Lovenox

It is recommended that agents which affect hemostasis should be discontinued prior to LOVENOX therapy unless strictly indicated. If the combination is indicated, LOVENOX should be used with careful clinical and laboratory monitoring when appropriate.

LOVENOX should be used with caution in patients receiving oral anticoagulants, platelet inhibitors and thrombolytic agents because of increased risk of bleeding. Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarction and acute ST-segment Elevation Myocardial Infarction (see Dosage and Administration).

Since LOVENOX use may be associated with a rise in hepatic transaminases, this observation should be considered when liver funtion tests are assessed (see Adverse Reactions, Post-market Adverse Drug Reactions, Liver).

For intravenous injection, the multiple-dose vial should be used. LOVENOX should be administered through an intravenous line. LOVENOX should not be mixed or co-administered with other medications. To avoid the possible mixture of LOVENOX with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of LOVENOX to clear the port of drug. LOVENOX may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

Care should be taken to ensure use of the correct formulation, either LOVENOX (100 mg/mL concentration) or LOVENOX HP (150 mg/mL concentration), when using these products.

All patients with renal impairment treated with low molecular weight heparins should be monitored carefully.

Exposure to enoxaparin increases with degree of renal impairment. In patients with renal impairment, the increased exposure to enoxaparin has been shown to increase risk of bleeding (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency).

A dosage adjustment is required for patients with severe renal impairment (creatinine clearance <30 mL/min) since enoxaparin exposure is significantly increased in this patient population. The following dosage adjustments are recommended for prophylaxis and treatment in patients with severe renal impairment:

• For prophylaxis in conjunction with hip or knee orthopedic surgery, the recommended dosage is 30 mg (3000 IU) once daily

  
  

• For prophylaxis in conjunction with abdominal or colorectal surgery, or for prophylaxis in medical patients at risk of DVT, the recommended dosage is 20 mg (2000 IU) or 30 mg (3000 IU) once daily based on individual risk/benefit assessment

  
  

• For treatment of deep vein thrombosis, with or without pulmonary embolism, the recommended dosage is 1 mg/kg once daily

  
  

• For treatment of unstable angina or non-Q-wave myocardial infarction, the recommended dosage is 1 mg/kg once daily.

  
  

• For treatment of acute ST-segment Elevation Myocardial Infarction, the recommended dosage is 30 mg-single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily.

  
  

• For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age, the recommended dosage is 1 mg/kg administered SC once daily (no initial bolus).

  
  

Dosage adjustment may also need to be considered in patients who have renal characteristics close to those of patients with severe renal impairment.

For acute ST-segment Elevation Myocardial Infarction, treatment is to be initiated with a single IV bolus injection immediately followed by a subcutaneous injection.

In medical patients at risk for deep vein thrombosis due to severely restricted mobility during acute illness (see Warnings and Precautions, General, Selection of Medical Patients), the recommended dose of LOVENOX is 40 mg (4000 IU) once daily by subcutaneous injection. The usual duration of administration is 6 to 11 days.

If the last LOVENOX SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last LOVENOX SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of LOVENOX injection should be administered. (See Warnings and Precautions, Peri-Operative considerations, Percutaneous Coronary Revascularisation Procedures.)

The subcutaneous injection of LOVENOX should be carried out with the patient in the decubitus position. Inject in the subcutaneous tissue of the anterolateral and posterolateral abdominal girdle, alternatively on the left and right sides. With the thickness of skin held between the operator's thumb and finger, introduce the entire length of the needle vertically into the skin.

LOVENOX can be administered subcutaneously either as 1.5 mg/kg once daily or as twice daily injections of 1 mg/kg.

The 1.5 mg/kg once daily dose is the equivalent of 150 IU/kg and should be given at the same time every day. The single daily dose should not exceed 18 000 IU. The expected plasma anti-Xa levels during subcutaneous treatment, when enoxaparin is used as the reference standard, would be <0.3 IU anti-Xa/mL before injection and <1.7 IU anti-Xa/mL 3-4 hours post injection. The measurement of plasma anti-Xa circulating activities depends on the experimental conditions of the assay, particularly on the reference standard used.

