Lovenox

Each ml of the solution contains 10000 anti-Xa IU equivalent to 100 mg enoxaparin sodium. One mg (0.01 ml) of enoxaparin sodium corresponds approximately to 100 anti-Xa IU.
LOVENOX 2000 anti-Xa IU is equivalent to 20 mg.
LOVENOX 4000 anti-Xa IU is equivalent to 40 mg.
LOVENOX 6000 anti-Xa IU is equivalent to 60 mg.

Pharmacotherapeutic Group: Antithrombotic agent. ATC Code: B01AB05.
Pharmacology: Pharmacodynamics: Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. It is characterized by a higher ratio of anti-Xa activity to anti-IIa (or antithrombin) activity.
The ratio between these two activities is 3.6.
As with standard heparin, the anti-Xa and anti-IIa activity of enoxaparin results from its effect on antithrombin.
When used as prophylactic treatment, it does not significantly affect the activated partial thromboplastin time (aPTT).
When used as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.
This prolongation reflects the residual antithrombin activity.
4000 Anti-Xa IU: Prophylactic treatment of venous thromboembolism in patients who are bedridden due to an acute medical disorder: A randomized, double-blind, placebo-contorlled study (Medenox) was carried out to compare the safety and efficacy of enoxaparin 2000 anti-Xa IU/0.2 ml (20 mg/0.2 ml) and 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) in preventing venous thromboembolism. The study medication or placebo were administered once daily for 6 to 14 days to 1102 patients who were bedridden due to an acute medical disorder occurring within the previous three days and who were at moderate risk of venous thromboembolism. The patients were over 40 years of age and had heart failure (NYHA class III or IV), acute respiratory failure revealing or complicating chronic respiratory insufficiency, an acute infectious or rheumatic disease associated with at least one thromboembolic risk factor (age >75 years, cancer, history of venous thromboembolism, obesity, varicose, hormone therapy, chronic heart or respiratory failure).
Medical patients at high risk of venous thromboembolism complications (acute phase of myocardial infarction, heart disease such as arrhythmia or valvular disease requiring anticoagulant therapy, intubated patients or patients who had experienced a stroke within the last three months) were not included in the study.
The primary efficacy criterion was the incidence of venous thromboembolic events on treatment day 10 (±4) defined as: deep vein thrombosis (DVT) documented systematically by venography (83.4% of evaluable patients) or by Doppler ultrasound (16.6% of evaluable patients) in patients with symptomatic DVT. Non-fatal symptomatic pulmonary embolism confirmed by pulmonary angiography or spiral CT; or fatal pulmonary embolism.
A significant decrease in the incidence of venous thromboembolic events was observed in the 866 evaluable patients on day 10 (±4), 16/291 (5.5%) in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group versus 43/288 (14.9%) in the placebo group (p=0.0002). This was mainly due to the significant decrease in the incidence of total DVT (proximal and distal), i.e., 16/291 (5.5%) in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group versus 41/288 (14.2%) in the placebo group (p=0.0004). Most DVTs were asymptomatic (only 6 were symptomatic). The observed benefit was maintained after 3 months.
Fifty-nine percent (59%) of patients in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group regained autonomous mobility (>10 meters) during the treatment period.
Regarding safety, the incidence of hematomas or ecchymoses larger than 5 cm at the injection site was significantly higher in the Lovenox 4000 anti-Xa IU/0.4 ml/day (40 mg/day) group than in the placebo group.
This study showed no significant difference in efficacy between Lovenox 2000 anti-Xa IU/0.2 ml (20 mg/0.2 ml) and the placebo.
6000 Anti-Xa IU: Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent in patient who are eligible or not for subsequent coronary angioplasty: In a large multicenter study, 20479 patients with acute ST-segment elevation myocardial infarction having received fibrinolytic, treatment were randomized to receive either: enoxaparin as an IV bolus injection of 3 000 anti-Xa IU immediately followed by a dose of 100 anti-Xa IU/kg SC, then by an SC injection of 100 anti-Xa IU/kg every 12 hours, or unfractionated heparin by the IV route as a bolus injection of 60 IU/kg (maximum 4 000 IU) followed by a continuous infusion at a dose adjusted to the activated partial thromboplastin time. The SC injections of enoxaparin were administered until discharge from hospital or for a maximum period of 8 days (in 75% of cases for at least 6 days). Half the patients receiving heparin were administered the drug for less than 48 hours (in 89.5% of cases ≥36 hours). All the patients were also treated with aspirin for at least 30 days. The enoxaparin dosage was adjusted for patients aged 75 years or more: 75 IU/kg as an SC injection every 12 hours, without an initial IV bolus injection.
During the study, 4716 (23%) patients underwent coronary angioplasty under antithrombotic treatment using blinded study drugs.
Patients did not receive an additional dose if the last SC injection of enoxaparin had been given less than 8 hours balloon inflation, or, received an IV bolus injection of 30 anti-Xa IU/kg if the last SC injection of enoxaparin had been given more than 8 hours before balloon inflation.
Enoxaparin significantly reduced the incidence of primary end point events (composite end point consisting of myocardial infarction relapse and all-cause mortality within 30 days after inclusion : 9.9% in the enoxaparin group versus 12.0% in the unfractionated heparin group (relative risk reduction of 17% (p<0.01)). The incidence of myocardial infarction relapse was significantly lower in the enoxaparin group (3.4% versus 5%, p<0.001, relative risk reduction 31%). The incidence of deaths was lower in the enoxaparin group, with no statistically significant difference between the groups (6.9% versus 7.5%, p=0.11).
