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Enoxaparin


Pronunciation

 (ee noks a PA rin)


U.S. Brand Names

 Lovenox®


Synonyms

 Enoxaparin Sodium


Generic Available

 No


Canadian Brand Names

 Lovenox®; Lovenox® HP


Use

DVT Treatment (acute): Inpatient treatment (patients with and without pulmonary embolism) and outpatient treatment (patients without pulmonary embolism)

DVT prophylaxis: Following hip or knee replacement surgery, abdominal surgery, or in medical patients with severely-restricted mobility during acute illness in patients at risk of thromboembolic complications

Note: High-risk patients include those with one or more of the following risk factors: >40 years of age, obesity, general anesthesia lasting >30 minutes, malignancy, history of deep vein thrombosis or pulmonary embolism

Unstable angina and non-Q-wave myocardial infarction (to prevent ischemic complications)


Use - Unlabeled/Investigational

 Prophylaxis and treatment of thromboembolism in children


Pregnancy Risk Factor

 B


Pregnancy Implications

 There are no adequate and well-controlled studies using enoxaparin in pregnant women. Animal studies have not shown teratogenic or fetotoxic effects. Postmarketing reports include congenital abnormalities (cause and effect not established) and also fetal death when used in pregnant women. In addition, prosthetic valve thrombosis, including fatal cases, has been reported in pregnant women receiving enoxaparin as thromboprophylaxis. Multiple-dose vials contain benzyl alcohol; use caution in pregnant women.


Lactation

 Excretion in breast milk unknown/use caution


Contraindications

 Hypersensitivity to enoxaparin, heparin, or any component of the formulation; thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin; hypersensitivity to pork products; active major bleeding; not for I.M. or I.V. use


Warnings/Precautions

 Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis. Consider risk versus benefit prior to neuraxial anesthesia; risk is increased by concomitant agents which may alter hemostasis, as well as traumatic or repeated epidural or spinal puncture. Patient should be observed closely for bleeding if enoxaparin is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia.

Not recommended for thromboprophylaxis in patients with prosthetic heart valves (especially pregnant women). Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins. Use caution in patients with history of heparin-induced thrombocytopenia. Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; use shortly after brain, spinal, or ophthalmology surgery; patients treated concomitantly with platelet inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Monitor platelet count closely. Rare cases of thrombocytopenia have occurred. Manufacturer recommends discontinuation of therapy if platelets are <100,000/mm 3 . Risk of bleeding may be increased in women <45 kg and in men <57 kg. Use caution in patients with renal failure; dosage adjustment needed if Clcr<30 mL/minute. Safety and efficacy in pediatric patients have not been established. Use with caution in the elderly (delayed elimination may occur). Heparin can cause hyperkalemia by affecting aldosterone. Similar reactions could occur with LMWHs. Monitor for hyperkalemia. Multiple-dose vials contain benzyl alcohol (use caution in pregnant women).


Adverse Reactions

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

1% to 10%:

Central nervous system: Fever (5% to 8%), confusion, pain

Dermatologic: Erythema, bruising

Gastrointestinal: Nausea (3%), diarrhea

Hematologic: Hemorrhage (5% to 13%), thrombocytopenia (2%), hypochromic anemia (2%)

Hepatic: Increased ALT/AST

Local: Injection site hematoma (9%), local reactions (irritation, pain, ecchymosis, erythema)

<1% and/or postmarketing case reports (limited to important or life-threatening): Allergic reaction, anaphylactoid reaction, eczematous plaques, hyperlipidemia, hypersensitivity cutaneous vasculitis, hypertriglyceridemia, itchy erythematous patches. pruritus, purpura, skin necrosis, thrombocytosis, urticaria, vesicobullous rash. Retroperitoneal or intracranial bleed (some fatal). Spinal or epidural hematomas can occur following neuraxial anesthesia or spinal puncture, resulting in paralysis. Risk is increased in patients with indwelling epidural catheters or concomitant use of other drugs affecting hemostasis. Prosthetic valve thrombosis, including fatal cases, has been reported in pregnant women receiving enoxaparin as thromboprophylaxis.

Thrombocytopenia with thrombosis: Cases of heparin-induced thrombocytopenia (some complicated by organ infarction, limb ischemia, or death) have been reported.


Overdosage/Toxicology

 Symptoms of overdose include hemorrhage. Protamine sulfate has been used to reverse effects (protamine 1 mg neutralizes enoxaparin 1 mg). Monitor aPTT 2-4 hours after first infusion; consider readministration of protamine (50% of original dose). Note: anti-Xa activity is never completely neutralized (maximum of 60% to 75%). Avoid overdose of protamine.


Drug Interactions

Drugs which affect platelet function (eg, aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel) may potentiate the risk of hemorrhage.

