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Enoxaparin (Systemic)


VA CLASSIFICATION
Primary: BL111

Commonly used brand name(s): Lovenox; Lovenox HP.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antithrombotic—
Note: Enoxaparin is one of a group of substances known as low molecular weight heparins (LMWHs).



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
The use of low molecular weight heparins (LMWHs) has several advantages compared to heparin. Improved bioavailability at low doses when administered subcutaneously, a longer plasma half-life, and a more predictable anticoagulant response allow for simpler dosing without laboratory monitoring {47} {48}. Studies in animals show that with doses of equivalent antithrombotic effect, LMWHs produce less bleeding than standard heparin {47} {48}. The clinical importance of this observation is uncertain, but may allow the use of higher anticoagulant doses of LMWHs, thereby improving efficacy without compromising safety {47} {48}. The potential advantage of reduced bleeding has been demonstrated in studies in patients receiving high doses for the treatment of venous thrombosis {47} {48} {49} {50}. However, in studies using prophylactic doses, no difference in bleeding has been demonstrated {47} {48} {51} {52}. This contrasting effect may be due to inappropriate dosage regimens in early studies, and the difficulty of measuring hemorrhagic tendencies in humans {53}. LMWHs are associated with a lower incidence of heparin-induced thrombocytopenia, possibly due to reduced effects on platelet function and binding {47} {48} {54}. These advantages must be weighed against the higher cost of the LMWHs, although the simpler dosing regimens used with LMWHs may allow home treatment in selected patients, thereby reducing overall costs and improving patient satisfaction {47} {55} {56} {57}.

Accepted

Thromboembolism, pulmonary (prophylaxis); and
Thrombosis, deep venous (prophylaxis)—Enoxaparin is indicated to prevent deep venous thrombosis (DVT) and to reduce the risk of pulmonary embolism following hip or knee replacement surgery {01} {02} {05} {12} {18} {19} {22} {24}. In addition, following hip replacement surgery, enoxaparin is indicated for extended prophylaxis following hospitalization {01} .1
—Enoxaparin is also indicated to prevent DVT and reduce the risk of pulmonary embolism in patients undergoing abdominal surgery who are at increased risk of thromboembolic complications. Patients at risk include patients who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or patients who have additional risk factors such as malignancy or a history of DVT or pulmonary embolism. {01} {02}
—Enoxaparin is indicated to prevent DVT in patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.{61}{62}
—[Enoxaparin has been shown to be as effective as unfractionated heparin in preventing deep venous thrombosis and is indicated following general surgical procedures, including gynecological, urological and colorectal surgery, that leave the patient immobilized {02} {06} {27} {36} {37} {38} {39} {40} {41} {42} {43} {46} . ]

Thrombosis, deep venous (treatment)—Enoxaparin is indicated for the inpatient treatment of acute deep vein thrombosis with and without pulmonary embolism , and the outpatient treatment of acute deep vein thrombosis without pulmonary embolism, both when administered in conjunction with warfarin sodium.{01}

Thrombosis, coronary arterial, acute (prophylaxis) 1—Enoxaparin is indicated to prevent ischemic complications associated with unstable angina and non–Q-wave myocardial infarction, when concurrently administered with aspirin {01}.

[Unstable angina and non-Q-wave myocardial infarction (treatment)]—Enoxaparin is indicated for the treatment of unstable angina and non-Q-wave myocardial infarction, concurrently with ASA {62}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa {01} {02} {06} {07} {08} {12} {14} {16} {18} {20}.
Molecular weight—
    3500 to 5500 daltons (average 4500 daltons) {01} {02} {12} {19} {20}


pH
    5.5 to 7.5 {01} {02}


Specific activity
    Anti-factor Xa: 100 to 160 International Units (IU) per mg {01} {02} {06} {07} {08} {16} {24}.
    Anti-factor IIa: 20 to 40 IU per mg {07} {08}.