The benefit of enoxaparin in terms of the primary endpoint was consistent, irrespective of sub-group: age, sex, location of myocardial infarction, history of diabetes of myocardial infarction, type of thrombolytic administered and interval between the first clinical signs and treatment initiation.
Enoxaparin demonstrated a significant benefit versus unfractionated heparin in terms of the primary efficacy criterion, both in patients who had undergone coronary angioplasty within 30 days after inclusion (10.8% versus 13.9%, 23% reduction in relative risk) and in patients who did not have coronary angioplasty (9.7% versus 11.4%, 15% reduction in relative risk).
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the enoxaparin group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial bleeding was similar in both groups (0.8% with enoxaparin versus 0.7% with heparin).
The analysis of the composite criteria measuring overall clinical benefit showed statistically significant superiority (p<0.0001) for enoxaparin versus unfractionated heparin: a relative risk reduction of 14% in favor of enoxaparin (11.0% versus 12.85) for the composite criteria consisting of death, myocardial infarction relapse, or major bleeding (TIMI criteria) at 30 days, and of 17% (10.1% versus 12.2%) for the composite criteria consisting of death, myocardial infarction relapse or intracranial bleeding at 30 days.
Pharmacokinetics: The pharmacokinetic parameters of enoxaparin have been evaluated based on the time course of plasma anti-Xa and anti-IIa activity at the recommended doses (validated amidolytic methods) following single and repeated SC administration, and following single IV injection.
Bioavailability: Subcutaneously administered enoxaparin is rapidly and almost completely absorbed (nearly 100%). Peak plasma activity is observed between 3 and 4 hours after administration.
This peak activity (expressed as Anti-Xa IU) is 0.18±0.04 (after administration of 2000 Anti-Xa IU), 0.43±0.11 (after administration of 4000 Anti-Xa IU) in prophylactic treatment, and 1.01±0.14 (after administration of 10,000 Anti-Xa IU) in curative treatment.
Enoxaparin pharmacokinetics appears to be linear over the recommended dose ranges. Intra- and inter-patient variability is low. After repeated SC administration of Anti-Xa 4000 IU once daily in healthy volunteers, the steady state is reached on day 2 with mean enoxaparin activity of approximately 15% higher than that obtained after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics.
After repeated SC administration of 100 Anti-Xa IU/kg twice daily, the steady state is reached between day 3 and 4 with mean exposure about 65% higher than after a single dose, and with maximum and minimum anti-Xa activity of about 1.2 and 0.52 Anti-Xa IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and is within the therapeutic range.
Plasma anti-IIa activity after SC administration is about 10-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3-4 hours following SC injection and reaches 0.13 anti-IIa IU/ml following repeated administration of a 100 Anti-Xa IU/kg-dose twice daily.
6000 Anti-Xa IU: An IV bolus injection of 3000 Anti-Xa IU followed by 100 anti-Xa IU/kg by the SC route every 12 hours leads to a first peak in anti-Factor Xa levels of 1.16 IU/ml (n=16) and a mean exposure corresponding to 88% of the steady state level. Steady state is reached as of the second day of treatment.
No pharmacokinetic interaction has been observed between enoxaparin and the thrombolytic agent when co-administered.
Distribution: The volume of distribution of enoxaparin anti-Xa activity is about 5 liters and is close to the blood volume.
Metabolism: Enoxaparin is primarily metabolized in the liver (desulfation, depolymerization).
Elimination: Following SC injection, the apparent anti-Xa activity elimination half-life is higher for LMWHs than for unfractionated heparins.
Enoxaparin exhibits a monophasic elimination pattern with a half-life of about 4 hours after a single SC dose to about 7 hours after repeated dosing by SC route.
With LMWH, plasma decay occurs more quickly for anti-IIa activity than for anti-Xa activity.
Enoxaparin and its metabolites are eliminated via the renal route (nonsaturable mechanism) and by the biliary route. Renal clearance of fragments with anti-Xa activity accounts for about 10% of the administered dose, and the total renal excretion of active and non-active compounds for 40% of the dose.
Special Populations: Elderly Subjects: As kidney function is physiologically impaired in this population, elimination is slower. This does not affect doses or the administration schedule in prophylactic treatment as long as the renal function of these patients remains within acceptable limits i.e., only slightly impaired.
It is essential to systematically assess renal function in elderly patients aged over 75 years using the Cockcroft formula before initiating treatment with LMWH.
2000/4000 Anti-Xa IU: Hemodialysis: LMWH is injected in the arterial line of the dialysis circuit at sufficient doses to avoid coagulation in the circuit.
The pharmacokinetic parameters remain, in principle, unchanged except in cases of overdose or where the drug passes into the general circulation, causing high anti-Xa activity related to end-stage renal failure.
Pregnancy: Low molecular weight heparins are unlikely to cross the placental barrier, but data on the subject remain insufficient.
6000 Anti-Xa IU: Patients with mild to moderate renal failure (i.e. creatinine clearance >30 ml/min): In certain cases, it may be useful to monitor the circulating anti-factor Xa activity to prevent overdose when enoxaparin is used as curative treatment.