In patients with complicated thromboembolic disorders (i.e. with increased risk of recurrent VTE such as obese patients, cancer patients or patients with symptomatic PE), a dose of 1 mg/kg administered twice daily is recommended. This is the equivalent of 100 IU/kg. The expected plasma anti-Xa levels during subcutaneous treatment, when enoxaparin is used as the reference standard, would be <0.3 IU anti-Xa/mL before injection and <1.15 IU anti-Xa/mL 3-4 hours post injection.

Oral anticoagulant therapy should be initiated as soon as possible, and LOVENOX should be continued until a therapeutic anticoagulant effect has been achieved (INR: 2 to 3), in general for approximately 7 days.

In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of LOVENOX is 40 mg (4000 IU) once daily administered by subcutaneous injection, with the initial dose given 2 hours prior to surgery (see Warnings and Precautions, General, Selection of General Surgery Patients). The usual duration of treatment is from 7 to 10 days for a maximum of 12 days.

LOVENOX must not be administered by the intramuscular route.

The recommended dose of LOVENOX is 1 mg/kg every 12 hours by subcutaneous injection. This is the equivalent of 100 IU/kg. The maximum dose should not exceed 10 000 IU / 12 hours. The expected plasma anti-Xa levels during subcutaneous treatment would be <0.3 IU anti-Xa/mL before injection and <1.15 IU anti-Xa/mL 3-4 hours after injection. Treatment should continue for a minimum of 2 days until clinical stabilization has been achieved, in general, for up to 8 days. The effect of the short-term treatment was sustained over a one-year period.

Concomitant therapy with ASA (100 to 325 mg once daily) is recommended. (See Warnings and Precautions, Peri-Operative considerations, Percutaneous Coronary Revascularisation Procedures.)

When the LOVENOX dose to be given is equivalent to the full amount of the pre-filled syringe, no attempt should be made to expel air prior to giving the injection. If the graduated syringes (60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1.0 mL, 120 mg/0.8 mL, 150 mg/1.0 mL) are used and the dose of LOVENOX has to be adjusted, it is necessary to expel the air bubble and any excess drug solution.

Under normal conditions of use, LOVENOX does not modify global clotting tests of activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin clotting time (TT). Therefore treatment can not be monitored with these tests. The plasma levels of the drug can be verified by measuring anti-Xa and anti-IIa activities.

The recommended dose of LOVENOX is 30 mg (3000 IU) every 12 hours administered by subcutaneous injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. The usual duration of treatment is from 7 to 14 days.

Treatment should be continued for as long as the risk of DVT persists. Continued therapy with LOVENOX 40 mg once daily for 3 weeks following the initial phase of thromboprophylaxis in hip replacement surgery patients has been proven to be beneficial.

Enoxaparin sodium is administered by subcutaneous injection for the prevention of venous thromboembolic disease, treatment of deep vein thrombosis, treatment of unstable angina and non-Q-wave myocardial infarction and treatment of acute ST-segment Elevation Myocardial Infarction.

For subcutaneous use LOVENOX should not be mixed with other injections or infusions.

For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses). No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired.

As with any antithrombotic treatment, hemorrhagic manifestations can occur (also see Adverse Reactions, Local Reactions).

The incidence of major hemorrhagic complications during LOVENOX treatment has been low and generally did not differ from that observed with unfractionated heparin. Patients taking LOVENOX are at risk for major bleeding complications when the plasma anti-factor Xa levels approach 2.0 IU/mL. Other risk factors associated with bleeding on therapy with heparins include a serious concurrent illness, chronic heavy alcohol consumption, use of platelet inhibiting drugs, renal failure, age and possibly, the female gender. Petechiae or easy bruising may precede frank hemorrhage. Bleeding may range from minor local hematoma to major hemorrhage. The early signs of bleeding may include epistaxis, hematuria, or melena. Bleeding may occur at any site and may be difficult to detect; such as retroperitoneal bleeding. Bleeding may also occur from surgical sites.

Major hemorrhage, including retroperitoneal and intracranial bleeding, has been reported in association with LOVENOX use, in some cases leading to fatality.

