CLEXANE Enoxaparin Sodium 4000IU / 0.4mL Solution for SC Injection 0.4mL 1's
RXDRUG-BR-797-1
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Features
Brand
Clexane
Full Details
Dosage Strength
4000 IU (equivalent to 40 mg) / 0.4 ml
Drug Ingredients
- Enoxaparin
Drug Packaging
Solution for SC Injection 0.4mL 1's
Generic Name
Enoxaparin Sodium
Dosage Form
Solution for SC Injection
Registration Number
BR-797
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Prophylaxis of venous thrombo-embolic disease, in particular those which may be associated with orthopedic or general surgery.
Prophylaxis of venous thrombo-embolism in medical patients bedridden due to acute illnesses including cardiac insufficiency, respiratory failure, severe infections, rheumatic diseases.
Treatment of deep vein thrombosis with or without pulmonary embolism.
Prevention of thrombus formation in extra corporeal circulation during hemodialysis.
Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).
Prophylaxis of venous thrombo-embolism in medical patients bedridden due to acute illnesses including cardiac insufficiency, respiratory failure, severe infections, rheumatic diseases.
Treatment of deep vein thrombosis with or without pulmonary embolism.
Prevention of thrombus formation in extra corporeal circulation during hemodialysis.
Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI).
Dosage/Direction for Use
General: Prophylaxis of venous thrombosis in surgical patients: In patients with a moderate risk of thrombo-embolism (e.g. abdominal surgery), the recommended dose of enoxaparin sodium is 20 mg or 40 mg once daily by subcutaneous injection. In general surgery, the first injection should be given 2 hours before the surgical procedure.
In patients with a high risk of thrombo-embolism (e.g. orthopedic surgery), the recommended dose of enoxaparin sodium given by subcutaneous injection, is 40 mg once daily, initiated 12 hours prior to surgery or 30 mg twice daily, initiated 12 to 24 hours after surgery.
Enoxaparin sodium treatment is usually prescribed for an average period of 7 to 10 days. Longer treatment duration may be appropriate in some patients and enoxaparin sodium should be continued for as long as there is a risk of venous thrombo-embolism and until the patient is ambulatory. Continued therapy with 40 mg once daily for 3 weeks following the initial therapy has been proven to be beneficial in orthopedic surgery.
For special recommendations concerning dosing intervals for Spinal/Epidural Anesthesia and Percutaneous coronary revascularisation procedures: see Warnings.
Prophylaxis of venous thrombo-embolism in medical patients: The recommended dose of enoxaparin sodium is 40 mg once daily by subcutaneous injection. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until the return to full ambulation, for a maximum of 14 days.
Treatment of deep vein thrombosis with or without pulmonary embolism: Enoxaparin sodium can be administered subcutaneously either as a single injection of 1.5 mg/kg or as twice daily injections of 1 mg/kg. In patients with complicated thrombo-embolic disorders, a dose of 1 mg/kg administered twice daily is recommended.
Enoxaparin sodium treatment is usually prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate and enoxaparin sodium treatment should be continued until a therapeutic anticoagulant effect has been achieved (International Normalisation Ratio 2 to 3).
Prevention of extra corporeal thrombus during hemodialysis: The recommended dose is 1 mg/kg of enoxaparin sodium.
For patients with a high risk of hemorrhage, the dose should be reduced to 0.5 mg/kg for double vascular access or 0.75 mg/kg for single vascular access. During hemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if fibrin rings are found, for example after a longer than normal session, a further dose of 0.5 to 1 mg/kg may be given.
Treatment of unstable angina and non-Q-wave myocardial infarction: The recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours by subcutaneous injection, administered concurrently with oral aspirin (100 to 325 mg once daily).
Treatment with enoxaparin sodium in these patients should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days.
Treatment of acute ST-segment Elevation Myocardial Infarction: The recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (max 100 mg for each of the first two SC doses only, followed by 1 mg/kg SC dosing for the remaining doses). For dosage in patients ≥75 years of age, see Special Populations Elderly.
When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained under (75 to 325 mg once daily) unless contraindicated.
The recommended duration of enoxaparin sodium treatment is 8 days or until hospital discharge, whichever comes first.
For patients managed with Percutaneous Coronary Intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium should be administered.