This heparin is a low molecular weight heparin (LMWH).
2000/4000 Anti-Xa IU: Prophylactic treatment of venous thromboembolic disease in moderate or high risk surgery.
Prevention of clotting in the extracorporeal circulation during hemodialysis (generally a session of 4 hours or less).
4000 Anti-Xa IU: Prophylactic treatment of deep vein thrombosis in patients who are bedridden due to an acute medical condition: heart failure (NYHA class III or IV); acute respiratory failure; episode of acute infection or acute rheumatic disorder associated with at least one other risk of venous thromboembolism factor.
6000 Anti-Xa IU: Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) as an adjunctive to thrombolytic treatment and in combination with antiaggregation treatment, including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).

General recommendation: Regular monitoring of the platelet count is essential throughout the treatment due to the risk of heparin-induced thrombocytpenia (HIT). (See Precautions.)
Subcutaneous route (2000/4000 Anti-Xa IU: except in the hemodialysis indication. 6000 Anti-Xa IU: except for patient with acute ST-segment elevation myocardial infarction in whom IV bolus administration is required): This presentation is suitable for adults.
Do not inject via the the intramuscular route.
One milliliter of solution for injection is equivalent to approximately 10,000 anti-Xa IU of enoxaparin.
2000/4000 Anti-Xa IU: Prophylactic treatment of venous thromboembolic disease in surgery: As a general rule, these recommendations apply to surgical procedures carried out under general anesthesia.
For spinal and epidural anesthesia techniques, the benefit of a preoperative injection of enoxaparin should be weighed against the theoretically increased risk of spinal hematoma (see Precautions).
Administration schedule: One injection per day.
Dosage: The dose must be determined based on the risk related to the patient and the type of surgery.
Surgery involving moderate thrombogenic risk: In surgery involving moderate thrombogenic risk and in patients who are not at high risk of thromboembolism, effective prevention is achieved by daily injection of 2 000 anti-Xa IU (0.2 mL).
The studied dosage regimen involves administration of the first injection approximately 2 hours before surgery.
Surgery involving high thrombogenic risk: Hip and knee surgery: The dosage is 4 000 anti-Xa IU (0.4 mL) injected once daily. The studied dosage regimen involves either administration of the first injection of 4 000 anti-Xa IU (total dose) 12 hours before surgery, or a first injection of 2 000 anti-Xa IU (half dose) 2 hours before surgery.
Other situations: When there appears to be an increased risk of venous thromboembolism related to the type of surgery (particularly cancer surgery) and/or due to the patient (particularly history of venous thromboembolism), administering a prophylactic dose identical to that for high risk surgery, such as hip or knee surgery, can be considered.
Duration of treatment: Treatment with LMWH should be maintained, along with the usual methods of elastic support for the legs, until the patient is fully and actively ambulatory.
In general surgery, the duration of LMWH treatment must be less than 10 days, unless there is a patient-specific risk of venous thromboembolism (see Precautions).
The therapeutic benefit of prophylactic treatment consisting of a daily injection of 4 000 anti-Xa IU/day of enoxaparin for 4 to 5 weeks after hip surgery has been established.
However, the clinical benefit of long-term treatment with low molecular weight heparins or oral anticoagulants has not yet been evaluated.
4000 Anti-Xa IU: If the patient is still at risk of venous thromboembolism after the recommended treatment duration, continuing prophylactic therapy must be considered, particularly by administration of oral anticoagulants.
Prevention of clotting in the extracorporeal circulation/hemodialysis: Inject by the intravascular route (in the arterial line of the dialysis circuit).
In patients undergoing repeated hemodialysis sessions, preventing of clotting in the extrarenal purification system is obtained by injecting an initial dose of 100 anti-Xa IU/kg in the arterial line of the dialysis circuit at the beginning of session.
This dose, administered as a single intravascular bolus injection, is only suitable for hemodialysis sessions of 4 hours or less. If fibrin rings are found in the dialysis device, an additional dose of 50 to 100 anti-Xa IU/kg may be injected, depending on the time to the end of dialysis.
In hemodialysis patients at high risk of hemorrhage (particularly pre- and post-operative dialysis) or with active hemorrhage, dialysis sessions may be carried out using a dose of 50 anti-Xa IU/kg (double vascular access) or 75 anti-Xa IU/kg (single vascular access).
4000 Anti-Xa IU: Prophylactic treatment of deep vein thrombosis in patients who are bedridden due to an acute medical condition: Dosage: 40 mg or 4000 anti-Xa IU/0.4 ml injected subcutaneously once daily.
Duration of treatment: It has been demonstrated that treatment is beneficial for between 6 to 14 days. To date, no efficacy and safety data are available concerning prophylaxis for more than 14 days. If the risk of venous thromboembolism persists, prolonged prophylactic treatment, particularly with oral anticoagulants, must be considered.
6000 Anti-Xa IU: Curative treatment of deep vein thrombosis (DVT), with or without pulmonary embolism, without signs of clinical severity: Any suspected deep vein thrombosis should be quickly confirmed by the appropriate examinations.
Administration schedule: Two injections daily at 12-hour intervals.
Dose: The dose per injection is 100 anti-Xa IU/kg.
LMWH dosage has not been evaluated in terms of body weight in patients weighing more than 100 kg or less than 40 kg. The efficacy of LMWH treatment may be slightly lower in patients weighing more than 100 kg, and the risk of hemorrhage may be higher in patients weighing less than 40 kg. Specific clinical monitoring must be carried out in these patients.
DVT treatment duration: Treatment with low molecular weight heparins should be quickly replaced by oral anticoagulant therapy, unless contraindicated. Treatment duration with LMWH should not exceed 10 days, including the time needed to reach the required oral anticoagulant effect, except when this is difficult to achieve (see Laboratory Tests: Platelet Monitoring under Precautions). Oral anticoagulant treatment should, therefore, be initiated as soon as possible.
Curative treatment of unstable angina/non-Q-wave myocardial infarction: A dose of 100 anti-Xa IU/kg of enoxaparin is administered by subcutaneous injection twice daily at 12-hour intervals, in combination with aspirin (recommended doses: 75 to 325 mg orally, following a minimum loading dose of 160 mg).
The recommended duration of treatment is about 2-8 days, until the patient is clinically stable.
Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent in patients eligible or not for subsequent coronary angioplasty: An initial IV bolus injection of 3 000 anti-Xa IU followed by an SC injection of 100 anti-Xa IU/kg within 15 minutes, then every 12 hours (a maximum of 10,000 anti-Xa IU for the first two SC doses). The first dose of enoxaparin should be administered at any time between 15 minutes before and 30 minutes after the start of thrombolytic treatment (whether fibrin-specific or not). The recommended duration of treatment is 8 days, or until the patient is discharged from hospital if the hospitalization period is less than 8 days.
Concomitant treatment: administration of aspirin must be instituted as soon as possible after symptoms appear and maintained at a dosage between 75 mg and 325 mg daily for at least 30 days, unless otherwise indicated.
Patient treated by coronary angioplasty: if the last SC injection of enoxaparin was performed less than 8 hours before balloon inflation, no additional administration is necessary.
If the last SC injection was performed more than 8 hours before balloon inflation, an IV bolus of enoxaparin 30 anti-Xa IU/kg must be administered. In order to improve the accuracy of the volumes to be injected, it is recommended to dilute the drug to 300 IU/ml (i.e. 0.3 ml of enoxaparin diluted in 10 ml) (see Table 1 as follows.)