Thrombocytopenia, skin rash (including bullous eruptions), purpura, allergic reactions and skin necrosis usually occurring at the injection site are rare, and occur with all low molecular weight heparins. Skin necrosis is usually preceded by purpura or erythematous plaques, infiltrated and painful. In case such reaction is observed, treatment with enoxaparin sodium must be discontinued. Hypersensitivity reactions, including angioedema and anaphylactic/anaphylactoid reactions, have been observed rarely with unfractionated heparin and low molecular weight heparins. Very rare cases of hypersensitivity cutaneous vasculitis have been reported. These cases may include leukocytoclastic vasculitis. LOVENOX should be discontinued in patients showing local or systemic allergic responses.

Use of low molecular weight heparins over extended periods has been reported to be associated with development of osteopenia.

Cases of hyperkalaemia have been reported with heparins and Low Molecular Weight Heparins.

Pain and mild local irritation may follow the subcutaneous injection of enoxaparin sodium. Rarely, hard inflammatory nodules have been observed at the injection site. Injection site hematomas are a common side effect with LOVENOX (enoxaparin) occurring at a frequency of 5% or less with lower (prophylaxis) doses to 10% or more with higher (treatment) doses.

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only additional possibly related adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was thrombocytopenia (1.5%).

Transient, asymptomatic elevations of liver transaminases (AST and ALT) to greater than three times the upper limit of normal has been observed in up to 6% of patients taking LOVENOX. This is a consistent finding with all members of the LMWH class, as well as with unfractionated heparin. The mechanism associated with the increased levels of liver transaminases has not been elucidated. No consistent irreversible liver damage has been observed. Transaminase levels returned to normal within 3 to 7 days after discontinuation of enoxaparin.

Severe immunologically-mediated thrombocytopenia has been observed rarely with LOVENOX use, resulting in arterial and/or venous thrombosis or thromboembolism (see Warnings and Precautions, Hematologic, Thrombocytopenia, Platelets, Immune). In some cases thrombosis was complicated by organ infarction or limb ischemia.

Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety and a brief discussion can be found in Warnings and Precautions, under Special Populations, Geriatrics.

In the clinical study for treatment of acute STEMI, with adjustment in dose for patients ≥75 years of age, there was no evidence of difference in efficacy between patients ≥75 years of age (n=1241) and patients less than 75 years of age (n=9015).

No data is available.

Each syringe contains: enoxaparin sodium 100 mg in 1 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 1 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

The 60 mg/0.6 mL, 80 mg/0.8 mL, and the 100 mg/1 mL syringes are imprinted with a graduation scale of 1 mL with major increments of 0.1 mL and minor increments of 0.025 mL.

Each LOVENOX presentation has a solution pH of 5.5 to 7.5 with an approximate anti-factor Xa activity of 100 IU/1 mg of drug (with reference to the WHO First International Low Molecular Weight Heparin Reference Standard).

Each syringe contains: enoxaparin sodium 30 mg in 0.3 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 0.3 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

Each syringe contains: enoxaparin sodium 60 mg in 0.6 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 0.6 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

Each syringe contains: enoxaparin sodium 120 mg in 0.8 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 0.8 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

Each multidose vial contains: enoxaparin sodium 300 mg in 3 mL water for injection (concentration 10 mg/0.1 mL) and 1.5% (w/v) benzyl alcohol as a preservative.

Each syringe contains: enoxaparin sodium 150 mg in 1 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 1 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

The 120 mg/0.8 mL and 150 mg/1 mL syringes are imprinted with a graduation scale of 1 mL with major increments of 0.1 mL and minor increments of 0.02 mL.

The pH of the syringe and multiple dose solution is 5.5 to 7.5 with an approximate anti-factor Xa activity of 100 IU/1 mg of drug (with reference to the WHO First International Low Molecular Weight Heparin Reference Standard). Nitrogen is used in the headspace to inhibit oxidation.

Each syringe contains: enoxaparin sodium 40 mg in 0.4 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 0.4 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

Each syringe contains: enoxaparin sodium 80 mg in 0.8 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Pre-filled syringes 27 G of 0.8 mL with protective shield, cartons of 10, blisters of 2, each in individual blister pack.

LOVENOX should be used with caution in patients with renal insufficiency.

LOVENOX dosage should be reduced in patients with severely impaired renal function (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency, and Dosage and Administration, Use in Patients with Renal Impairment).