Mechanism of action/Effect:

Enoxaparin, like unfractionated heparin, potentiates the actions of an endogenous inhibitor of blood coagulation, antithrombin III (heparin cofactor) {28}. Antithrombin III combines in a 1:1 molar ratio {29} {30} with activated serine proteases of the intrinsic and common coagulation pathways (primarily thrombin [factor IIa] and factor Xa, and, to a lesser extent, factors IXa, XIa, and XIIa) {29} {30} {31} {32} {33} to form inactive complexes {29} {30}. Enoxaparin binds to antithrombin III, producing a conformational change in the cofactor molecule {07} {19} that results in significantly more rapid binding with and inactivation of the clotting factors than is achieved by the endogenous inhibitor alone {29} {31} {32}.

Enoxaparin acts primarily by increasing antithrombin III–mediated inhibition of the formation and activity of factor Xa. This activity, in turn, reduces thrombin generation. These actions decrease thrombin-mediated events in coagulation, including the conversion of fibrinogen to fibrin, thereby inhibiting fibrin clot formation. Unlike unfractionated heparin, which has an anti-factor Xa (antithrombotic) to anti-factor IIa (anticoagulant) activity ratio of approximately 1 to 1, enoxaparin has an anti-factor Xa to anti-factor IIa activity ratio of approximately 3 to 1. {01} {04} {12} {19} Enoxaparin's higher ratio of antithrombotic to anticoagulant activity is thought to result in an antithrombotic effect equivalent to that of unfractionated heparin with a lower risk of bleeding {14} {19} {24}. However, it has not been consistently demonstrated that the risk of bleeding is lower with enoxaparin than with unfractionated heparin {05} {07} {19} {25} {36} {45}. Enoxaparin also decreases inhibition of platelet function {04} {05} {11} {14} {18} {19} {24} {26} and disrupts vascular permeability {14} {19} to a lesser extent than does unfractionated heparin.


Other actions/effects:

Enoxaparin has been shown to increase the plasma concentration of nonesterified fatty acids, without affecting plasma cholesterol, triglycerides, or phospholipids {02}.

Absorption:

Absorbed rapidly and almost completely following subcutaneous injection {01} {02} {07}, with approximately 92% bioavailability based on anti-Factor Xa activity. {63}

Distribution:

The volume of distribution of anti-Factor Xa activity is about 6 liters. {63}.

Biotransformation:

Hepatic {02} {08}; weakly metabolized by desulfation and depolymerization {02}.

Half-life:

Elimination, based on anti-factor Xa activity—4.5 hours after subcutaneous administration. {63}. May be prolonged in the presence of chronic, severe renal failure {02} {03} {19}.

Time to peak effect:

3 to 5 hours following subcutaneous injection {01} {02} {08} {21}.

Duration of action:

Up to 24 hours following subcutaneous injection {03} {05} {10}. Anti-Factor Xa activity persists in plasma approximately 12 hours following a 40 milligram SC, once a day dose.{63}

Elimination:
    Primarily renal {02} {07} {12} {19}. After intravenously dosing with enoxaparin labeled with the gamma-emmiter, 99mTc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Total body clearance following an intravenous dose is approximately 26 milliliters per minute. Following a subcutaneous (SC) dose of enoxaparin, the apparent clearance (CL/F) is approximately 15 mL per minute. {63}Apparent{63} clearance is decreased approximately 30%{63} in patients with chronic, severe renal failure {02} {07}{63}.