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In patients aged 75 years and over treated for acute ST-segment elevation myocardial infarction, the initial IV bolus injection should not be administered. An SC dose of 75 anti-Xa IU/kg every 12 hours should be administered (maximum of 7,500 anti-Xa IU for the first two injections only).
Administration: Subcutaneous injection technique: Enoxaparin should be administered by injection into the subcutaneous tissue preferably with the patient supine. Administration should be alternated between the left and right anterolateral or posterolateral abdominal wall.
The whole length of the needle should be inserted perpendicularly, not from the side, into a skin fold held between the thumb and index finger. The skin fold should be held throughout the injection.
2000 Anti-Xa IU/4000 anti-Xa IU: The pre-filled syringe is ready for immediate use; do not press on the plunger to expel any air bubbles before injecting the drug.
6000 Anti-Xa IU: The dose of enoxaparin to be injected should be adjusted according to patient body weight and any excess volume discarded before administering the injection. When there is no excess volume, the air should not be expelled from the syringe before the injection. Intravenous (bolus) injection technique / Using the multidose vial of Lovenox 30 000 anti- Xa IU/3 ml for the treatment of acute ST-segment elevation myocardial infarction: 6000 Anti-Xa IU: Treatment is initiated with an IV bolus injection, immediately followed by an SC injection. The multidose vial should be used to allow the initial dose of 3 000 IU, i.e. 0.3 ml to be withdrawn using a graduated 1 ml syringe (insulin-type syringe). This dose of enoxaparin should be injected into a venous line, and must not be mixed or administered with other medicinal products. To avoid any traces of other medicinal products and therefore to prevent them from mixing with enoxaparin, the injection line must be rinsed with a sufficient quantity of normal saline or glucose solution before and after IV bolus injection of enoxaparin. Enoxaparin can be safely administered with 0.9% normal saline solution or 5% glucose solution.
In the hospital setting, the multidose vial can be used to: obtain the required 100 IU/kg dose for the first SC injection, to be given along with the IV bolus, and then the required 100 IU/kg doses for SC injection, repeated every 12 hours; obtain the 30 IU/kg dose for IV bolus injection for patients undergoing subsequent coronary angioplasty.

Accidental overdose following subcutaneous administration of massive doses of low molecular weight heparin may result in hemorrhagic complications.
In case of hemorrhage, certain patients can be treated with protamine sulfate, taking the following factors into account: its efficacy is far lower than that reported in overdoses with unfractionated heparin; due to its unwanted effects (particularly anaphylactic shock), the benefit/risk ratio of protamine sulfate should be carefully weighed beforehand.
Neutralization is performed by slow intravenous injection of protamine (sulfate or hydrochloride).
The protamine dose required depends on: The heparin dose injected (100 anti-heparin units of protamine neutralizes the activity of 100 anti-Xa IU of low molecular weight heparin), if the enoxaparin sodium was administered within the last 8 hours.
The time since the heparin injection: An infusion of 50 anti-heparin units of protamine per 100 anti-Xa IU of enoxaparin sodium can be administered if the enoxaparin sodium was given more than 8 hours earlier, or if a second dose of protamine appears necessary; administration of protamine is not necessary if the enoxaparin injection was given more than 12 hours earlier. The above recommendations are intended for patients with normal renal function receiving repeated doses.
Nevertheless, the anti-Xa activity of enoxaparin cannot be completely neutralized.
Furthermore, the neutralization may only be transient due to the absorption pharmacokinetics of low molecular weight heparin.
This may require dividing the total calculated dose of protamine into several injections (2 to 4) given over 24 hours.
Serious consequences are likely after ingestion of low molecular weight heparin, even in massive quantities (no cases reported), due to the low gastric and intestinal absorption of the drug.