Patients with impaired renal function should be carefully monitored because half-life for anti-Xa activity after administration of low molecular weight heparin may be prolonged in this patient population (see Dosage and Administration, Use in Patients with Renal Impairment).

In patients with renal impairment, there is an increase in exposure to enoxaparin which increases the risk of bleeding. Since exposure to enoxaparin is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for both therapeutic and prophylactic dosage ranges (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency, and Dosage and Administration, Use in Patients with Renal Impairment).

LOVENOX should be used with caution in patients with gastrointestinal ulceration.

Safety and efficacy of low molecular weight heparins in high weight (e.g. >120 kg) and low weight (e.g. <45 kg) patients has not been fully determined. Individualised clinical and laboratory monitoring is recommended in these patients (see also Action and Clinical Pharmacology, Special Population and Conditions, Low-Weight Patients).

The risk factors for the development of thrombosis in the individual medical patient are important in determining whether thromboprophylaxis is appropriate. In one clinical trial, LOVENOX 40 mg once daily reduced the risk of the development of deep vein thrombosis (DVT) from 14.9% to 5.5% during the short term risk period in bedridden patients. Careful consideration should be given to the selection of patients. Patients at high risk of developing DVT or other thrombosis (such as patients with a malignant disease, a history of thrombophilia and known deficiency in antithrombin III, protein C or protein S, or APC resistance) are not candidates for therapy with LOVENOX 40 mg once daily because this dose may be inadequate for those patients. Furthermore, LOVENOX should not be given for thromboprophylaxis in medical patients who are bedridden due to infections with septic shock. Medical patients who require short term thromboprophylaxis for the risk of DVT due to severely restricted mobility during acute illness including moderate to severe heart failure, acute respiratory failure revealing or complicating chronic respiratory insufficiency not requiring ventilatory support, and acute respiratory infections may be selected for thromboprophylaxis with LOVENOX 40 mg once daily.

The safety and efficacy of LOVENOX 40 mg once daily following hospital discharge has not been established in the medical patient population. In the clinical trial mentioned above, thromboembolic events were not common following discontinuation of LOVENOX 40 mg at discharge. However, a significant number of patients did require antithrombotic therapy following discharge; specifically 13.63%. During the 3-month period following discharge, less than 1% of events were serious and included deep vein thrombosis, pulmonary embolism and death which is considered to be thromboembolic in origin. Therefore, the physician should consider whether thromboprophylaxis post-discharge would be necessary for the individual patient.

Cases of prosthetic valve thrombosis have been reported in patients who have received low molecular weight heparins for thromboprophylaxis. Some of these patients were pregnant women in whom thrombosis led to maternal and/or fetal deaths. Pregnant women are at higher risk of thromboembolism (see Warnings and Precautions, Pregnant Women).

LOVENOX at a dose of 40 mg once daily should not be given for thromboprophylaxis other than deep vein thrombosis (DVT) prevention or in medical patients who, in the opinion of the attending physician, would be at a higher risk of thromboembolism (such as patients with a malignant disease, a history of thrombophilia and known deficiency in antithrombin III, protein C or protein S, or APC resistance). Furthermore, LOVENOX should not be given for thromboprophylaxis in medical patients who are bedridden due to infections with septic shock. Patients with severe COPD complicated by right heart failure are candidates for another form of thromboprophylaxis. LOVENOX at a dose of 40 mg once daily has been studied in medical patients who require short term thromboprophylaxis to prevent the development of DVT while they are bedridden (6 to 11 days). If, in the opinion of the attending physician, longer thromboprophylaxis is necessary, then consideration should be given to a thromboprophylactic agent, which has been proven effective.

The safety and effectiveness of LOVENOX in children has not been established.

The multiple dose vial of LOVENOX (300 mg/3 mL) contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a potentially fatal “Gasping Syndrome” in neonates. Manifestations of the disease included: metabolic acidosis, respiratory distress, gasping respirations, central nervous system dysfunction, convulsions, intracranial hemorrhages, hypoactivity, hypotonia, cardiovascular collapse and death. Because benzyl alcohol may cross the placenta, LOVENOX preserved with benzyl alcohol should not be used in pregnant women.