Pharmacokinetic Profile

The following table represents the pharmacokinetic parameters after 5 days of 1.5 mg/kg SC, once daily dosing regimen of enoxaparin using 100 mg/mL or 200 mg/mL concentrations. {63}



Pharmacokinetic Activity  Concentration (mg/mL)  Anti-Xa (IU/mL)  Anti-IIa (IU/mL) 
Amax (IU/mL) or Δ sec   100  1.37 ± 0.23  0.23 ± 0.05 
  200  1.45 0.22  0.26 0.05 
tmax (h)   100  3.0  4.0 
  200  3.5  4.5 
AUC (h*IU/mL) or h*Δ sec  100  14.26 ± 2.93  1.54 ± 0.61 
  200  15.43 ± 2.96  1.77 ± 0.67 
{63}

{63}
* ± SD at Day 5 and 90% confidence interval of the ratio


Precautions to Consider

Cross-sensitivity and/or related problems

Patients with a history of allergies, especially those who are allergic to heparin, or to pork or pork products, may be allergic to this medication also {01} {02} {13} {19}.

Carcinogenicity

The carcinogenic potential of enoxaparin has not been investigated {01}.

Mutagenicity

No mutagenicity was demonstrated in vitro , in the Ames test {01} {02}, mouse lymphoma cell forward mutation test, or human lymphocyte chromosomal aberration test; or in vivo , in the rat bone marrow chromosomal aberration test {01}.

No disruption of chromosomes was demonstrated in vitro , in rat bone marrow cells, or in vivo , in human peripheral lymphocytes {02}.

Pregnancy/Reproduction

Pregnancy—
The use of enoxaparin is not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. In a clinical study, 2 of 7 women with prosthetic heart valves given enoxaparin developed clots resulting in blockage of the valve leading to maternal and fetal death.{63} {64}

Adequate and well-controlled studies in humans have not been done, however pregnant women receiving enoxaparin should be carefully monitored. 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.{63}{64}

Note: In post marketing reports, there have been reports of fetal death and congenital anomalies in infants born to women who received enoxaparin during pregnancy including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defect. A causal relationship has not been established nor has the incidence been shown to be higher than in the general population. {63}{64}
Pregnant women are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus.{63}{64}


No evidence of teratogenicity was found in studies in mice receiving 30 mg per kg of body weight per day or 211 mg per square meter of body surface area per day, or in rabbits receiving 410 mg per square meter of body surface area per day {01}.

FDA Pregnancy Category B {01}.

Breast-feeding

It is not known whether enoxaparin is distributed into breast milk {01} {02}.

Pediatrics

Appropriate studies on the relationship of age to the effects of enoxaparin have not been performed in the pediatric population. Safety and efficacy have not been established. {01} {02}


Geriatrics


Elderly patients, especially females, may be more susceptible than other patients to bleeding during enoxaparin therapy {27} {36} {38} {39} {40} {42} {44} {46}. The risk of associated bleeding and serious adverse events increases with age.{63}. Also, the time to peak concentration and the half-life of enoxaparin may be prolonged in elderly patients {01} {02}. Careful attention to dosing intervals and concomitant mediations (especially antiplatelet medications is advised. Monitoring of elderly patients with low body weight (< 45 kg) and those predisposed to decreased renal function should be considered.{63}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
In addition to the interactions listed below, the possibility should be considered that multiple effects leading to further impairment of blood clotting and/or increased risk of bleeding may occur if enoxaparin is administered to a patient receiving any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage {34}.

Anticoagulants, coumarin- or indandione-derivative    (concurrent use may increase the risk of bleeding)


» Anti-inflammatory drugs, nonsteroidal (NSAIDs) including
ketorolac tromethamineEpidural or spinal hematoma formation have occurred in ongoing safety surveillance since 1993 with concurrent use of enoxaparin and spinal/epidural anesthesia or receiving additional drugs affecting hemostasis such as NSAID's; resulted in neurologic injury, including long term or permanent paralysis.{63}
» Platelet aggregation inhibitors, other (see Appendix II ), especially:
» Aspirin or
» Dipyridamole or
» Salicylates or
» Sulfinpyrazone or
» Ticlopidine    (inhibition of platelet function by these agents may increase the risk of bleeding)