Thrombolytic agents increase the risk of hemorrhage.

Warfarin: Risk of bleeding may be increased during concurrent therapy. Enoxaparin is commonly continued during the initiation of warfarin therapy to assure anticoagulation and to protect against possible transient hypercoagulability.


Ethanol/Nutrition/Herb Interactions

 Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).


Stability

 Store at 15°C to 25°C (59°F to 77°F); do not freeze; do not mix with other injections or infusions


Compatibility

 Stable in NS


Mechanism of Action

 Standard heparin consists of components with molecular weights ranging from 4000-30,000 daltons with a mean of 16,000 daltons. Heparin acts as an anticoagulant by enhancing the inhibition rate of clotting proteases by antithrombin III impairing normal hemostasis and inhibition of factor Xa. Low molecular weight heparins have a small effect on the activated partial thromboplastin time and strongly inhibit factor Xa. Enoxaparin is derived from porcine heparin that undergoes benzylation followed by alkaline depolymerization. The average molecular weight of enoxaparin is 4500 daltons which is distributed as ( 20%) 2000 daltons ( 68%) 2000-8000 daltons, and ( 15%) >8000 daltons. Enoxaparin has a higher ratio of antifactor Xa to antifactor IIa activity than unfractionated heparin.


Pharmacodynamics/Kinetics

Onset of action: Peak effect: SubQ: Antifactor Xa and antithrombin (antifactor IIa): 3-5 hours

Duration: 40 mg dose: Antifactor Xa activity: ~12 hours

Metabolism: Hepatic, to lower molecular weight fragments (little activity)

Protein binding: Does not bind to heparin binding proteins

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

Excretion: Urine (40% of dose; 10% as active fragments)


Dosage

 SubQ:

Infants and Children (unlabeled use):

Infants <2 months: Initial:

Prophylaxis: 0.75 mg/kg every 12 hours

Treatment: 1.5 mg/kg every 12 hours

Infants >2 months and Children 18 years: Initial:

Prophylaxis: 0.5 mg/kg every 12 hours

Treatment: 1 mg/kg every 12 hours

Maintenance: See Dosage Titration table:


Note:

Enoxaparin Pediatric Dosage Titration

Antifactor Xa Dose Titration Time to Repeat Antifactor Xa Level
<0.35 units/mL Increase dose by 25% 4 h after next dose
0.35-0.49 units/mL Increase dose by 10% 4 h after next dose
0.5-1 unit/mL Keep same dosage Next day, then 1 wk later, then monthly
(4 h after dose)
1.1-1.5 units/mL Decrease dose by 20% Before next dose
1.6-2 units/mL Hold dose for 3 h
and decrease dose by 30%		 Before next dose,
then 4 h after next dose
>2 units/mL Hold all doses until
antifactor Xa is 0.5 units/mL,
then decrease dose by 40%		 Before next dose and
every 12 h until
antifactor Xa <0.5 units/mL
Modified from Monagle P, Michelson AD, Bovill E, et al, "Antithrombotic Therapy in Children," Chest , 2001, 119:344S-70S.

Adults:

DVT prophylaxis:

Hip replacement surgery:

Twice-daily dosing: 30 mg twice daily, with initial dose within 12-24 hours after surgery, and every 12 hours until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin.

Once-daily dosing: 40 mg once daily, with initial dose within 9-15 hours before surgery, and daily until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin.

Knee replacement surgery: 30 mg twice daily, with initial dose within 12-24 hours after surgery, and every 12 hours until risk of DVT has diminished (usually 7-10 days).

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

Medical patients with severely-restricted mobility during acute illness: 40 mg once daily; continue until risk of DVT has diminished

DVT treatment (acute): Note: Start warfarin within 72 hours and continue enoxaparin until INR is between 2.0 and 3.0 (usually 7 days).

Inpatient treatment (with or without pulmonary embolism): 1 mg/kg/dose every 12 hours or 1.5 mg/kg once daily.

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

Unstable angina or non-Q-wave MI: 1 mg/kg twice daily in conjunction with oral aspirin therapy (100-325 mg once daily); continue until clinical stabilization (a minimum of at least 2 days)

Elderly: Increased incidence of bleeding with doses of 1.5 mg/kg/day or 1 mg/kg every 12 hours; injection-associated bleeding and serious adverse reactions are also increased in the elderly. Careful attention should be paid to elderly patients <45 kg.

Dosing adjustment in renal impairment: SubQ:

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

Clcr<30 mL/minute:

DVT prophylaxis in abdominal surgery, hip replacement, knee replacement, or in medical patients during acute illness: 30 mg once daily

DVT treatment (inpatient or outpatient treatment in conjunction with warfarin): 1 mg/kg once daily

Unstable angina, non-Q-wave MI (with ASA): 1 mg/kg once daily

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

Hemodialysis: Supplemental dose is not necessary.

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


Administration

 Should be administered by deep SubQ injection to the left or right anterolateral and left or right posterolateral abdominal wall. To avoid loss of drug from the 30 mg and 40 mg syringes, do not expel the air bubble from the syringe prior to injection. In order to minimize bruising, do not rub injection site. An automatic injector (Lovenox EasyInjector™) is available with the 30 mg and 40 mg syringes to aid the patient with self-injections. Note: Enoxaparin is available in 100 mg/mL and 150 mg/mL concentrations.


Monitoring Parameters

 Platelets, occult blood, and anti-Xa activity, if available; the monitoring of PT and/or aPTT is not necessary


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. This drug can only be administered by injection. If self-administered, follow exact directions for injection and needle disposal. You may have a tendency to bleed easily while taking this drug (brush teeth with soft brush, use waxed dental floss, use electric razor, avoid scissors or sharp knives, and potentially harmful activities). Report chest pain; persistent constipation; persistent erection; unusual bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool); pain in joints or back; or redness, swelling, burning, or pain at injection site. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Consult prescriber if breast-feeding.


Anesthesia and Critical Care Concerns/Other Considerations

 Many critically-ill and surgical patients require preventative measures for venous thromboembolism. Low molecular weight heparins (LMWHs) compare favorably to unfractionated heparin in the prevention and treatment of venous thromboembolism. LMWHs are associated with less thrombocytopenia, compared to heparin, and do not require routine therapeutic monitoring.

Obesity/Renal Dysfunction: There is no consensus for adjusting/correcting the weight-based dosage of LMWH for patients who are morbidly obese. Monitoring of antifactor Xa concentration 4 hours after injection may be warranted. Patients who have a reduction in calculated creatinine clearance are at risk of accumulated anticoagulant effect when they are treated with certain LMWHs. All LMWHs may not behave the same in patients with renal dysfunction. Some clinicians monitor anti-Xa levels in patients with Clcr<30 mL/minute.


Cardiovascular Considerations

 Low molecular weight heparins (LMWHs) compare favorably to unfractionated heparin (UFH) in the prevention and treatment of venous thromboembolism. LMWHs are associated with less thrombocytopenia, compared to heparin, and do not require routine therapeutic monitoring. In patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI), the 2002 ACC/AHA guidelines recommend anticoagulation with subcutaneous LMWH or intravenous UFH be added to antiplatelet therapy with aspirin and/or clopidogrel. Enoxaparin is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours (Class IIa recommendation; level of evidence: A). In patients with ST-segment elevation myocardial infarction, most studies are limited to small numbers of patients treated with dalteparin or enoxaparin. Control groups (placebo, UFH), dosing, primary endpoints (composite ones), and bleeding definitions vary. In general, the studies suggest equivalent or superior outcomes with these LMWHs and less major bleeding. Preliminary results of a larger trial comparing prehospital dosing of enoxaparin (30 mg I.V. bolus; 1 mg/kg SubQ twice daily for a maximum of 7 days) versus UFH in patients receiving tenecteplase suggests a higher incidence of major bleeding and intracranial hemorrhage in the enoxaparin group (Wallentin L, 2003). Almost all cases of intracranial hemorrhage were confined to patients >75 years of age. Another ongoing trial will address this safety issue. In the 2004 ACC/AHA guideline for patients with ST-elevation MI (STEMI), a low molecular weight heparin might be considered an acceptable alternative to unfractionated heparin for patients <75 years of age who are receiving fibrinolytic therapy. The patient must have reasonable renal function (serum creatinine <2.5 mg/dL in men and <2 mg/dL in women. Enoxaparin in combination with full-dose tenecteplase is the best studied regimen (Wallentin L, 2003).

Obesity/Renal Dysfunction: There is no consensus for adjusting/correcting the weight-based dosage of LMWH for patients who are morbidly obese. Monitoring of antifactor Xa concentration 4 hours after injection may be warranted. Patients who have a reduction in calculated creatinine clearance are at risk of accumulated anticoagulant effect when they are treated with certain LMWHs. All LMWHs may not behave the same in patients with renal dysfunction. Some clinicians monitor anti-Xa levels for patient with Clcr<30 mL/minute.


Dental Health: Effects on Dental Treatment

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


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause confusion


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

Injection, solution, as sodium [graduated prefilled syringe; preservative free]: 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL); 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)

Injection, solution, as sodium [multidose vial]: 100 mg/mL (3 mL) [contains benzyl alcohol]

Injection, solution, as sodium [prefilled syringe; preservative free]: 30 mg/0.3 mL (0.3 mL); 40 mg/0.4 mL (0.4 mL)


References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction-Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation , 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed August 26, 2004.

Antman EM, Cohen M, Radley D, et al, "Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non-Q-Wave Myocardial Infarction. TIMI 11B-ESSENCE Meta-analysis," Circulation , 1999, 100(15):1602-8.

Antman EM, McCabe CH, Gurfinkel EP, et al, "Enoxaparin Prevents Death and Cardiac Ischemic Events in Unstable Angina/Non-Q-Wave Myocardial Infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 11B Trial," Circulation , 1999, 100(15):1593-601.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Cohen M, Bigonzi F, Le Louer V, et al, "One Year Follow-Up of the ESSENCE Trial (Enoxaparin Versus Heparin in Unstable Angina and Non-Q Wave Myocardial Infarction)," J Am Coll Cardiol , 1998, 31:79A.

Cohen M, Demers C, Gurfinkel EP, et al, "A Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin for Unstable Coronary Artery Disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group," N Engl J Med , 1997, 337(7):447-52.

Farooq V, Hegarty J, Chandrasekar T, et al, "Serious Adverse Incidents With the Usage of Low Molecular Weight Heparins in Patients With Chronic Kidney Disease," Am J Kidney Dis , 2004, 43(3):531-7.

Fox KA, " Low Molecular Weight Heparin (Enoxaparin) in the Management of Unstable Angina: The ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events," Heart , 1999, 82(Suppl 1):112-4.

Gerlach AT, Pickworth KK, Seth SK, et al, "Enoxaparin and Bleeding Complications: A Review in Patients With and Without Renal Insufficiency," Pharmacotherapy , 2000, 20(7):771-5.

Hirsh J, Dalen J, and Guyatt G, et al, "The Sixth (2000) ACCP Guidelines for Antithrombotic Therapy for Prevention and Treatment of Thrombosis. American College of Chest Physicians," Chest , 2001, 119(1 Suppl):346-7.

Monagle P, Michelson AD, Bovill E, et al, "Antithrombotic Therapy in Children," Chest , 2001, 119:344S-70S.

Montalescot G, Philippe F, Ankri A, et al, "Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable Coronary Artery Disease: Beneficial Effects of Enoxaparin. French Investigators of the ESSENCE Trial," Circulation , 1998, 98(4):294-9.

Nagge J, Crowther M, and Hirsh J, "Is Impaired Renal Function a Contraindication to the Use of Low-Molecular Weight Heparin?" Arch Intern Med , 2002, 162(22):2605-9.

Polkinghorne KR, McMahon LP, and Becker GJ, "Pharmacokinetic Studies of Dalteparin (Fragmin), Enoxaparin (Clexane), and Danaparoid Sodium (Orgaran) in Stable Chronic Hemodialysis Patients," Am J Kidney Dis , 2002, 40(5):990-5.

Reach L, Debure A, de Groc F, et al, "Anticoagulation With Enoxaparin 0.5 mg/kg in 630 Dialysis Sessions," Haemostasis , 1994, 24(Suppl 1):280 [Abstract 281]

Simonneau G, Charbonnier B, Decousus H, et al, "Subcutaneous Low-Molecular-Weight Heparin Compared With Continuous Intravenous Unfractionated Heparin in the Treatment of Proximal Deep Vein Thrombosis," Arch Intern Med , 1993, 153(13):1541-6.

Von Visger J and Magee C, "Low Molecular Weight Heparins in Renal Failure," J Nephrol , 2003, 16(6):914-6.

Wallentin L, Goldstein P, Armstrong PW, et al, "Efficacy amd Safety of Tenecteplase in Combination With the Low-Molecular-Weight Heparin Enoxaparin or Unfractionated Heparin in the Prehospital Setting: The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS Randomized Trial in Acute Myocardial Infarction," Circulation , 2003, 108(2): 135-42.

Wong GC, Giugliano RP, and Antman EM, "Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention," JAMA , 2003, 289:331-42.

Zed PJ, Tisdale JE, and Borzak S, "Low-Molecular-Weight Heparins in the Management of Acute Coronary Syndromes," Arch Intern Med , 1999, 159(16):1849-57.


International Brand Names

 Clexane® (AR, AU, BD, BE, BR, CH, CL, CO, CR, CZ, DE, DO, EC, ES, GB, GT, HN, HR, HU, IE, IL, IN, IT, LU, MX, NL, NZ, PA, PL, RO, RU, SG, SI, SV, TH, TR, YU, ZA); Decipar® (ES); Flunox® (BR); Klexane® (DK, FI, NO, SE); Lovenox® (AT, CA, FR, ID, PT); Lovenox® HP (CA)


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