Teratogenic effects: As with other low molecular weight heparins, LOVENOX should not be used in pregnant women unless the therapeutic benefits to the patients outweigh the possible risks. There have been reports of congenital anomalies in infants born to women who received low molecular weight heparin during pregnancy including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia and cardiac defects. A causal relationship has not been established nor has the incidence been shown to be higher than in the general population.

Non-teratogenic effects: There have been post-marketing reports of fetal death when pregnant women received low molecular weight heparins. Causality for these cases has not been established. Pregnant women receiving anticoagulants, including LOVENOX, are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving LOVENOX should be carefully monitored. Pregnant women and women of child-bearing potential should be informed of the potential hazard to the fetus and the mother if LOVENOX is administered during pregnancy.

There are also postmarketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving low molecular weight heparins for thromboprophylaxis. These events led to maternal death or surgical interventions.

Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of thromboembolism. An incidence of thromboembolism approaching 30% has been reported in these patients, in some cases even with apparent adequate anticoagulation at treatment doses of low molecular weight heparins or unfractionated heparin. Any attempt to anticoagulate such patients should normally only be undertaken by medical practitioners with documented expertise and experience in this clinical area.

Platelet counts should be determined prior to the commencement of treatment with LOVENOX and, subsequently, twice weekly for the duration of therapy.

Caution is recommended when administering LOVENOX to patients with congenital or drug induced thrombocytopenia, or platelet defects.

Elderly patients (especially patients eighty years of age and older) receiving low molecular weight heparins are at increased risk of bleeding. Careful attention to dosing and concomitant medications, especially anti-platelet preparations, is advised. Close monitoring of elderly patients with low body weight (e.g. <45 kg) and those predisposed to decreased renal function is recommended.

For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients, the incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years). Patients ≥75 years of age did not receive a 30-mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours. (See Dosage and Administration, Recommended Dose and Dosage Adjustment, Treatment of acute ST-Segment Elevation Myocardial Infarction, Geriatrics (≥75 years of age).)

LOVENOX should be used with caution in patients with hepatic insufficiency.

During LOVENOX administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100 000/µL). A positive or indeterminate result obtained from in vitro tests for antiplatelet antibody in the presence of enoxaparin or other low molecular weight heparins and/or heparin would contraindicate LOVENOX.

LOVENOX (enoxaparin) must not be administered by the intramuscular route.

LOVENOX cannot be used interchangeably (unit for unit) with unfractionated heparin (UFH) or other low molecular weight heparins (LMWHs) as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosages. Special attention and compliance with instructions for use of each specific product is required during any change in treatment.

Determination of anti-Xa levels in plasma is the only method available for monitoring LOVENOX activity. The effect of LOVENOX on global clotting tests such as aPTT, PT and TT is dose-dependent. At lower doses, used in prophylaxis, LOVENOX does not prolong these tests. At higher doses, aPTT prolongation is observed but treatment cannot be monitored with these tests.

Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered in patients at higher risk of bleeding and receiving LOVENOX, such as the elderly, patients with renal impairment or the extremes of body weight, during pregnancy, or for children. At treatment doses, peak anti-Xa levels should generally be maintained at no more than 1.5 IU/mL in these patients (see Action and Clinical Pharmacology, and Warnings and Precautions, Monitoring and Laboratory Tests).

Bleeding may occur in conjunction with unfractionated heparin or low molecular weight heparin use. As with other anticoagulants, LOVENOX should be used with extreme caution in patients at increased risk of hemorrhage. Bleeding can occur at any site during therapy with LOVENOX. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site (see Adverse Reactions, Bleeding).

There have been cases of intra-spinal hematomas with the concurrent use of LOVENOX and spinal/epidural anesthesia resulting in long-term or permanent paralysis. The risk of these events may be higher with the use of post-operative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis: nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other drugs affecting coagulation including glycoprotein IIb/IIIa antagonists. The risk is greater with higher LOVENOX dosage regimens (e.g. at 1 mg/kg twice daily or 1.5 mg/kg once daily) than with prophylactic doses. The risk also appears to be increased by traumatic or repeated epidural or spinal procedure. LOVENOX should only be used concurrently with spinal/epidural anaesthesia when the therapeutic benefits to the patients outweigh the possible risks (also see Contraindications). When used concurrently, no spinal invasion should be performed for at least 12 hours following the last dose of LOVENOX (higher doses may require longer delays) and that the next dose should be held until at least 2 hours after the anaesthetic procedure. The same rules apply to the withdrawal or manipulation of the catheter. Careful vigilance for neurological signs such as: midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction is recommended with rapid diagnosis and treatment, if signs occur (see Adverse Reactions).