This medical product must not be used in the following situations: Hypersensitivity to enoxaparin, heparin or heparin derivatives, including other LMWHs; Organic lesion likely to bleed; Clinically significant active bleeding.
History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies.
As there are no relevant data, severe renal failure (creatinine clearance of approximately 30 ml/min as per the Cockroft formula), except in the particular case of dialysis patients.
In patients with severe renal failure, unfractionated heparin should be used. For the calculation using the Cockroft formula, a recent bodyweight measurement is necessary (see Precautions).
Hemorrhagic manifestations or tendency to bleed related to impaired hemostasis (a possible exception to this contraindication may be disseminated intravascular coagulation, when it is not related to heparin therapy (see Precautions).
2000/4000 Anti-Xa IU: History of thrombocytopenia with enoxaparin or any other heparin, whether caused by unfractionated or low molecular weight heparin (see Precautions).
Acute infectious endocarditis (except when occurring on a mechanical prosthesis).
6000 Anti-Xa IU: History of serious type II heparin-induced thrombocytopenia (HIT), whether caused by unfractionated or low molecular weight heparin (see Precautions); Intracerebral hemorrhage; Spinal or epidural anesthesia must never be performed in patients under curative LMWH treatment.
This medicinal product is generally not advisable in the following cases: Mild to moderate renal failure (creatinine clearance >30 and <60 ml/min).
2000/4000 Anti-Xa IU: Haemorrhagic stroke. Uncontrolled arterial hypertension.
6000 Anti-Xa IU: Acute extensive ischemic stroke, with or without impaired consciousness.
If the stroke is caused by embolism, enoxaparin must not be administered for 72 hours following the event.
The efficacy of curative doses of LMWH has however not yet been established, regardless of the cause, extent or clinical severity of cerebral infarction.
Acute infectious endocarditis (except for some emboligenic cardiac conditions).
In addition, this drug is generally not advisable when combined with the following (see Interactions): Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses; NSAIDs (systemic use); dextran 40 (parenteral use); ticlopidine.

Quantification: The concentrations of the various low molecular weight heparins are expressed using different systems, i.e. non equivalent units or mg. Special care is therefore required and the specific instructions for each product should be followed exactly.
Risk of hemorrhage: The recommended dosage regimens must be respected (dosage and duration of treatment). Failure to comply with these recommendations can lead to hemorrhage, particularly in high-risk patients (the elderly, patients with renal failure, etc.)
Serious hemorrhage events have been reported in the following situations: Elderly subjects, particularly due to age-related renal impairment; patients with renal failure; bodyweight below 40 kg; treatment lasting longer than the recommended mean duration of ten days; non-compliance with therapeutic recommendations; co-administration with drug increasing the risk of hemorrhage.
In any event, special monitoring is indispensable in the elderly and/or patients with renal failure, as well as during treatment for more than ten days.
Assay of anti-Xa activity may in certain cases be useful in detecting accumulation.
Risk of heparin-induced thrombocytopenia (HIT): Should a patient treated with LMWH (curative or preventive dose) develop thromboembolic complications such as: exacerbation of the thrombosis being treated; phlebitis; pulmonary embolism; acute ischemia of the lower limbs; or even myocardial infarction or ischemic stroke.
HIT should systematically be suspected and a platelet count performed urgently.
Use in children: As no relevant data are available, use of LHWH is not recommended in children.
2000/4000 Anti-Xa IU: Spinal/epidural anesthesia: As with other anticoagulants, there have been rare reports of spinal haematomas following the administration of enoxaparin during spinal/epidural anesthesia, resulting in long-term or permanent paralysis. The risk of these rare events may be increased by prolonged use of postoperative indwelling epidural catheters.
Mechanical prosthetic heart valves: The use of enoxaparin in the prevention of thromboembolic events in patients with mechanical prosthetic heart has not been specifically investigated. However, some isolated cases of thrombosis have been reported in patients with this devise who received enoxaparin as prophylactic treatment of thomboembolic events.
Pregnant women: During a clinical study in pregnant women with mechanical prosthetic heart valves receiving 100 anti-Xa IU/kg bodyweight of enoxaparin twice daily to reduce the risk of thromboembolic events, two of eight women developed thrombosis which led to an obstructed valve with fatal outcome for both the woman and the fetus. In addition, other isolated post-marketing cases of thrombosis have been reported in pregnant women with mechanical prosthetic heart valves who received thromboembolic prophylaxis with enoxaparin. Therefore, the risk of thromboembolic events in this population might be higher.
4000 Anti-Xa IU: Prophylactic treatment in acute medical conditions: In the event of an acute episode of infection or bone-joint disease, prophylactic treatment is only justified if the condition is associated with at least one of the following venous thromboembolic risk factor: age >75 years; cancer; history of venous thromboembolism; obesity; hormone therapy; heart failure; chronic respiratory failure.
In medical prophylaxis, there is very limited clinical experience in elderly patients over 80 years of age whose bodyweight is below 40 kg.