SPECIAL POPULATIONS: Children: The safety and efficacy of enoxaparin sodium in children has not been established.
Elderly: For treatment of acute ST-segment Elevation Myocardial Infarction in elderly 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 each of the first two SC doses only, followed by 0.75 mg/kg SC dosing for the remaining doses).
For other indications, no dose reduction is necessary in the elderly, unless kidney function is impaired (see Pharmacology: Pharmacokinetics: Elderly under Actions, Dosage & Administration, and Precautions).
Hepatic impairment: In the absence of clinical studies, caution should be used in hepatically impaired patients.
Renal impairment: (See Pharmacology: Pharmacokinetics under Actions and Precautions).
Severe renal impairment: A dosage adjustment is required for patients with severe renal impairment (creatinine clearance <30 ml/min), according to the following tables, since enoxaparin sodium exposure is significantly increased in this patient population.
The following dosage adjustments are recommended for therapeutic dosage ranges: (see Table 1.)
In patients with a high risk of thrombo-embolism (e.g. orthopedic surgery), the recommended dose of enoxaparin sodium given by subcutaneous injection, is 40 mg once daily, initiated 12 hours prior to surgery or 30 mg twice daily, initiated 12 to 24 hours after surgery.
Enoxaparin sodium treatment is usually prescribed for an average period of 7 to 10 days. Longer treatment duration may be appropriate in some patients and enoxaparin sodium should be continued for as long as there is a risk of venous thrombo-embolism and until the patient is ambulatory. Continued therapy with 40 mg once daily for 3 weeks following the initial therapy has been proven to be beneficial in orthopedic surgery.
For special recommendations concerning dosing intervals for Spinal/Epidural Anesthesia and Percutaneous coronary revascularisation procedures: see Warnings.
Prophylaxis of venous thrombo-embolism in medical patients: The recommended dose of enoxaparin sodium is 40 mg once daily by subcutaneous injection. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until the return to full ambulation, for a maximum of 14 days.
Treatment of deep vein thrombosis with or without pulmonary embolism: Enoxaparin sodium can be administered subcutaneously either as a single injection of 1.5 mg/kg or as twice daily injections of 1 mg/kg. In patients with complicated thrombo-embolic disorders, a dose of 1 mg/kg administered twice daily is recommended.
Enoxaparin sodium treatment is usually prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate and enoxaparin sodium treatment should be continued until a therapeutic anticoagulant effect has been achieved (International Normalisation Ratio 2 to 3).
Prevention of extra corporeal thrombus during hemodialysis: The recommended dose is 1 mg/kg of enoxaparin sodium.
For patients with a high risk of hemorrhage, the dose should be reduced to 0.5 mg/kg for double vascular access or 0.75 mg/kg for single vascular access. During hemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if fibrin rings are found, for example after a longer than normal session, a further dose of 0.5 to 1 mg/kg may be given.
Treatment of unstable angina and non-Q-wave myocardial infarction: The recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours by subcutaneous injection, administered concurrently with oral aspirin (100 to 325 mg once daily).
Treatment with enoxaparin sodium in these patients should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days.
Treatment of acute ST-segment Elevation Myocardial Infarction: The recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (max 100 mg for each of the first two SC doses only, followed by 1 mg/kg SC dosing for the remaining doses). For dosage in patients ≥75 years of age, see Special Populations Elderly.
When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained under (75 to 325 mg once daily) unless contraindicated.
The recommended duration of enoxaparin sodium treatment is 8 days or until hospital discharge, whichever comes first.
For patients managed with Percutaneous Coronary Intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium should be administered.
SPECIAL POPULATIONS: Children: The safety and efficacy of enoxaparin sodium in children has not been established.
Elderly: For treatment of acute ST-segment Elevation Myocardial Infarction in elderly 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 each of the first two SC doses only, followed by 0.75 mg/kg SC dosing for the remaining doses).
For other indications, no dose reduction is necessary in the elderly, unless kidney function is impaired (see Pharmacology: Pharmacokinetics: Elderly under Actions, Dosage & Administration, and Precautions).
Hepatic impairment: In the absence of clinical studies, caution should be used in hepatically impaired patients.
Renal impairment: (See Pharmacology: Pharmacokinetics under Actions and Precautions).
