg, and CrCl >60 mL/ minute

Non–weight-based dosing: Subcutaneously: 40 mg every 12 hours; consider dose adjustment based on anti-factor Xa level, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Weight-based dosing: Subcutaneously: 0.5 mg/kg every 12 hours; consider dose adjustment based on anti-factor Xa level, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Patients >65 years of age, <50 kg, CrCl 30 to 60 mL/minute, traumatic brain injury, or spine trauma: Subcutaneously: 30 mg every 12 hours; consider dose adjustment based on anti-factor Xa level, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Patients >90 kg: Subcutaneously: 40 mg every 12 hours; dose adjustment based on anti-factor Xa level is recommended, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Patients ≤90 kg: Subcutaneously: 30 mg every 12 hours; dose adjustment based on anti-factor Xa level is recommended, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Subcutaneously: 1 mg/kg every 12 hours (preferred) or 1.5 mg/kg once every 24 hours.

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

Provoked venous thromboembolism: 3 months (provided the provoking risk factor is no longer present).

Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of VTE recurrence and bleeding.

Months 1 to 6: Subcutaneously: Initial: 1 mg/kg every 12 hours or 1.5 mg/kg once daily for a total duration of 3 to 6 months.

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

Subcutaneously: 1 mg/kg every 12 hours. Consider anti-factor Xa monitoring for dose adjustment. For additional information regarding anti-factor Xa monitoring, refer to the Reference Range field.

Prophylaxis of Ischemic Complications of Unstable Angina and Non–Q-Wave Myocardial Infarction

1 mg/kg subcutaneously every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once a day)

Treatment of Acute ST-Segment Elevation Myocardial Infarction

30 mg IV bolus once plus 1 mg/kg subcutaneously once followed by 1 mg/kg subcutaneously every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg for the remaining doses)

Duration of therapy: Optimal duration is unknown, but it is likely to be longer than 8 days.

Prophylaxis and Treatment of Thrombosis in Pediatrics (off-label)

Infants 1 to <2 months

Subcutaneously: 0.75 mg/kg/dose every 12 hours.

Infants ≥2 months, Children, and Adolescents

Subcutaneously: 0.5 mg/kg/dose every 12 hours.

Infants 1 to <2 months

Subcutaneously: 1.5 mg/kg/dose every 12 hours.

Infants ≥2 months, Children, and Adolescents

Subcutaneously: 1 mg/kg/dose every 12 hours.

OR

1 to <3 months

Subcutaneously: 1.8 mg/kg/dose every 12 hours.

3 to 12 months

Subcutaneously: 1.5 mg/kg/dose every 12 hours.

1 to 5 years

Subcutaneously: 1.2 mg/kg/dose every 12 hours.

6 to 18 years

Subcutaneously: 1.1 mg/kg/dose every 12 hours.

Enoxaparin is available in various strengths as 40 mg/0.4 mL; 60 mg/0.6 mL; 80 mg/0.8 mL; 100 mg/mL; 30 mg/0.3 mL; 300 mg/3 mL; 120 mg/0.8 mL; 150 mg/mL.

Enoxaparin is available in the form of Injectable Solution.

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

Venous thromboembolism prophylaxis in trauma patients, moderate to high risk (off-label use): CrCl 50 to 60 mL/minute: Subcutaneously: 30 mg every 12 hours; consider dose adjustment based on anti-factor Xa level, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

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

Venous thromboembolism prophylaxis in trauma patients, moderate to high risk (off-label use): Subcutaneously: 30 mg every 12 hours; consider dose adjustment based on anti-factor Xa level, targeting a peak level of 0.2 to 0.4 units/mL or a trough level of 0.1 to 0.2 units/mL.

Venous thromboembolism prophylaxis (except in trauma patients): Subcutaneously: 30 mg once daily.

Venous thromboembolism prophylaxis in trauma patients, moderate to high risk (off-label use): Use another form of pharmacologic prophylaxis (eg, unfractionated heparin).

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

<75 years of age: Initial: IV: 30 mg as a single dose with the first dose of the Subcutaneously maintenance regimen administered at the same time as the IV bolus; maintenance: Subcutaneously: 1 mg/kg once daily.

≥75 years of age: Omit IV bolus; maintenance: Subcutaneously: 1 mg/kg once daily.

Non-ST-elevation acute coronary syndromes

Subcutaneously: 1 mg/kg once daily.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Enoxaparin is contraindicated in patients with

To minimize risk of bleeding following PCI, achieve hemostasis at the puncture site after PCI. If a closure device is used, sheath can be removed immediately. If manual compression is used, remove sheath 6 hours after the last IV/ Subcutaneously dose of enoxaparin. Do not administer further doses until 6 to 8 hours after sheath removal; observe for signs of bleeding/hematoma formation.