LOVENOX has only a moderate prolonging effect on clotting time assays such as aPTT or thrombin time. For lab monitoring of effect, anti-Xa methods are recommended. Prolongation of aPTT during therapy with LOVENOX to the same extent as with unfractionated heparin should only be used as a criteria of overdose. Dose increases aimed at prolonging aPTT to the same extent as with unfractionated heparin could cause overdose and bleeding.

LOVENOX is administered subcutaneously, and therefore, the individual patient's antifactor Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval. In patients treated with enoxaparin 1.0 mg/kg twice daily for proximal deep vein thrombosis, mean peak plasma anti-Xa levels were 0.91 IU/mL. In patients given enoxaparin 1.0 mg/kg twice daily for acute treatment of unstable angina, peak anti-Xa activity levels were 1.0-1.1 IU/mL. At steady-state in patients given a 1.5 mg/kg qd regimen for treatment of DVT, mean peak activity was 1.7 IU anti-Xa/mL. The steady-state is practically achieved at the second or the third dose depending on the dosage regimen, once or twice daily, respectively. LOVENOX should be administered as directed (see Dosage and Administration).

As with all anti-thrombotic agents, there is a risk of systemic bleeding with LOVENOX administration. Consequently, therapy should not be started before primary hemostasis has been established and preferably no sooner than 12 hours after surgery, see Dosage and Administration. Care should be taken with LOVENOX use in high dose treatment of newly operated patients.

After treatment is initiated, patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and anti-factor Xa determinations.

With normal prophylactic doses, LOVENOX does not modify global clotting tests of activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin clotting time (TT). Therefore, treatment cannot be monitored with these tests.

At higher doses, increases in aPTT (activated partial thromboplastin time) and ACT (activated clotting time) may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin activity.

When thrombolytic treatment is considered appropriate in patients with unstable angina, non-Q-wave myocardial infarction and acute ST-segment Elevation Myocardial Infarction, the concomitant use of an anticoagulant such as LOVENOX may increase the risk of bleeding.

Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of LOVENOX. Its incidence is unknown at present.

Major orthopedic surgery carried out on the lower extremities is associated with a higher risk of VTE, and a notable percentage of patients will develop a thrombosis if they are not given prophylaxis. Factors shown to predispose patient to VTE following major orthopedic surgery include a history of VTE, current obesity, delayed mobilization advanced age or cancer. Other risk factors that might be clinically important include congestive heart failure, chronic obstructive pulmonary disease (COPD) as well as female gender. High risk period for VTE lasts up to 3 months after hip surgery, therefore thromboprophylaxis should start as soon as possible and continue for up to 28 to 35 days after surgery. (ACCP guidelines 2004.)

To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction, and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between LOVENOX injection doses. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, it is recommended to remove the sheath 6 hours after the last IV/SC injection. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation. (See Dosage and Administration, Recommended Dose and Dosage Adjustment, Treatment of Unstable Angina or Non-Q-Wave Myocardial Infarction and Treatment of acute ST-Segment Elevation Myocardial Infarction.)

It is not known whether LOVENOX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOVENOX is administered to nursing women.

Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, age 60 years or above.

Store at room temperature (15-25°C).

Protect from heat.

Do not store the multiple dose vials for more than 28 days after the first use.

Based on the results of a population pharmacokinetic analysis, the enoxaparin kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal. However, since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin (see Warnings and Precautions, Renal and Special Populations, Geriatrics).

The volume of distribution of enoxaparin is about 5 liters. Following subcutaneous dosing, the apparent clearance of enoxaparin is approximately 15 mL/min.

Information from a clinical trial with a very small number of volunteers indicates that enoxaparin, as detected by anti-factor Xa activity, does not appear to cross the placental barrier, at least during the second trimester of pregnancy.