Severe renal impairment: A dosage adjustment is required for patients with severe renal impairment (creatinine clearance <30 ml/min), according to the following tables, since enoxaparin sodium exposure is significantly increased in this patient population.
The following dosage adjustments are recommended for therapeutic dosage ranges: (see Table 1.)
The following dosage adjustments are recommended for prophylactic dosage ranges: (see Table 2.)
The recommended dosage adjustments do not apply to the hemodialysis indication.
Moderate and mild renal impairment: Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised.
Spinal/epidural anesthesia: For patients receiving spinal/epidural anesthesia, see Warnings.
ADMINISTRATION: Subcutaneous injection: Enoxaparin sodium is administered by subcutaneous injection for the prevention of venous thrombo-embolic 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.
IV bolus injection: For acute ST-segment Elevation Myocardial Infarction, treatment is to be initiated with a single IV bolus injection immediately followed by a subcutaneous injection.
Arterial line injection: It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the extra-corporeal circulation during haemodialysis.
It must not be administered by the intramuscular route.
The pre-filled disposable syringe is ready for immediate use.
Subcutaneous injection technique: Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by deep subcutaneous injection. Do not expel the air bubble from the syringe before the injection to avoid the loss of drug when using the 20 and 40 mg pre-filled syringes. The administration should be alternated between the left and right anterolateral or posterolateral abdominal wall.
The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and index finger. The skin fold should not be released until the injection is complete. Do not rub the injection site after administration (see Cautions for Usage).
Intravenous (Bolus) Injection Technique (for acute STEMI indication only): Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium 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 enoxaparin sodium to clear the port of drug.
Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Initial 30-mg bolus: For the initial 30-mg bolus, using an enoxaparin sodium graduated pre-filled syringe, expel the excessive volume to retain only 30 mg (0.3 ml in the syringe. The 30-mg dose can then be directly injected into the intravenous line.
Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation: For patients being managed with Percutaneous Coronary Intervention (PCI), an additional IV bolus of 0.3 mg/kg is to be administered if last SC administration was given more than 8 hours before balloon inflation (see Dosage & Administration).
In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the drug to 3 mg/ml.
To obtain a 3-mg/ml solution, using a 60-mg enoxaparin sodium pre-filled syringe, it is recommended to use a 50-ml infusion bag (i.e. using either normal saline solution (0.9%) or 5% dextrose in water) as follows: Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject the complete contents of the 60-mg enoxaparin sodium prefilled syringe into the 20 ml remaining in the bag. Gently mix the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration into the intravenous line.
After dilution is completed, the volume to be injected can be calculated using the following formula [Volume of diluted solution (ml) = Patient weight (kg) x 0.1] or using the table below. It is recommended to prepare the dilution immediately before use.
Volume to be injected through intravenous line after dilution is completed. (See Table 3.)
Moderate and mild renal impairment: Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised.
Spinal/epidural anesthesia: For patients receiving spinal/epidural anesthesia, see Warnings.
ADMINISTRATION: Subcutaneous injection: Enoxaparin sodium is administered by subcutaneous injection for the prevention of venous thrombo-embolic 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.
IV bolus injection: For acute ST-segment Elevation Myocardial Infarction, treatment is to be initiated with a single IV bolus injection immediately followed by a subcutaneous injection.
Arterial line injection: It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the extra-corporeal circulation during haemodialysis.
It must not be administered by the intramuscular route.
The pre-filled disposable syringe is ready for immediate use.
Subcutaneous injection technique: Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by deep subcutaneous injection. Do not expel the air bubble from the syringe before the injection to avoid the loss of drug when using the 20 and 40 mg pre-filled syringes. The administration should be alternated between the left and right anterolateral or posterolateral abdominal wall.
The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and index finger. The skin fold should not be released until the injection is complete. Do not rub the injection site after administration (see Cautions for Usage).
Intravenous (Bolus) Injection Technique (for acute STEMI indication only): Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium 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 enoxaparin sodium to clear the port of drug.
Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Initial 30-mg bolus: For the initial 30-mg bolus, using an enoxaparin sodium graduated pre-filled syringe, expel the excessive volume to retain only 30 mg (0.3 ml in the syringe. The 30-mg dose can then be directly injected into the intravenous line.
Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation: For patients being managed with Percutaneous Coronary Intervention (PCI), an additional IV bolus of 0.3 mg/kg is to be administered if last SC administration was given more than 8 hours before balloon inflation (see Dosage & Administration).
In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the drug to 3 mg/ml.
To obtain a 3-mg/ml solution, using a 60-mg enoxaparin sodium pre-filled syringe, it is recommended to use a 50-ml infusion bag (i.e. using either normal saline solution (0.9%) or 5% dextrose in water) as follows: Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject the complete contents of the 60-mg enoxaparin sodium prefilled syringe into the 20 ml remaining in the bag. Gently mix the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration into the intravenous line.
After dilution is completed, the volume to be injected can be calculated using the following formula [Volume of diluted solution (ml) = Patient weight (kg) x 0.1] or using the table below. It is recommended to prepare the dilution immediately before use.
Volume to be injected through intravenous line after dilution is completed. (See Table 3.)
Overdosage
Signs and Symptoms: Symptoms and severity: Accidental overdosage with enoxaparin sodium after intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin sodium will be absorbed.
Management: Antidote and treatment: The anticoagulant effects can be largely neutralized by the slow intravenous injection of protamine. The dose of protamine depends on the dose of enoxaparin sodium injected, 1 mg protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium injection, protamine administration may not be required. However, even with high doses of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralized (maximum about 60%). (See the prescribing information for protamine salts).
Management: Antidote and treatment: The anticoagulant effects can be largely neutralized by the slow intravenous injection of protamine. The dose of protamine depends on the dose of enoxaparin sodium injected, 1 mg protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium injection, protamine administration may not be required. However, even with high doses of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralized (maximum about 60%). (See the prescribing information for protamine salts).
Contraindications
Hypersensitivity to enoxaparin sodium, heparin or its derivatives including other Low Molecular Weight Heparins.
Active major bleeding and conditions with a high risk of uncontrolled hemorrhage, including recent hemorrhagic stroke.
Active major bleeding and conditions with a high risk of uncontrolled hemorrhage, including recent hemorrhagic stroke.
Warnings
General: Low Molecular Weight Heparins should not be used interchangeably since they differ in their manufacturing process, molecular weights, specific anti-Xa activities, units and dosage. This results in differences in pharmacokinetics and associated biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.
Spinal/Epidural Anesthesia: There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia resulting in long term or permanent paralysis). These events are rare with enoxaparin sodium dosage regimens 40 mg once daily or lower. The risk is greater with higher enoxaparin sodium dosage regimen, use of post-operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDs (see Interactions). The risk also appears to be increased by traumatic or repeated neuraxial puncture or in patients with a history of spinal surgery or spinal deformity.
To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered (see Pharmacology: Pharmacokinetics under Actions).
Placement and 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.
Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (20 mg once daily, 30 mg once or twice daily or 40 mg once daily) of enoxaparin, and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial haematoma will be avoided. Patients receiving the 0.75 mg/kg twice-daily dose or the 1 mg/kg twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30ml/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day).
Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
Heparin-induced thrombocytopenia: Enoxaparin sodium is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist several years. If a history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests have limited predictive value. The decision to use enoxaparin sodium in such a case must be made only in consultation with an expert in the field.
Percutaneous coronary revascularisation procedures: 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 Enoxaparin sodium (Clexane) 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, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium 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.
Pregnant women with mechanical prosthetic heart valves: The use of Enoxaparin sodium (Clexane) Injection for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg bid) to reduce the risk of thrombo-embolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. There have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thrombo-embolism (see Precautions).
Laboratory tests: At doses used for prophylaxis of venous thrombo-embolism, enoxaparin sodium does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets.
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 sodium antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity.
Spinal/Epidural Anesthesia: There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia resulting in long term or permanent paralysis). These events are rare with enoxaparin sodium dosage regimens 40 mg once daily or lower. The risk is greater with higher enoxaparin sodium dosage regimen, use of post-operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDs (see Interactions). The risk also appears to be increased by traumatic or repeated neuraxial puncture or in patients with a history of spinal surgery or spinal deformity.
To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered (see Pharmacology: Pharmacokinetics under Actions).
Placement and 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.
Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (20 mg once daily, 30 mg once or twice daily or 40 mg once daily) of enoxaparin, and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial haematoma will be avoided. Patients receiving the 0.75 mg/kg twice-daily dose or the 1 mg/kg twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30ml/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day).
Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
Heparin-induced thrombocytopenia: Enoxaparin sodium is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist several years. If a history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests have limited predictive value. The decision to use enoxaparin sodium in such a case must be made only in consultation with an expert in the field.
Percutaneous coronary revascularisation procedures: 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 Enoxaparin sodium (Clexane) 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, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium 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.
Pregnant women with mechanical prosthetic heart valves: The use of Enoxaparin sodium (Clexane) Injection for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg bid) to reduce the risk of thrombo-embolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. There have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thrombo-embolism (see Precautions).
Laboratory tests: At doses used for prophylaxis of venous thrombo-embolism, enoxaparin sodium does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets.
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 sodium antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity.
Special Precautions
Do not administer by the intramuscular route.
Hemorrhage: As with other anticoagulants, bleeding may occur at any site (see Adverse Reactions).
If bleeding occurs, the origin of the hemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as: Impaired hemostasis, history of peptic ulcer, recent ischemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro- or ophthalmologic surgery, concomitant use of medications affecting hemostasis (see Interactions).
Mechanical prosthetic heart valves: The use of Enoxaparin sodium (Clexane) Injection has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal death. Pregnant women with prosthetic heart valves may be at higher risk for thrombo-embolism (see Warnings).
Hemorrhage in the elderly: No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical monitoring is advised (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Renal impairment: In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the risk of bleeding. Since exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Low weight: An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see Pharmacology: Pharmacokinetics under Actions).
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.
Monitoring of platelet counts: The risk of antibody-mediated heparin-induced thrombocytopenia also exists with Low Molecular Weight Heparins. Should thrombocytopenia occur, it usually appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another therapy.
Driving a Vehicle or Performing Other Hazardous Tasks: Enoxaparin sodium has no effect on the ability to drive and operate machines.
Hemorrhage: As with other anticoagulants, bleeding may occur at any site (see Adverse Reactions).
If bleeding occurs, the origin of the hemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as: Impaired hemostasis, history of peptic ulcer, recent ischemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro- or ophthalmologic surgery, concomitant use of medications affecting hemostasis (see Interactions).
Mechanical prosthetic heart valves: The use of Enoxaparin sodium (Clexane) Injection has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal death. Pregnant women with prosthetic heart valves may be at higher risk for thrombo-embolism (see Warnings).
Hemorrhage in the elderly: No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical monitoring is advised (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Renal impairment: In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the risk of bleeding. Since exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Low weight: An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see Pharmacology: Pharmacokinetics under Actions).
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.
Monitoring of platelet counts: The risk of antibody-mediated heparin-induced thrombocytopenia also exists with Low Molecular Weight Heparins. Should thrombocytopenia occur, it usually appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another therapy.
Driving a Vehicle or Performing Other Hazardous Tasks: Enoxaparin sodium has no effect on the ability to drive and operate machines.
Use In Pregnancy & Lactation
Pregnancy: Animal studies have not shown any evidence of fetotoxicity or teratogenicity.
In the pregnant rat, the transfer of 35S-enoxaparin sodium across the maternal placenta to the fetus is minimal.
In humans, there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available concerning the first and the third trimesters.
As there are no adequate and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this drug should be used during pregnancy only if the physician has established a clear need. (See section Warnings and Precautions).
Lactation: In lactating rats, the concentration of 35S-enoxaparin sodium or its labelled metabolites in milk is very low.
It is not known whether unchanged enoxaparin sodium is excreted in human breast milk. The oral absorption of enoxaparin sodium is unlikely.
However, as a precaution, lactating mothers receiving enoxaparin sodium should be advised to avoid breast-feeding.
In the pregnant rat, the transfer of 35S-enoxaparin sodium across the maternal placenta to the fetus is minimal.
In humans, there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available concerning the first and the third trimesters.
As there are no adequate and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this drug should be used during pregnancy only if the physician has established a clear need. (See section Warnings and Precautions).
Lactation: In lactating rats, the concentration of 35S-enoxaparin sodium or its labelled metabolites in milk is very low.
It is not known whether unchanged enoxaparin sodium is excreted in human breast milk. The oral absorption of enoxaparin sodium is unlikely.