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

Use with extreme caution or avoid in patients with history of HIT. In patients with a history of HIT, use only if >100 days have elapsed since the prior HIT episode and no circulating antibodies are present (HIT may still occur in these patients; assess risk vs benefit and use only after non-heparin alternative treatments are considered). Discontinue therapy and consider alternative treatment if platelets are <100,000/mm3 and/or thrombosis develops.

It is not known whether Enoxaparin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Enoxaparin, a decision should be made whether to discontinue nursing or discontinue Enoxaparin, considering the importance of Enoxaparin to the mother and the known benefits of nursing.

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Enoxaparin to increase the risk of developmental abnormalities above the background risk. Enoxaparin does not cross the placenta and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Enoxaparin does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Anemia, hemorrhage, Peripheral edema, Ecchymoses, Nausea, Hematuria, Major hemorrhage, retroperitoneal, or intraocular hemorrhage, thrombocytopenia, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, bleeding at injection site, hematoma at injection site, pain at injection site, confusion, fever.

Atrial fibrillation, cardiac failure, Pneumonia, pulmonary edema, bruising at injection site, erythema at injection site, irritation at injection site.

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Concurrent use may enhance the anticoagulant effect of Enoxaparin.

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

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

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

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

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

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

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

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

Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants.

Inotersen: May enhance the anticoagulant effect of Anticoagulants.

Kanamycin: May enhance the anticoagulant effect of Anticoagulants.

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

Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants.

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants.

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants.

Nonsteroidal Anti-Inflammatory Agents (Topical): Concurrent use may enhance the anticoagulant effect of Anticoagulants.

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

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

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

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

The common side effects of Enoxaparin include the following

Upset stomach, fever, irritation or burning at site of injection.

Unusual bleeding or bruising, black or bloody stools, blood in urine, swollen ankles and/or feet.

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Enoxaparin to increase the risk of developmental abnormalities above the background risk. Enoxaparin does not cross the placenta and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Enoxaparin does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities.

It is not known whether Enoxaparin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Enoxaparin, a decision should be made whether to discontinue nursing or discontinue Enoxaparin, taking into account the importance of Enoxaparin to the mother and the known benefits of nursing.

As per FDA, safety and effectiveness of Enoxaparin in pediatric patients have not been established.

Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non–Q-Wave Myocardial Infarction

Over 2800 patients, 65 years and older, have received Enoxaparin in clinical trials. The efficacy of Enoxaparin in the geriatric (≥65 years) was like that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once day doses of Enoxaparin were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Enoxaparin was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Enoxaparin-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Enoxaparin. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Enoxaparin between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Enoxaparin should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.

In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n=1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg intravenous bolus prior to the normal dosage regimen and had their subcutaneous dose adjusted to 0.75 mg/kg every 12 hours. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).

The use of Enoxaparin has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves 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 fetal deaths. Insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism

Accidental overdosage following administration of Enoxaparin may lead to hemorrhagic complications. Injected Enoxaparin may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Enoxaparin injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Enoxaparin if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours before the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of Enoxaparin may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the antiFactor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.

This drug has an immediate onset of action. Enoxaparin increases Thrombin Time (TT) and activated partial thromboplastin time (aPTT), preventing and reducing thromboembolic complications such as DVT, pulmonary embolism, and ischemic cardiac complications. Administered at 1.5 mg/kg subcutaneously in a pharmacodynamic study, enoxaparin led to a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ±SD, 14.0±3.1) (based on areas under anti-Factor activity versus time curves) when compared to that of heparin (mean ±SD, 1.22±0.13). Increases in the TT and aPTT were 1.8 times those of the control group. Enoxaparin at 1 mg/kg subcutaneously every 12 hours led to aPTT values of 45 seconds or less in most patients. Average aPTT prolongation time on Day 1 was approximately 16% higher than on Day 4 of enoxaparin therapy. Caution is advised during treatment with enoxaparin - the risk of hemorrhage and thrombocytopenia is increased. In pregnant women with prosthetic mechanic heart valves, the risk of thromboembolism is increased.

Rapidly and almost completely absorbed. The bioavailability is approximately 100%. The peak plasma concentrations are about 1-5 hours.

The volume of distribution of anti-Factor Xa activity is about 4.3 L.

Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26 mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single SC dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg SC once a day dose. Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.

There are some clinical studies of the drug Enoxaparin mentioned below: