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Acute coronary syndromes: Unstable angina (UA), non-ST-elevation (NSTEMI), and ST-elevation myocardial infarction (STEMI)
DVT prophylaxis: Following hip or knee replacement surgery, abdominal surgery, or in medical patients with severely-restricted mobility during acute illness who are at risk for thromboembolic complications. Note: Patients at risk of thromboembolic complications who undergo abdominal surgery 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
DVT treatment (acute): Inpatient treatment (patients with or without pulmonary embolism) and outpatient treatment (patients without pulmonary embolism)
Hypersensitivity to enoxaparin, heparin, pork products, or any component of the formulation (including benzyl alcohol in multiple-dose vials); thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin; active major bleeding
Canadian labeling: Additional contraindications (not in U.S. labeling): Use of multiple-dose vials in newborns or premature neonates; history of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia; acute or subacute bacterial endocarditis; major blood clotting disorders; active gastric or duodenal ulcer; hemorrhagic cerebrovascular accident (except if there are systemic emboli); severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; other conditions or diseases involving an increased risk of hemorrhage; injuries to and operations on the brain, spinal cord, eyes, and ears; spinal/epidural anesthesia when repeated dosing of enoxaparin (1 mg/kg every 12 hours or 1.5 mg/kg daily) is required, due to increased risk of bleeding.
Note: Use of enoxaparin in patients with current heparin-induced thrombocytopenia (HIT) or HIT with thrombosis is not recommended and considered contraindicated due to high cross-reactivity to heparin-platelet factor-4 antibody (Guyatt [ACCP], 2012; Warkentin, 1999).
Epidural or spinal hematomas may occur in patients who are anticoagulated with LMWHs or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures.
Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, and other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; and a history of spinal deformity or spinal surgery. Optimal timing between the administration of enoxaparin and neuraxial procedures is not known.
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
Note: One mg of enoxaparin is equal to 100 units of anti-Xa activity (World Health Organization First International Low Molecular Weight Heparin Reference Standard). Weight-based doses (eg, 1 mg/kg) are commonly rounded to the nearest 10 mg; also see institution-specific rounding protocols if available. Most available prefilled syringes are graduated in 10 mg increments.
DVT prophylaxis: SubQ:
Obesity: Note: In morbidly-obese patients (BMI ≥40 kg/m2), increasing the prophylactic dose by 30% may be appropriate for some indications (Nutescu, 2009). For bariatric surgery, dose increases may be >30% based on clinical trial data.
Abdominal surgery: 40 mg once daily, with initial dose given 2 hours prior to surgery; continue until risk of DVT has diminished (usually 7 to 10 days).
Hip replacement surgery:
Twice-daily dosing: 30 mg every 12 hours, with initial dose within 12 to 24 hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt, 2012).
Once-daily dosing: 40 mg once daily, with initial dose within 9 to 15 hours before surgery, and daily for at least 10 days (or up to 35 days postoperatively) or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt, 2012).
Knee replacement surgery: 30 mg every 12 hours, with initial dose within 12 to 24 hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. The American College of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested (Guyatt, 2012).
Medical patients with severely-restricted mobility during acute illness: 40 mg once daily; continue until risk of DVT has diminished (usually 6 to 11 days).
Bariatric surgery (off-label use): Roux-en-Y gastric bypass: Appropriate dosing strategies have not been clearly defined (Borkgren-Okonek, 2008; Scholten, 2002):
BMI ≤50 kg/m2: 40 mg every 12 hours
BMI >50 kg/m2: 60 mg every 12 hours
Note: The 2013 AACE/TOS/ASMBS bariatric surgery guidelines recommend, along with early ambulation, both sequential compression devices and subcutaneous LMWH or unfractionated heparin administered within 24 hours after surgery with consideration of extended prophylaxis for those who are at high risk for VTE (eg, history of DVT) (AACE/TOS/ASMBS [Mechanick, 2013]).
Prevention of recurrent venous thromboembolism in pregnancy (off-label use): 40 mg once daily. Therapy should continue for 6 weeks postpartum in high-risk women (Bates, 2012).
DVT treatment (acute): SubQ: Note: Start warfarin on the first or second treatment day and continue enoxaparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days) (Guyatt, 2012).
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.
Obesity: Use actual body weight to calculate dose; dose capping not recommended; use of twice daily dosing preferred (Nutescu, 2009)
Pregnant women (off-label use): 1 mg/kg/dose every 12 hours. Discontinue ≥24 hours prior to the induction of labor or cesarean section. Enoxaparin therapy may be substituted with heparin near term. Continue anticoagulation therapy for ≥6 weeks postpartum (minimum duration of therapy: 3 months). LMWH or heparin therapy is preferred over warfarin during pregnancy (Bates, 2012).
Percutaneous coronary intervention (PCI), adjunctive therapy (off-label dosing) (ACCF/AHA/SCAI [Levine, 2011]): IV:
If patient undergoing PCI has been treated with multiple doses of enoxaparin and PCI occurs within 8 hours after the last SubQ enoxaparin dose: No additional enoxaparin is needed.
If PCI occurs 8 to 12 hours after the last SubQ enoxaparin dose or the patient received only 1 therapeutic SubQ dose (eg, 1 mg/kg): Administer a single IV dose of 0.3 mg/kg.
If PCI occurs >12 hours after the last SubQ dose: May use an established anticoagulation regimen (eg, full-dose unfractionated heparin or bivalirudin).
If patient has not received prior anticoagulant therapy: 0.5 to 0.75 mg/kg IV bolus dose
ST-elevation MI (STEMI):
Patients <75 years of age: Initial: 30 mg IV single bolus plus 1 mg/kg (maximum: 100 mg for the first 2 doses only) SubQ every 12 hours. The first SubQ dose should be administered with the IV bolus. Maintenance: After first 2 doses, administer 1 mg/kg SubQ every 12 hours.
Patients ≥75 years of age: Initial: SubQ: 0.75 mg/kg every 12 hours (Note: No IV bolus is administered in this population); a maximum dose of 75 mg is recommended for the first 2 doses. Maintenance: After first 2 doses, administer 0.75 mg/kg SubQ every 12 hours
Obesity: Use weight-based dosing; a maximum dose of 100 mg is recommended for the first 2 doses (Nutescu, 2009)
Additional notes on STEMI treatment: Therapy may be continued for up to 8 days or until revascularization. Unless contraindicated, all patients should receive aspirin (indefinitely) and clopidogrel (ACCF/AHA [OGara, 2013]). In patients with STEMI receiving thrombolytics, initiate enoxaparin dosing between 15 minutes before and 30 minutes after fibrinolytic therapy.
Mechanical heart valve (aortic or mitral position) to bridge anticoagulation (off-label use): SubQ: 1 mg/kg every 12 hours (ACCP [Douketis, 2012]). Note: If used in pregnant patients, target anti-Xa level of 0.8 to 1.2 units/mL, 4 to 6 hours postdose (AHA/ACC [Nishimura, 2014]).
Unstable angina or non-ST-elevation MI (NSTEMI): SubQ: 1 mg/kg every 12 hours in conjunction with oral aspirin therapy; continue for the duration of hospitalization (a minimum of at least 2 days) or up to 8 days (ACCF/AHA [Anderson, 2013])
Obesity: Use actual body weight to calculate dose; dose capping not recommended (Nutescu, 2009)
Conversion:
Conversion from IV unfractionated heparin (UFH) infusion to SubQ enoxaparin (Nutescu, 2007): Calculate specific dose for enoxaparin based on indication, discontinue UFH and begin enoxaparin within 1 hour.
Conversion from SubQ enoxaparin to IV UFH infusion (Nutescu, 2007): Discontinue enoxaparin, calculate specific dose for IV UFH infusion based on indication, omit heparin bolus/loading dose:
Converting from SubQ enoxaparin dosed every 12 hours: Start IV UFH infusion 10 to 11 hours after last dose of enoxaparin
Converting from SubQ enoxaparin dosed every 24 hours: Start IV UFH infusion 22 to 23 hours after last dose of enoxaparin
SubQ: Refer to adult dosing. Increased incidence of bleeding with doses of 1.5 mg/kg/day or 1 mg/kg every 12 hours; injection-associated bleeding and serious adverse reactions are also increased in the elderly. Careful attention should be paid to elderly patients, particularly those <45 kg. Note: Dosage alteration/adjustment may be required.
Note: One mg of enoxaparin is equal to 100 units of anti-Xa activity (World Health Organization First International Low Molecular Weight Heparin Reference Standard).
Thromboembolism (off-label use; Monagle, 2012): SubQ:
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:
Enoxaparin Pediatric Dosage Titration1Anti-Xa Result
Dose Titration
Time to Repeat Anti-Xa
Measurement
1Nomogram to be used for treatment dosing.
Modified from Duplaga BA, et al, "Dosing and Monitoring of Low-Molecular-Weight Heparins in Special Populations, " ¯ Pharmacotherapy, 2001, 21(2):218-34.
<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 anti-Xa is 0.5 units/mL, then decrease dose by 40%
Before next dose and every 12 h until anti-Xa <0.5 units/mL
Table has been converted to the following text.
Enoxaparin Pediatric Dosage Titration1
Anti-Xa <0.35 units/mL:
Increase dose by 25%; repeat anti-Xa level 4 hours after next dose
Anti-Xa 0.35-0.49 units/mL:
Increase dose by 10%; repeat anti-Xa level 4 hours after next dose
Anti-Xa 0.5-1 unit/mL:
Keep same dosage; repeat anti-Xa level next day, then1 week later, then monthly (4 hours after dose)
Anti-Xa 1.1-1.5 units/mL:
Decrease dose by 20%; repeat anti-Xa level before next dose
Anti-Xa 1.6-2 units/mL:
Hold dose for 3 hours and decrease dose by 30%; repeat anti-Xa level before next dose, then 4 hours after next dose
Anti-Xa >2 units/mL:
Hold all doses until anti-Xa is 0.5 units/mL, then decrease dose by 40%; repeat anti-Xa level before next dose and every 12 hours until anti-Xa <0.5 units/mL
1Nomogram to be used for treatment dosing
Modified from Duplaga BA, et al, "Dosing and Monitoring of Low-Molecular-Weight Heparins in Special Populations, " ¯ Pharmacotherapy, 2001, 21(2):218-34.
CrCl ≥30 mL/minute: No specific adjustment recommended (per manufacturer); monitor closely for bleeding.
CrCl <30 mL/minute:
DVT prophylaxis in abdominal surgery, hip replacement, knee replacement, or in medical patients during acute illness: SubQ: 30 mg once daily. Note: The Canadian labeling recommends 20 to 30 mg once daily (based on risk/benefit assessment) for prophylaxis in abdominal or colorectal surgery or in medical patients during acute illness.
DVT treatment (inpatient or outpatient treatment in conjunction with warfarin): SubQ: 1 mg/kg once daily
STEMI:
<75 years: Initial: IV: 30 mg as a single dose with the first dose of the SubQ maintenance regimen administered at the same time as the IV bolus; Maintenance: SubQ: 1 mg/kg once daily. Note: Canadian labeling recommends a maximum dose of 100 mg for the first SubQ dose.
≥75 years of age: Omit IV bolus; Maintenance: SubQ: 1 mg/kg once daily. Note: Canadian labeling recommends a maximum dose of 100 mg for the first SubQ dose.
Unstable angina, NSTEMI: SubQ: 1 mg/kg once daily
Dialysis: Enoxaparin has not been FDA approved for use in dialysis patients. Its 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 levels frequently monitored, as accumulation may occur with repeated doses. Many clinicians would not use enoxaparin in this population especially without timely anti-Xa levels.
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Significant drug removal is unlikely based on physiochemical characteristics.
There are no dosage adjustments provided in the manufacturer 's labeling (has not been studied); use with caution.
Note: Enoxaparin is available in 100 mg/mL and 150 mg/mL concentrations.
SubQ: Administer by deep SubQ injection alternating between the left or right anterolateral and left or right posterolateral abdominal wall. Do not mix with other infusions or injections. In order to minimize bruising, do not rub injection site. To avoid loss of drug from the 30 mg and 40 mg prefilled syringes, do not expel the air bubble from the syringe prior to injection.