Hemorrhage: As with all anticoagulants, bleeding may occur. If the event of bleeding, the cause must be investigated and appropriate treatment instituted.
Renal function: Before low molecular weight heparin treatment is initiated, it is essential to evaluate renal function in subjects 75 years or older by determining creatinine clearance (CrCl) using Cockcroft's formula and recent bodyweight measurement: In male patients: Clcr = (140-age) x weight / (0.814 x serum creatinine) where age is expressed in years , weight in kg and serum creatinine in mcg μmol/L.
This formula must be adjusted for female patients by multiplying the result by 0.85.
When serum creatinine is expressed in mg/mL, the value should be multiplied by a factor of 8.8.
In patients diagnosed with severe renal failure (creatinine clearance of about 30 ml/min), the use of LMWH as curative intent is contraindicated.
Obese patients: Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI > 30 kg/m²) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.
History of HIT (>100 days): Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated (see section Contraindications). Circulating antibodies may persist several years. Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments are considered.
Laboratory tests: Platelet monitoring: Heparin-induced thrombocytopenia (HIT): There is a risk of serious, occasionally thrombogenic heparin-induced thrombocytopenia (reported with unfractionated heparin and less often with LMWH) of immunologic origin, called type II HIT.
As a result of this risk, platelet counts must be performed regardless of the therapeutic indication and the dose administered.
Platelet counts must be performed before administration or at the latest within 24 hours of initiating treatment, then twice a week during the usual treatment duration.
Should long-term treatment prove necessary in certain specific cases (i.e. hip surgery, second and third trimesters of high-risk pregnancy, the schedule for platelet counts is twice a week during the first month of treatment (highest risk period) and then once a week until treatment discontinuation.
HIT should be suspected when the platelet count is below 100,000/mm3 and/or when there is a drop of 30 to 50% between two successive platelet counts. HIT mainly develops 5 to 21 days after heparin treatment is instituted (with a peak incidence after about 10 days).
This complication can however occur much earlier in patients with a history of heparin-induced thrombocytopenia and extremely rare cases have been reported after 21 days. This type of patient history must therefore be systematically investigated by means of an in-depth interview before starting treatment.
Furthermore, the risk of recurrence when reinstituting heparin may remain for years or even indefinitely.
In all cases, the occurrence of HIT constitutes an emergency situation and requires a specialist opinion.
Any significant drop in the platelet count (30% to 50% versus baseline) is a warning sign even before values reach a critical level. Should a decrease in platelets be observed, the following must be performed in all cases: an immediate platelet count for verification; discontinuation of heparin treatment, if the drop is confirmed or even increased based on these results and when no other obvious cause is identified. A sample must be taken using a citrate tube in order to perform in vitro platelet aggregation and immunological assays. However, under these conditions, the immediate measures to be taken are not based on in vitro platelet aggregation or immunological test results as only a few specialized laboratories perform these tests routinely and the results are available at best after several hours. These tests are, however, necessary to assist in diagnosis of the complication as the risk of thrombosis is very high if heparin treatment is continued.
Prevention or treatment of HIT-related thrombotic complications. If continued anticoagulant therapy appears to be essential, heparin must be replaced by an antithrombotic agent of a different chemical group of such as sodium danaparoid or hirudine, prescribed at curative or preventive doses on a case-by-case basis.
Replacement by oral anticoagulants can only take place after the platelet count has reverted to normal due to the risk of exacerbation of thrombosis by oral anticoagulants.
Replacement of heparin by oral anticoagulants: Clinical monitoring and laboratory tests (one stage prothrombin time expressed as the INR) must be intensified to monitor the effect of oral anticoagulants. As there is an interval before the oral anticoagulant has reached its maximum effect, heparin therapy should be maintained at an equivalent dose so that the INR remains within the desired therapeutic range for the indication in two successive tests.
Monitoring of anti-factor Xa activity: As most of the clinical studies which demonstrated the efficacy of LMWH were conducted using a dose based on bodyweight without specific laboratory monitoring, the utility of laboratory tests for assessing the efficacy of LMWH treatment has not been established. However, monitoring of anti-Xa activity may be useful in managing the risk of bleeding in certain clinical conditions often associated with a risk of overdose.
These situations mainly concern the curative indications of LMWH, due to the doses administered, in patients with: mild to moderate renal insufficiency (creatinine clearance of approximately 30 ml/min to 60 ml/min calculated using the Cockcroft formula). As LMWH is primarily eliminated by the renal route, unlike standard unfractionated heparin, any renal insufficiency can result in relative overdose. Severe renal insufficiency is a contraindication to the use of LMWH at curative treatment. Extreme bodyweight (thinness or even cachexia, obesity). Unexplained bleeding.
In contrast, laboratory monitoring is not recommended at prophylactic doses if the LMWH treatment is consistent with the therapeutic recommendations (particularly treatment duration), nor during hemodialysis.
To detect possible heparin accumulation following repeated administration, it is recommended, if necessary, to collect a blood sample at peak activity (based on available data), i.e. approximately 4 hours after the third injection when the drug is given as 2 subcutaneous injections per day.
Repeating anti-Xa activity assays to determine blood heparin levels, for example every 2 to 3 days, should be decided on a case-by-case basis, depending on the results of the preceding assay, and a possible LMWH dose adjustment should be considered.
The anti-Xa activity observed varies for each LMWH and each dosage regimen.
For information, based on available data, the mean value (± standard deviation) observed 4 hours after 7th injection of enoxaparin given at a dose of 100 anti-Xa IU/kg/injection b.i.d. was 1.20 ± 0.17 anti-Xa IU/ml.
This mean value was observed during clinical trials for anti-Xa activity assays carried out by a chromogenic method (amidolytic).
Activated partial thromboplastin time (aPTT): Some LMWHs moderately increase aPTT. As no clinical relevance has been established, there is no need to monitor treatment using this tests.
2000/4000 Anti-Xa IU: Spinal/epidural anesthesia in patients given preventive treatment with LMWH: Epidural or spinal anesthesia must never be performed in patients under curative LMWH treatment.
As with other anticoagulants, there have been rare reports of spinal hematomas following administration of LMWH during spinal/epidural anesthesia, resulting in long-term or permanent paralysis.
The risk of intra-spinal hematoma appears to be higher in epidural anesthesia with a catheter than in spinal anesthesia.
The risk of these rare events may be increased by prolonged post-operative use of indwelling epidural catheters and in patients who have undergone spinal surgery or have spinal deformities (e.g. ankylosing spondylitis).
Placement or removal of the catheter is best performed when the anticoagulant effect of enoxaparin is low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
If pre-operative LMWH treatment is required (long term bedridden patients, trauma) and if the benefit of local/regional spinal anesthesia has been carefully weighed, patients who received a pre-operative injection of LMWH can be anesthetized provided that an interval of at least 12 hours is respected between the heparin injection and the spinal anesthesia. Since anti-Xa levels are, however, still detectable after this 12-hour interval, a neuraxial hematoma can still occur. Close neurological monitoring is recommended due to the risk of intraspinal hematoma.
In almost all patients, prophylactic treatment with LMWH can be initiated within 6 to 8 hours after the anesthesia or removal of the catheter, under neurogical monitoring.
Extra caution should be exercised during co-administration with other drugs which affect hemostasis (specifically non-steroidal anti-inflammatory drugs, aspirin).
Situations involving particular risk: Monitoring of treatment should be intensified in the following cases: hepatic insufficiency; history of gastrointestinal ulcers or any other organic lesion likely to bleed; vascular chorioretinal disease; post-operatively, following cerebral or spinal cord surgery; lumbar puncture: this should only be considered taking into account the risk of intraspinal bleeding. It should be postponed whenever possible; combined use with drug which have an effect on hemostasis.
6000 anti-Xa IU: Coronary angioplasty revascularization procedure: To minimize the risk of hemorrhage during coronary angioplasty for unstable angina, non-Q-wave myocardial infarction and acute ST segment elevation myocardial infarction, it is recommended that the advised intervals between enoxaparin injections be strictly complied with. It is important to perform hemostasis at the vascular puncture site following coronary angioplasty. If an occlusion device is used, the introducer can be removed immediately. If manual compression is performed, the introducer must be removed 6 hours after the last SC/IV injection of enoxaparin. If enoxaparin treatment is continued, the following injection must be performed at the earliest 6 to 8 hours after removal of the introducer. The puncture site must be monitored to detect any signs of bleeding or hematoma.

Pregnancy: There is no evidence from animal studies that enoxaparin has teratogenic potential.
In the absence of any teratogenic effect in animals, no such effect is expected in man. To date, substances responsible for malformation in humans have proved to be teratogenic in animals during well-conducted studies into two species.
Current clinical data are insufficiently relevant to determine a possible malformative or fetotoxic effect of enoxaparin administered at curative doses throughout pregnancy.
The use of curative doses of enoxaparin is therefore not recommended throughout pregnancy as a precaution.
Spinal or epidural anesthesia must never be performed during curative treatment with LMWH.
Prophylactic treatment during the first trimester: There are not enough relevant clinical data concerning possible teratogenic or fetotoxic effects of enoxaparin when the drug is administered preventively during the first trimester.
As a precautionary measure, enoxaparin prophylaxis should not be administered during the first trimester.
If epidural anesthesia is planned, prophylactic heparin treatment should be interrupted whenever possible within 12 hours before anesthesia at the latest.
Prophylactic treatment during the second and third trimesters: Administration of prophylactic doses of enoxaparin to women during the second and third trimesters in a limited number of pregnancies has apparently not resulted in any particular teratogenic or fetotoxic effects. However, additional studies are needed to evaluate the effects of exposure under these conditions.
Therefore, enoxaparin prophylaxis during the second and third trimesters should only be administered if necessary.
If epidural anesthesia is planned, preventive heparin treatment should be interrupted whenever possible within 12 hours before anesthesia at the latest.
Lactation: Since in principle, gastrointestinal absorption by neonates is unlikely in principle, treatment with enoxaparin is not contraindicated in breast-feeding.

The adverse reactions observed in clinical studies and reported in post-marketing experience are detailed as follows.
Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100), rare (≥1/10 000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Frequency for undesirable effects reported during the post-marketing period is defined as "not known" (cannot be estimated from the available data).
Clinical trials experience: Enoxaparin was evaluated in more than 15,000 patients in clinical trials.
The number of patients, indication and dosage regimen are presented in detail in the following table. (See Table 2.)