The pharmacokinetics of enoxaparin have been studied on the basis of plasma levels of anti-Xa activity. The mean absolute bioavailability of enoxaparin, when given subcutaneously, is about 92% in healthy volunteers.

The mean peak plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection. Levels of approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL were seen in healthy volunteers, following a single subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg, respectively.

Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is reached from Day 3 to 4 with mean exposure about 65% higher than after a single dose. Mean peak and trough levels of about 1.2 and 0.52 IU/mL respectively were seen with this regimen.

A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady-state levels. Steady state is achieved on the second day of treatment.

LOVENOX (enoxaparin) is a low molecular weight heparin fragment, which is obtained by controlled depolymerization of natural heparin from porcine intestinal mucosa. It possesses antithrombotic action. Enoxaparin is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site, that is essential for high affinity binding to the plasma protein antithrombin (formerly referred to as antithrombin III). With a molecular weight range of 3800-5000 daltons (versus 15 000 daltons for heparin), the enoxaparin molecule is too small to bind simultaneously to thrombin and antithrombin, the primary anticoagulant factor in blood.

The mechanism of action of enoxaparin is antithrombin-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. Enoxaparin potentiates preferentially the inhibition of coagulation factors Xa and IIa and only slightly affects other hemostatic mechanisms such as clotting time. The antithrombotic effect of enoxaparin is well correlated to the inhibition of factor Xa.

The ratio of anti-Xa/anti-IIa activity is greater than 4 with enoxaparin (whereas this ratio is equal to 1 with heparin). This dissociation between anti-Xa and anti-IIa activities has been shown in experimental models with an antithrombotic activity comparable to that of heparin while the bleeding effect is reduced. In man, clinical trials have not shown a causal relationship between the ratio of anti-Xa/anti-IIa activity and clinical/pharmacological effect.

LOVENOX cannot be measured directly in the bloodstream. Rather the effect on clotting mechanisms is measured. Heparin dosage is monitored by both prolongation of aPTT and by anti-Xa activity. For enoxaparin, the aPTT may not be significantly prolonged relative to unfractionated heparin at prophylactic doses, and at therapeutic doses aPTT prolongation is not used to measure the therapeutic effect of LOVENOX. Enoxaparin potency is described in international anti-Xa units (e.g., 1 mg of enoxaparin is equivalent to 100 IU of anti-Xa).

Elimination appears monophasic with a half-life of about 4 hours after a single subcutaneous dose and about 7 hours after repeated dosing, in healthy volunteers.

The main route of elimination is via the kidney. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.

Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin and thrombolytics when administered concomitantly.

A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, indicating decreased clearance of enoxaparin in patients with reduced renal function.

Anti-Xa exposure at steady-state, represented by AUC, is increased about 34% in mild renal impairment (creatinine clearance 50-80 mL/min), about 72% in moderate renal impairment (creatinine clearance 30-50 mL/min), and about 95% in severe renal impairment (creatinine clearance <30 mL/min) upon administration of enoxaparin 1.5 mg/kg once daily sc for 4 days. Anti-Xa exposure at steady-state is increased about 33% in mild renal impairment, about 46% in moderate and about 97% in severe renal impairment upon administration of enoxaparin 1 mg/kg bid sc for 4 days. When enoxaparin was administered at a fixed, prophylaxis dose of 40 mg once daily sc for 4 days, the anti-Xa exposure increased by about 20% in mild renal impairment, about 21% in moderate renal impairment, and about 65% in severe renal impairment (see Warnings and Precautions, Renal, and Dosage and Administration, Use in Patients with Renal Impairment).

The half-life for anti-Xa activity in patients with impaired renal function is much longer than for people with normal renal function (t_½=5.12 h in patients with chronic renal failure vs 2.94 h in young healthy volunteers) when enoxaparin was administered intravenously.

Enoxaparin is metabolized in the liver by desulfation and depolymerization.

When non-weight-adjusted dosing was administered, after a single-subcutaneous 40 mg dose, anti-Xa exposure was observed to be 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects, which may lead to a higher risk of bleeding (see Warnings and Precautions, Special Populations, Patients with Extreme Body Weight).