However, as a precaution, lactating mothers receiving enoxaparin sodium should be advised to avoid breast-feeding.
Adverse Reactions
Enoxaparin has been evaluated in more than 15,000 patients who received enoxaparin in clinical trials. These included 1,776 for prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility, 559 for treatment of deep vein thrombosis with or without pulmonary embolism, 1,578 for treatment of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute ST-elevation myocardial infarction.
Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The enoxaparin sodium dose was 40 mg SC once daily for prophylaxis of deep vein thrombosis following surgery or in acutely ill medical patients with severely restricted mobility. In treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE), patients receiving enoxaparin were treated with either a 1 mg/kg SC dose every 12 hours or a 1.5 mg/kg SC dose once a day. In the clinical studies for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 1 mg/kg SC every 12 hours and in the clinical study for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium regimen was a 30 mg IV bolus followed by 1 mg/kg SC every 12 hours.
The adverse reactions observed in these clinical studies and reported in post-marketing experience are detailed below.
Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) or not known (cannot be estimated from available data). Post-marketing adverse reactions are designated with a frequency "not known".
Haemorrhages: In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis (see Precautions and Interactions).
*: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage. (See Table 4.)
Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The enoxaparin sodium dose was 40 mg SC once daily for prophylaxis of deep vein thrombosis following surgery or in acutely ill medical patients with severely restricted mobility. In treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE), patients receiving enoxaparin were treated with either a 1 mg/kg SC dose every 12 hours or a 1.5 mg/kg SC dose once a day. In the clinical studies for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 1 mg/kg SC every 12 hours and in the clinical study for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium regimen was a 30 mg IV bolus followed by 1 mg/kg SC every 12 hours.
The adverse reactions observed in these clinical studies and reported in post-marketing experience are detailed below.
Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) or not known (cannot be estimated from available data). Post-marketing adverse reactions are designated with a frequency "not known".
Haemorrhages: In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis (see Precautions and Interactions).
*: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage. (See Table 4.)
In surgical patients, haemorrhage complications were considered major: (1) if the haemorrhage caused a significant clinical event, or (2) if accompanied by an haemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always considered major.
Thrombocytopenia and thrombocytosis *: Platelet increased > 400 G/L. (See Table 5.)
Thrombocytopenia and thrombocytosis *: Platelet increased > 400 G/L. (See Table 5.)
Other clinically relevant adverse reactions: These reactions are presented below, whatever the indications, by system organ class, frequency grouping and decreasing order of seriousness.
Post marketing experience: The following adverse reactions have been identified during post-approval use of Enoxaparin sodium (Clexane). The adverse reactions are derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).
Immune System Disorders: Anaphylactic/anaphylactoid reaction including shock.
Nervous System Disorders: Headache.
Vascular Disorders: Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/ epidural anaesthesia or spinal puncture. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see Warnings).
Blood and Lymphatic System Disorders: Haemorrhagic anemia; cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see Precautions); Eosinophilia.
Skin and subcutaneous disorders: Cutaneous vasculitis, skin necrosis usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful). Treatment with enoxaparin sodium must be discontinued; Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation; Alopecia.
Hepatobilary disorders: Hepatocellular liver injury; cholestatic liver injury.
Musculoskeletal and connective tissue disorders: Osteoporosis following long-term therapy (greater than 3 months).
Immune System Disorders: Anaphylactic/anaphylactoid reaction including shock.
Nervous System Disorders: Headache.
Vascular Disorders: Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/ epidural anaesthesia or spinal puncture. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see Warnings).
Blood and Lymphatic System Disorders: Haemorrhagic anemia; cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see Precautions); Eosinophilia.
Skin and subcutaneous disorders: Cutaneous vasculitis, skin necrosis usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful). Treatment with enoxaparin sodium must be discontinued; Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation; Alopecia.
Hepatobilary disorders: Hepatocellular liver injury; cholestatic liver injury.
Musculoskeletal and connective tissue disorders: Osteoporosis following long-term therapy (greater than 3 months).
Drug Interactions
It is recommended that agents which affect hemostasis should be discontinued prior to enoxaparin sodium therapy unless strictly indicated.