IV: STEMI and PCI only: The U.S. labeling recommends using the multiple-dose vial to prepare IV doses. The Canadian labeling recommends either the multiple-dose vial or a prefilled syringe. Do not mix or coadminister with other medications; may be administered with NS or D5W. Flush IV access site with a sufficient amount of NS or D5W prior to and following IV bolus administration. When used prior to percutaneous coronary intervention or as part of treatment for ST-elevation myocardial infarction (STEMI), a single dose may be administered IV except when the patient is ≥75 years of age and is experiencing STEMI then only administer by SubQ injection.
Store at 25 ‚ °C (77 ‚ °F); excursions permitted to 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F); do not freeze. Do not store multiple-dose vials for >28 days after first use.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection, as sodium:
Lovenox: 300 mg/3 mL (3 mL) [contains benzyl alcohol, pork (porcine) protein]
Generic: 300 mg/3 mL (3 mL)
Solution, Subcutaneous, as sodium [preservative free]:
Lovenox: 30 mg/0.3 mL (0.3 mL); 40 mg/0.4 mL (0.4 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL); 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL) [contains pork (porcine) protein]
Generic: 30 mg/0.3 mL (0.3 mL); 40 mg/0.4 mL (0.4 mL); 60 mg/0.6 mL (0.6 mL); 80 mg/0.8 mL (0.8 mL); 100 mg/mL (1 mL); 120 mg/0.8 mL (0.8 mL); 150 mg/mL (1 mL)
Stable in D5W, NS; do not mix with other injections or infusions.
5-ASA Derivatives: May enhance the adverse/toxic effect of Heparin (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Monitor therapy
ACE Inhibitors: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Aliskiren: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Aliskiren. Monitor therapy
Angiotensin II Receptor Blockers: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy
Antithrombin: May enhance the anticoagulant effect of Heparin (Low Molecular Weight). Monitor therapy
Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Canagliflozin: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Canagliflozin. Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy
Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination
Eplerenone: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone. Monitor therapy
Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy
Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification
Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Palifermin: Heparin (Low Molecular Weight) may increase the serum concentration of Palifermin. Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Pentoxifylline: May enhance the anticoagulant effect of Heparin (Low Molecular Weight). Monitor therapy
Potassium Salts: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts. Monitor therapy
Potassium-Sparing Diuretics: Heparin (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. Monitor therapy
Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination
Platelets, occult blood, anti-Xa levels, serum creatinine; monitoring of PT and/or aPTT is not necessary. Routine monitoring of anti-Xa levels is not required, but has been utilized in patients with obesity and/or renal insufficiency. Monitoring anti-Xa levels is recommended in pregnant women receiving therapeutic doses of enoxaparin or when receiving enoxaparin for the prevention of thromboembolism with mechanical heart valves (Guyatt, 2012). For patients >190 kg, if anti-Xa monitoring is available, adjusting dose based on anti-Xa levels is recommended; if anti-Xa monitoring is unavailable, reduce dose if bleeding occurs (Nutescu, 2009). Monitor obese patients closely for signs/symptoms of thromboembolism.
As with all anticoagulants, bleeding is the major adverse effect of enoxaparin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables. At the recommended doses, single injections of enoxaparin do not significantly influence platelet aggregation or affect global clotting time (ie, PT or aPTT).
>10%: Hematologic & oncologic: Anemia ( ≤16%), hemorrhage (4% to 13%)
1% to 10%:
Cardiovascular: Peripheral edema (6%)
Central nervous system: Confusion (2%)
Gastrointestinal: Nausea (3%)
Hematologic & oncologic: Major hemorrhage (<1% to 4%; includes cases of intracranial [up to 0.8%], retroperitoneal, or intraocular hemorrhage; incidence varies with indication/population), ecchymoses (3%), thrombocytopenia (1% to 2%)
Hepatic: Increased serum ALT (>3 x ULN: 6%), increased serum AST (>3 x ULN: 6%)
Local: Hematoma at injection site (9%), bleeding at injection site (3% to 5%), pain at injection site (2%)
Renal: Hematuria ( ≤2%)
Miscellaneous: Fever ( ≤8%)
<1% (Limited to important or life-threatening): Acute posthemorrhagic anemia, atrial fibrillation, eosinophilia, epidural hematoma (spinal; after neuroaxial anesthesia or spinal puncture; risk may be increased with indwelling epidural catheter or concomitant use of other drugs affecting hemostasis), hepatic injury (hepatocellular and cholestatic), hyperkalemia, hyperlipidemia (very rare), hypersensitivity angiitis, hypersensitivity reaction, hypertriglyceridemia, osteoporosis (following long-term therapy), pneumonia, pulmonary edema, shock, skin necrosis, thrombocythemia, thrombosis in heparin-induced thrombocyptopenia, thrombosis (prosthetic value [in pregnant females] or associated with enoxaparin-induced thrombocytopenia; can cause limb ischemia or organ infarction)
AUC increased 65% in patients with severe renal impairment (CrCl <30 mL/minute).
The 10-day mean AUC was about 15% higher than the mean day 1 AUC value.
Apparent clearance and maximum observed activity derived from anti " “factor Xa values following subcutaneous dosing were slightly higher in men than in women.
Body weight: Mean AUC of anti " “Factor Xa activity is marginally higher at steady state in obese healthy patients. Anti " “factor Xa exposure was found to be 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg).
Concerns related to adverse effects:
- Bleeding: Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmic surgery; in patients treated concomitantly with platelet inhibitors; recent GI bleeding or ulceration; renal dysfunction and hemorrhage; thrombocytopenia or platelet defects or history of heparin-induced thrombocytopenia; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Discontinue if bleeding occurs. Protamine may be considered as a partial reversal agent in overdose situations (consult Protamine monograph for dosing recommendations). To minimize risk of bleeding following PCI, achieve hemostasis at the puncture site after PCI. If a closure device is used, sheath can be removed immediately. If manual compression is used, remove sheath 6 hours after the last IV/SubQ dose of enoxaparin. Do not administer further doses until 6 to 8 hours after sheath removal; observe for signs of bleeding/hematoma formation.
- Hyperkalemia: Monitor for hyperkalemia; can cause hyperkalemia possibly by suppressing aldosterone production. Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, renal dysfunction, concomitant use of potassium-sparing diuretics or potassium supplements, hematoma in body tissues).
- Thrombocytopenia: Cases of enoxaparin-induced thrombocytopenia and thrombosis (similar to heparin-induced thrombocytopenia [HIT]), some complicated by organ infarction, limb ischemia, or death, have been observed. Use with extreme caution or avoid in patients with history of HIT, especially if administered within 100 days of HIT episode (Warkentin, 2001); monitor platelet count closely. Use is contraindicated in patients with thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin. Discontinue therapy and consider alternative treatment if platelets are <100,000/mm3 and/or thrombosis develops. Use caution in patients with congenital or drug-induced thrombocytopenia or platelet defects.
Disease-related concerns:
- Prosthetic heart valves: Cannot be recommended for long-term thromboprophylaxis in patients with prosthetic heart valves (especially pregnant women) due to insufficient evidence.
- Renal impairment: Use with caution in patients with renal failure; dosage adjustment needed if CrCl <30 mL/minute.
Special populations:
- Elderly: Use with caution in the elderly; delayed elimination may occur. Dosage alteration/adjustment may be required (eg, omission of IV bolus in acute STEMI in patients ≥75 years of age).
- Low weight patients: Risk of bleeding may be increased in women <45 kg and in men <57 kg.
- Obesity: Safety and efficacy of prophylactic dosing of enoxaparin has not been established in patients who are obese (>30 kg/m2) nor is there a consensus regarding dosage adjustments; monitor closely for signs/symptoms of thromboembolism. Anti-Xa levels are increased to appropriate levels when enoxaparin is dosed on actual body weight in obese patients weighing up to 144 kg (Sanderink, 2002). Monitoring of anti-Xa levels 4 hours after the dose may be warranted. The American College of Chest Physicians Practice Guidelines suggest consulting with a pharmacist regarding dosing in bariatric surgery patients and other obese patients who may require higher doses of LMWH (ACCP [Gould, 2012]).
Dosage form specific issues:
- Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and should not be used in pregnant women. In neonates, large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " ¯); the "gasping syndrome " ¯ consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP [Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer 's labeling.
Other warnings/precautions:
- Administration: Do not administer intramuscularly.
- Appropriate use: Surgical patients: Discontinue use 12 to 24 hours prior to CABG and dose with unfractionated heparin per institutional practice (ACCF/AHA [Anderson, 2013]).
- Conversion to other products: Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.
- Neuraxial anesthesia: [U.S. Boxed Warning]: Spinal or epidural hematomas, including subsequent long-term or permanent paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients anticoagulated with LMWH or heparinoids. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis, the use of indwelling epidural catheters, a history of spinal deformity or spinal surgery, as well as a history of traumatic or repeated epidural or spinal punctures. Optimal timing between neuraxial procedures and enoxaparin administration is not known. Delay placement or removal of catheter for at least 12 hours after administration of low-dose enoxaparin (eg, 30 to 60 mg/day) and at least 24 hours after high-dose enoxaparin (eg, 0.75 to 1 mg/kg twice daily or 1.5 mg/kg once daily) and consider doubling these times in patients with creatinine clearance <30 mL/minute; risk of neuraxial hematoma may still exist since antifactor Xa levels are still detectable at these time points. Patients receiving twice daily high-dose enoxaparin should have the second dose withheld to allow a longer time period prior to catheter placement or removal. Upon removal of catheter, consider withholding enoxaparin for at least 4 hours. Patient should be observed closely for bleeding and signs and symptoms of neurological impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia. If neurological compromise is noted, urgent treatment is necessary. If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered although it may not prevent or reverse neurological sequelae.
B
Adverse events were not observed in animal reproduction studies. Low molecular weight heparin (LMWH) does not cross the placenta; increased risks of fetal bleeding or teratogenic effects have not been reported (Bates, 2012).
LMWH is recommended over unfractionated heparin for the treatment of acute venous thromboembolism (VTE) in pregnant women. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant women with certain risk factors (eg, homozygous factor V Leiden, antiphospholipid antibody syndrome with ≥3 previous pregnancy losses). Prophylaxis is not routinely recommended for women undergoing assisted reproduction therapy; however, LMWH therapy is recommended for women who develop severe ovarian hyperstimulation syndrome. LMWH should be discontinued at least 24 hours prior to induction of labor or a planned cesarean delivery. For women undergoing cesarean section and who have additional risk factors for developing VTE, the prophylactic use of LMWH may be considered (Bates, 2012).
LMWH may also be used in women with mechanical heart valves (consult current guidelines for details) (Bates, 2012; Nishimura, 2014). Women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (Bates, 2012). Monitoring antifactor Xa levels is recommended (Bates, 2012; Nishimura, 2014).
Multiple-dose vials contain benzyl alcohol (avoid in pregnant women due to association with gasping syndrome in premature infants); use of preservative-free formulations is recommended.
Standard heparin consists of components with molecular weights ranging from 4000 to 30,000 daltons with a mean of 16,000 daltons. Heparin acts as an anticoagulant by enhancing the inhibition rate of clotting proteases by antithrombin III impairing normal hemostasis and inhibition of factor Xa. Low molecular weight heparins have a small effect on the activated partial thromboplastin time and strongly inhibit factor Xa. Enoxaparin is derived from porcine heparin that undergoes benzylation followed by alkaline depolymerization. The average molecular weight of enoxaparin is 4500 daltons which is distributed as ( ≤20%) 2000 daltons ( ≥68%) 2000 to 8000 daltons, and ( ≤18%) >8000 daltons. Enoxaparin has a higher ratio of antifactor Xa to antifactor IIa activity than unfractionated heparin.
4.3 L (based on antifactor Xa activity)
Hepatic, via desulfation and depolymerization to lower molecular weight molecules with very low biological activity
Urine (40% of dose as active and inactive fragments; 10% as active fragments; 8% to 20% of antifactor Xa activity is recovered within 24 hours)
Clearance: Decreased by 30% in patients with CrCl <30 mL/minute
Peak effect: SubQ: Antifactor Xa and antithrombin (antifactor IIa): 3 to 5 hours
40 mg dose: Antifactor Xa activity: ~12 hours
Plasma: 2 to 4 times longer than standard heparin, independent of dose; based on anti-Xa activity: 4.5 to 7 hours
Does not bind to heparin binding proteins
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea, injection site irritation, or diarrhea. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that you cannot stop), severe dizziness, syncope, a fall hitting head, illogical thinking, severe headache, paresthesia, or loss of strength (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.