    (hypoprothrombinemia induced by large [antirheumatic] doses of aspirin, and the potential occurrence of gastrointestinal ulceration or hemorrhage during therapy with NSAIDs, aspirin, dipyridamole, salicylates, or sulfinpyrazone, also may increase the risk of bleeding in patients receiving enoxaparin If coadministration is essential, conduct close clinical and laboratory monitoring.{63})


Cefamandole or
Cefoperazone or
Cefotetan or
» Plicamycin or
» Valproic acid    (these medications may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with enoxaparin may increase the risk of hemorrhage and is not recommended)


» Thrombolytic agents, such as:
» Alteplase (tissue-type plasminogen activator, recombinant)
» Anistreplase (anisoylated plasminogen-streptokinase activator complex; APSAC)
» Streptokinase
» Urokinase    (concurrent or sequential use with enoxaparin may increase the risk of bleeding complications {35})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (serum values may be increased {01} {02} {07})


Hemoglobin concentration and
Hematocrit value and
Red blood cell count    (values may be decreased {02} {06} {12})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Abortion, threatened {34} , or
» Aneurysm, cerebral or dissecting aorta, except in conjunction with corrective surgery {34} , or
» Cerebrovascular hemorrhage, confirmed or suspected {01} {02} {24}    (increased risk of uncontrollable hemorrhage)


» Hemorrhage, active uncontrollable {01} {02} {05}
» Hypertension, severe uncontrolled {02} {24}    (increased risk of cerebral hemorrhage)


» Septic shock{62}
» Thrombocytopenia, severe, enoxaparin- or heparin-induced, within past several months {01} {02} {24}    (risk of recurrence, which may cause resistance to enoxaparin and new thromboembolic complications)


Risk-benefit should be considered when the following medical problems exist
Any medical or dental procedure or condition in which the risk of bleeding or hemorrhage is present, such as:
» Anesthesia, epidural or spinal {01}(risk of epidural or spinal hematoma, which can result in long-term or permanent paralysis; this risk is increased with the use of indwelling epidural catheters or by the concomitant use of medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants; the risk may also be increased by traumatic or repeated epidural or spinal puncture. See General Dosing Information for guidelines regarding the use of regional anesthesia in patients receiving perioperative enoxaparin.)
» Blood dyscrasias, hemorrhagic, especially thrombocytopenia, hemophilia, or von Willebrand disease; or other hemorrhagic tendency {01} {02} {05} {06} {18} {24} {25} {36}
» Childbirth, recent {34}
Diabetes, severe {34}
» Endocarditis, acute or subacute bacterial {01} {02}
Gastrointestinal ulceration, history of {01}
Intrauterine contraceptive device, use of {34}
» Neurosurgery, recent or contemplated {01}
» Ophthalmic surgery, recent or contemplated {01}
» Pericarditis or pericardial effusion {34}
Radiation therapy, recent {34}
Renal function impairment, mild to moderate {34}
» Renal function impairment, severe {34}
» Retinopathy, diabetic or hemorrhagic {02}
» Spinal puncture, recent {01}
» Trauma, severe, especially to the central nervous system (CNS) {34}
Tuberculosis, active {34}
» Ulceration or other lesions of the gastrointestinal, respiratory, or urinary tract, active {01} {02} {24}
» Vasculitis, severe {34}
» Wounds resulting in large open surfaces {34}
Hepatic function impairment, mild to moderate {34}
» Hepatic function impairment, severe {34}
Hypertension, mild to moderate {34}    (increased risk of cerebral hemorrhage)


Sensitivity to enoxaparin, heparin {01} {02} {13} {19}, or to pork or pork products{63}
» Prosthetic heart valves    (may lead to prosthetic heart valve thrombosis; pregnant women may be at greater risk; cases of maternal and fetal death have been reported{63}{64})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood coagulation tests    (although enoxaparin, in therapeutic doses, does not alter activated partial thromboplastin time [APTT] {01} {02} {03} {06} {08} {09} {10} {17} {25}, prothrombin time [PT] {01} {02}, or thrombin time {02} test values, these tests should be performed prior to therapy to establish a baseline or control value; also recommended to identify pre-existing coagulation defects and aid in determining whether the patient is a suitable candidate for treatment)