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Hemorrhage: In clinical studies, hemorrhages were the most commonly reported reaction. These included major hemorrhages, reported in 4.2 % of patients (surgical patients). Some of these cases were fatal.
Bleeding complications were considered major in the following cases: If the hemorrhage caused a significant clinical event; If accompanied by a hemoglobin decrease of ≥ 2 g/dl or transfusion of 2 or more units of blood products; Retroperitoneal and intracranial hemorrhages were always considered major.
As with other anticoagulants, hemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed; invasive procedures or concomitant use of medications affecting hemostasis. (See Table 3.)


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Thrombocytopenia and Thrombocytosis: (See Table 4.)


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Other adverse reactions observed in clinical studies: These reactions are presented below, irrespective of the indication, by system organ class, frequency grouping and decreasing order of seriousness. (See Table 5.)


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Post Marketing Experience: The following adverse reactions have been identified during postapproval use of Lovenox. Because these reactions are reported voluntarily, the frequency is “not known” (cannot be estimated from the available data).
Immune System Disorders: Cutaneous or systemic allergic effects (anaphylactic or anaphylactoid reactions, including shock), which, in certain cases, may lead to treatment discontinuation.
Nervous System Disorders: Headache.
Vascular Disorders: Hemorrhagic episodes that mainly occur in the following context: associated risk factors: organic lesions likely to bleed and certain drug combinations (see Interactions), age, renal failure, low body weight; failure to comply with therapeutic recommendations, particularly duration of treatment and dose adjustment based on body weight.
Rare cases of spinal hematoma have been reported with low molecular weight heparins (LMWH) in patients receiving spinal anesthesia, analgesia or epidural anesthesia. These hematomas have resulted in more or less serious neurologic injury, including long-term or permanent paralysis.
Blood and Lymphatic System Disorders: Thrombocytopenia has been reported.
There are two types: Type I, i.e. the most common cases, usually moderate (more than 100
000/mm3), of early onset (before the fifth day) which do not require treatment discontinuation; Type II, i.e. rare, serious immunoallergic thrombocytopenia (HIT). The incidence remains poorly evaluated.
Asymptomatic and reversible elevation of the platelet count.
Hemorrhagic anemia.
Hypereosinophilia, occurring in isolated cases or along with skin reactions, resolving on treatment discontinuation.
Skin and Subcutaneous Disorders: Vasculitis due to skin hypersensitivity.
Skin necrosis observed in most cases at the injection site. These reactions may be preceded by purpura or by infiltrated and painful erythematous plaques. Treatment must be discontinued immediately in these cases.
Alopecia.
Hepatobilary Disorders: Hepatocellular or cholestatic liver injury.
Musculoskeletal and Connective Tissue Disorders: Osteoporosis following long-term therapy.

Certain drugs or therapeutic classes may promote the occurrence of hyperkalemia: potassium salts, potassium-sparing diuretics, conversion enzyme inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory drugs, heparins (low molecular weight and unfractionated heparin), ciclosporin and tacrolimus, trimethoprim.
Occurrence of hyperkalemia may depend on possible related risk factors.
This risk is potentiated when the above-mentioned drugs are co-administered.
Inadvisable combinations: Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses (and, by extrapolation, other salicylates): Increased risk of hemorrhage (salicylic-induced platelet function inhibition and gastroduodenal mucosal damage).
Use a non-salicylate antipyretic analgesic (such as paracetamol).
NSAIDs (systemic use): Increased risk of hemorrhage (NSAID-induced platelet function inhibition and gastroduodenal mucosal damage).
If co-administration cannot be avoided, close clinical monitoring is required.
Dextran 40 (parenteral use): Increased risk of hemorrhage (inhibition of platelet function by dextran 40). Adjust heparin dosage so that the coagulation test performed as a measure of hypocoagulability does not exceed 1.5 times the control value during co administration and after discontinuation of dextran 40.
Ticlodipine: Increased risk of hemorrhage (inhibition of platelet function by ticlopidine).
Combinations requiring precautions for use: Corticoids (glucocorticoids) (except for hydrocortisone used as replacement therapy in Addison's disesase) (systemic use and, in certain cases local uses, i.e. intramuscular, intraarticular or cutaneous use of rectal washout).
Heparin-related increase in the risk of haemorrhage specific to corticoid therapy (gastric mucosa, vascular fragility), at high doses or during prolonged treatment lasting more than ten days. If the combination cannot be avoided clinical monitoring must be intensified.
Oral anticoagulants: Potentiation of the anticoagulant effect.
When heparin is replaced by an oral anticoagulant, clinical monitoring must be intensified.
Combinations to take into consideration: Platelet aggregation inhibitors (other than acetylsalicylic acid as analgesic, antipyretic and anti-inflammatory doses; NSAIDs): abciximab, acetylsalicylic acid at antiaggregant doses in cardiological and neurological indications, baraprost, clopidogrel, eptifibatide, iloprost, ticlopidine and tirofiban.
Increased risk of hemorrhage.
2000/4000 anti-Xa IU: Patients under 65 years of age: Combinations to take into consideration: Combined use of drugs which variably affect hemostasis potentiate the risk of bleeding. Therefore, regardless of the age of the patients, co-administration of LMWH at preventive doses with the following drugs must be taken into consideration by means of continued clinical monitoring and possible laboratory tests: oral anticoagulants, platelet aggregation inhibitors (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticloprost, ticlopidine, tirofiban) and thrombolytic agents.

Store below 25°C. Do not freeze.
Shelf life: 24 months.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AB05 - enoxaparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.

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