Blood pressure measurement
Hemoglobin concentration and
Hematocrit value    (recommended periodically during therapy {01} {02} {14}; an unexplained fall in the blood pressure or hematocrit may signal occult bleeding {01}; bleeding should be considered major if the hemoglobin concentration is decreased by more than 2 grams per deciliter [20 grams per liter], or if a transfusion of 2 or more units of blood is required {02} {14} {24})


» Neurologic status {01}    (monitor for signs and symptoms of neurologic impairment such as paresthesias, leg weakness, sensory loss, motor deficit, or bowel/bladder dysfunction indicating a potential epidural or spinal hematoma {58}; if neurologic compromise is noted, urgent intervention is necessary, which includes radiographic confirmation and decompressive laminectomy; good or partial recovery is more likely if surgery is performed within 8 hours of the development of paraplegia {58} {59} {60})


» Platelet aggregation test {02}    (recommended prior to initiation of therapy in patients who have developed thrombocytopenia following administration of unfractionated heparin; if the result is negative, enoxaparin therapy may be instituted, with daily monitoring of the platelet count; however, if the result is positive, enoxaparin should not be given)


» Platelet count    (recommended prior to initiation of therapy, then twice weekly for the duration of therapy to detect thrombocytopenia {01} {02})


Stool tests for occult blood loss {01}    (recommended periodically during therapy)




Side/Adverse Effects
Since 1993, there have been over 80 reports of epidural or spinal hematoma formation with concurrent use of enoxaparin injection and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.{63}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention

Note: Surgical procedure may be a contributing factor to the incidence of side effects.

Incidence more frequent
    
Anemia{63} (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness)—which may be severe
    
hemorrhage{63} ( bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath)—which may be severe
    
edema, peripheral {01} {02}{63} (swelling of ankles, feet, fingers)
    
thrombocytopenia (black, tarry stools; bleeding gums; blood in urine or stools; moderate to severe pain or numbness in the arms, legs, hands, feet; pinpoint red spots on skin; unusual bleeding or bruising; )— which may cause gangrene{01}{19}{26}{63}

Incidence less frequent
    
Bleeding complications, which may include blood in urine
bloody or black, tarry stools
bruising
coughing up blood
ecchymosis (large, nonelevated blue or purplish patches in the skin), hematoma (collection of blood under the skin), hypochromic anemia (fatigue; headache; irritability; lightheadedness ), nosebleed
persistent bleeding or oozing from mucous membranes or surgical wound
shortness of breath
vomiting of blood or material that looks like coffee grounds {01}{02}{05}{07}{13}{14}{24}{25}{46}
    
confusion {01} {02}
    
dyspnea{63} (shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
    
edema, central{63} (swelling)
    
hematuria {63}(blood in urine; lower back pain; pain or burning while urinating)
    
hemorrhage at injection site {63}(uncontrolled bleeding at site of injection)
    
organ infarction
pulmonary embolism (chest discomfort ; convulsions; dizziness or lightheadedness when getting up from a lying or sitting position; shortness of breath or fast breathing), and stroke —caused by excessive platelet aggregation{01}{19}{26}

Incidence rare
    
Angioedema {23} (swelling of the face, genitalia, larynx [voice box], mouth, or tongue)
    
atrial fibrillation{63} (fast or irregular heartbeat; dizziness; fainting )
    
cardiovascular toxicity {02} (chest pain; dizziness or lightheadedness when getting up from a lying or sitting position; fast or irregular heartbeat; shortness of breath; sudden fainting)
    
epidural or spinal hematoma (back pain; bowel/bladder dysfunction ; leg weakness; numbness; paralysis; paresthesias)— back pain is not a typical presentation but some patients may experience this symptom{01}{58}
    
heart failure{63}
    
lung edema{63} ( chest pain; chills; cough; fever; general feeling of discomfort or illness; shortness of breath; thickening of bronchial secretions; troubled breathing )
    
pneumonia{63} ( chest pain; cough; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest; wheezing)
    
skin rash or hives {23}

Note: If an epidural or spinal hematoma is suspected, urgent intervention is necessary, which includes radiographic confirmation and decompressive laminectomy. Good or partial recovery is more likely if surgery is performed within 8 hours of the development of paraplegia. {58} {59} {60}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Fever{63}

Incidence less frequent or rare
    
Diarrhea{63}
    
increased menstrual bleeding {46}
    
irritation, pain, or redness at injection site {01} {02} {18}
    
nausea {01}
    
vomiting {02}





Overdose
For specific information on the agents used in the management of enoxaparin overdose, see the Protamine (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Bleeding complications {01} {02} {16}


Note: A single SC dose of 46.4 mg per kg enoxaparin was lethal to rats. The symptoms of acute toxicity in rats were ataxia, decreased motility, dyspnea, cyanosis, and coma.{63}


Treatment of overdose
Specific treatment—Administration of protamine sulfate by slow intravenous injection. The dose of protamine sulfate should be equivalent, on a mg-per-mg basis, to the dose of enoxaparin. {01} {02} {16} A 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. {63}An equivalent dose of protamine sulfate will neutralize the anti-factor IIa (anticoagulant) activity of enoxaparin {19}, but will only neutralize approximately 60% of its anti-factor Xa (antithrombotic) activity {01} {02}. Care should be taken to avoid overdosage with protamine sulfate resulting in severe hypotensive and anaphylactoid reactions. For additional information see Protamine (Systemic)

Studies in animals indicate that protamine sulfate stops microvascular bleeding produced by very high concentrations of enoxaparin {19}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Enoxaparin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to enoxaparin, heparin, or to pork or pork products

Pregnancy—Pregnant woman taking enoxaparin are at increased risk for hemorrhage. Hemorrhage can occur at any site and may lead to death of mother and/or fetus; not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves.
Other medications, especially platelet aggregation inhibitors, hypoprothrombinemia-inducing medications, and thrombolytic agents
Other medical problems, especially threatened abortion; aneurysm; hemorrhage; hypertension; septic shock; thrombocytopenia; hemorrhagic blood dyscrasias; recent childbirth; endocarditis; pericarditis or pericardial effusion; severe renal function impairment; diabetic or hemorrhagic retinopathy; spinal puncture, surgery, or other trauma; ulcers or other lesions of the gastrointestinal, respiratory, or urinary tract; severe vasculitis; wounds resulting in large open surfaces; severe hepatic function impairment, and prosthetic heart valves (especially in pregnant women)

Proper use of this medication
» Proper injection technique

» Safe handling and disposal of syringe

» Proper dosing
Using as soon as possible; not using if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Need to inform all physicians and dentists that this medicine is being used

» Notifying physician immediately if signs and symptoms of bleeding or epidural/spinal hematoma occur

Notifying physician immediately if pregnancy is suspected because of possible harm to the mother and/or fetus


Side/adverse effects
Signs and symptoms of potential side effects, including anemia, angioedema, atrial fibrillation, bleeding complications, cardiovascular toxicity, confusion, central or peripheral edema, dyspnea, , epidural/spinal hematoma, heart failure, hematuria, hemorrhage, hemorrhage at injection site, lung edema, pneumonia, skin rash or hives, thrombocytopenia.


General Dosing Information
Enoxaparin is administered by deep subcutaneous (intrafat) injection into the abdominal fat layer; injection sites should be rotated. Enoxaparin must not be administered intramuscularly or intravenously. {01} {02}

The prefilled syringes are ready for use and no attempt should be made to expel air prior to giving the injection. {62}

When using enoxaparin injection ampules, to assure withdrawal of the appropriate volume of drug, the use of a tuberculin syringe or equivalent is recommended. {63}

A controlled, comparative study found that in non-dialyzed patients with severe renal impairment (mean creatinine clearance 11.4 mL per minute), the total clearance of enoxaparin was 1.9 times slower and the apparent half-lives of absorption and elimination were 1.7 times longer than in healthy subjects {02} {07}. Dosage modifications are therefore recommended in patients with severe renal impairment who are not receiving hemodialysis particularly when using high doses{02}{62}. However, dosage modifications are not required in dialysis patients {01} {02}.

Guidelines regarding the use of regional anesthesia in patients receiving perioperative enoxaparin {59} {60}
Preoperative enoxaparin—A single-dose spinal anesthetic may be the safest neuraxial technique. Needle placement should occur at least 10 to 12 hours after the last dose of enoxaparin. Subsequent dosing should be delayed for at least 2 hours after needle placement. The presence of blood during needle placement may justify a delay in the start of postoperative prophylaxis.

Postoperative enoxaparin—Patients may safely undergo single-dose and continuous catheter techniques. With a continuous technique, the epidural catheter should be left indwelling overnight and removed the following day, with the first dose of enoxaparin given 2 hours after catheter removal. Using postoperative prophylaxis in the presence of an indwelling catheter must be done carefully and with close surveillance of the patient's neurologic status. An opioid and/or dilute local anesthetic solution is recommended in these patients to allow intermittent assessment of neurologic function.

The timing of catheter removal is extremely important. Removal should be delayed for at least 10 to 12 hours after a dose of enoxaparin. Subsequent dosing should not occur for at least 2 hours following catheter removal.


Parenteral Dosage Forms

ENOXAPARIN INJECTION

Usual adult dose
Thromboembolism, pulmonary (prophylaxis); and
Thrombosis, deep venous (prophylaxis)


Hip or knee replacement surgery:
Subcutaneously, 30 mg every twelve hours for an average of seven to ten days{01}{02}{07}. The initial dose should be given twelve to twenty-four hours postoperatively{01}.

Alternatively, for hip replacement surgery, enoxaparin may be given subcutaneously, 40 mg once a day, with the initial dose given nine to fifteen hours prior to surgery. Following the initial phase of thromboprophylaxis for hip replacement surgery (either 30 mg every twelve hours or 40 mg once a day), continued prophylaxis at a dose of 40 mg once a day for three weeks is recommended{01} . The usual duration is 7 to 10 days, but up to 14 days administration has been well tolerated in clinical trials.{63}1



Abdominal, [and gynecological, urological, or colorectal ] surgery:
Subcutaneously, 40 mg once a day for an average of seven to ten days. The initial dose should be given two hours prior to surgery. {01}{02}Up to twelve days administration has been well tolerated in clinical trials.{63}


Thrombosis, deep venous (treatment)


Inpatient treatment, with and without pulmonary embolism:
Subcutaneous, 1 mg per kg of body weight every twelve hours or 1.5 mg per kg of body weight once a day, administered the same time each day, for an average of seven days.{01}



Medical patients during acute illness:
Subcutaneous, 40 mg once a day for six to eleven days.{61}{62}Administration for up to fourteen days was well tolerated in one controlled clinical trial.{61}



Outpatient treatment, without pulmonary embolism:
Subcutaneous, 1 mg per kg of body weight every twelve hours for an average of seven days.{01}


Note: In both inpatients and outpatients, warfarin sodium should be initiated as soon as appropriate and enoxaparin should be continued until the international normalized ratio (INR) has achieved a therapeutic level, usually 2.0 to 3.0. Therapy with enoxaparin should be at least five days; up to seventeen days have been well tolerated in clinical trials.{01}


Thrombosis, coronary arterial, acute; associated with unstable angina or non–Q-wave myocardial infarction (prophylaxis)1
Subcutaneous, 1 mg per kg of body weight every twelve hours in conjunction with oral aspirin therapy (100 to 325 mg once a day). Treatment should be prescribed for a minimum of two days, and continued until the patient is clinically stable (usual duration is two to eight days).{01} Up to 12.5 days administration has been well tolerated in clinical trials.{63}

Note: To minimize the risk of bleeding following vascular instrumentation during the treatment of unstable angina, adhere precisely to the recommended dosing intervals. The vascular access sheath for instrumentation should remain in place for six to eight hours following a dose of enoxaparin. Following sheath removal, the next scheduled dose of enoxaparin should be given no sooner than six to eight hours later. The site of the procedure should be observed for signs of bleeding or hematoma formation.{01}


[Unstable angina and non-Q-wave myocardial infarction (treatment)]
Subcutaneous, 1 mg per kg of body weight (100 IU per kg of body weight) every 12 hours. Concomitant therapy with ASA (100 to 325 mg once daily) is recommended. Treatment should be continued for a minimum of two days and continued until clinical stabilization has been achieved (two to eight days). The effect of the short-term treatment was sustained over a one-year period. {62}


Usual adult prescribing limits
Thrombosis, deep venous (treatment)


Inpatient treatment, with and without pulmonary embolism:
Subcutaneous, single daily dose should not exceed 18,000 IU.{62}


[Unstable angina and non-Q-wave myocardial infarction (treatment)]
Subcutaneous, maximum dose should not exceed 10,000 IU per 12 hours.
{62}

Usual pediatric dose
Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available

Note: Approximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard.{63}

U.S.—


30 mg in 0.3 mL of Water for Injection 100 mg per mL (3000 IU anti-Xa activity) (Rx) [Lovenox (in ampuls and single unit-dose syringes ){61}{63}]


40 mg in 0.4 mL of Water for Injection 100 mg per mL (4000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){61}{63}]


60 mg in 0.6 mL of Water for Injection 100 mg per mL (6000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){61}{63}]


80 mg in 0.8 mL of Water for Injection 100 mg per mL (8000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){61}{63}]


100 mg in 1 mL of Water for Injection 100 mg per mL (10,000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){61}{63}]


120 mg in 0.8 mL of Water for Injection 150 mg per mL (12,000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){63}]


150 mg in 1 mL of Water for Injection 150 mg per mL (15,000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){63}]

Canada—


30 mg in 0.3 mL of Water for Injection (3000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){62}{64}]


40 mg in 0.4 mL of Water for Injection (4000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){62}{64}]


60 mg in 0.6 mL of Water for Injection (6000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){62}{64}]


80 mg in 0.8 mL of Water for Injection (8000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){62}{64}]


100 mg in 1 mL of Water for Injection (10,000 IU anti-Xa activity) (Rx) [Lovenox (in single unit-dose syringes){62}{64}]


300 mg in 3 mL (10 mg per 0.1 mL) of Water for Injection(30,000 IU anti-Xa activity) (Rx) [Lovenox (in multiple-dose vials) (benzyl alcohol 1.5% w/v){62}{64}]


120 mg in 0.8 mL of Water for Injection (12,000 IU anti-Xa activity) (Rx) [Lovenox HP (in single unit-dose syringes){62}]


150 mg in 1 mL of Water for Injection (15,000 IU anti-Xa activity) (Rx) [Lovenox HP (in single unit-dose syringes){62}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F){01}{02}, unless otherwise specified by manufacturer. Protect from freezing{01}. Protect from heat {62}

Stability:
Because the injection contains no preservative{01}, each syringe should be used to administer a single dose only.

Incompatibilities:
Enoxaparin should not be admixed with intravenous fluids or other medications{01}{02}.

Additional information:
The 300-mg-per-3-mL multi-dose vial contains benzyl alcohol, which is not recommended for use in neonates. A fatal syndrome consisting of metabolic acidosis, central nervous system depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhage has been associated with the administration of benzyl alcohol to neonates.



Developed: 11/22/1993
Revised: 11/20/2002



References
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