These agents include medications such as: Systemic salicylates, acetylsalicylic acid, and NSAIDs including ketorolac; Dextran 40, ticlopidine and clopidogrel; Systemic glucocorticoids; Thrombolytics and anticoagulants; Other anti-platelet agents including glycoprotein IIb/IIIa antagonists.
If the combination is indicated, enoxaparin sodium should be used with careful clinical and laboratory monitoring when appropriate.
These agents include medications such as: Systemic salicylates, acetylsalicylic acid, and NSAIDs including ketorolac; Dextran 40, ticlopidine and clopidogrel; Systemic glucocorticoids; Thrombolytics and anticoagulants; Other anti-platelet agents including glycoprotein IIb/IIIa antagonists.
If the combination is indicated, enoxaparin sodium should be used with careful clinical and laboratory monitoring when appropriate.
Caution For Usage
Preparation and Handling: See Dosage & Administration.
Autoinjector: The patient should be advised to read the User Guide very carefully, especially with regard to handling precautions of the Autoinjector. The pre-filled disposable syringe is ready for immediate use.
When using ampoules or vials of enoxaparin sodium, the volume to be injected should be measured precisely with a graduated syringe fitted with an appropriate needle for subcutaneous injection.
Incompatibilities: Subcutaneous injection: Do not admix with other products.
Intravenous (Bolus) Injection (for acute STEMI indication only): Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Autoinjector: The patient should be advised to read the User Guide very carefully, especially with regard to handling precautions of the Autoinjector. The pre-filled disposable syringe is ready for immediate use.
When using ampoules or vials of enoxaparin sodium, the volume to be injected should be measured precisely with a graduated syringe fitted with an appropriate needle for subcutaneous injection.
Incompatibilities: Subcutaneous injection: Do not admix with other products.
Intravenous (Bolus) Injection (for acute STEMI indication only): Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Storage
Store at or below 25°C. Do not freeze pre-filled syringes and cartridges.
Action
Pharmacotherapeutic Group: Antithrombotic Agents; Hepatic Group: ATC code: B01A B05.
Pharmacology: Pharmacodynamics: Mechanism of action: Enoxaparin sodium is a Low Molecular Weight Heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is:
<2000 daltons ≤20%
2000 to 8000 daltons ≥68%
>8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or anti thrombin activity (approximately 28 IU/mg). These anticoagulant activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.
Beyond its anti-Xa/IIa activity, further anti-thrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall anti-thrombotic effect of enoxaparin.
Clinical Efficacy/Clinical Studies: Treatment of unstable angina and non-Q-wave myocardial infarction: In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave myocardial infarction were randomized to receive in association with aspirin (100 to 325 mg once daily), either subcutaneous enoxaparin sodium 1 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT). Patients had to be treated in hospital for a minimum of 2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be followed up to 30 days. Enoxaparin sodium compared to heparin significantly decreased the incidence of recurrent angina, myocardial infarction and death, with a relative risk reduction of 16.2% at Day 14, sustained over the 30 day period. Furthermore, fewer patients in the enoxaparin sodium group underwent revascularization with either percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) (15.8% relative risk reduction at Day 30).
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI): In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were randomized to receive either enoxaparin sodium in a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1.0 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT) for 48 hours. All patients were also treated with aspirin for a minimum of 30 days. The enoxaparin dosing strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded study drug. Therefore, for patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies i.e. no additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin, if the last SC administration given more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after randomization [9.9 percent in the enoxaparin group, as compared with 12.0 percent in the unfractionated heparin group] with a 17 percent relative risk reduction (P<0.001).
The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as compared with treatment with unfractionated heparin (P<0.001).
The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of fibrinolytic administered, and time to treatment with study drug.
There was a significant treatment benefit of enoxaparin, as compared with unfractionated heparin, in patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, P=0.27 for interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favor of treatment with Enoxaparin sodium (Clexane).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period.
Pharmacokinetics: General characteristics: The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated subcutaneous administration and after single intravenous administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods with specific substrates and an enoxaparin standard calibrated against the international standard for LMWHs (NIBSC).
Absorption: Bioavailability and Absorption: The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is close to 100%. Injection volume and dose concentration over the range 100-200 mg/ml does not affect pharmacokinetic parameters in healthy volunteers.
The mean maximum plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/ml following single-subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg doses, respectively.
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.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. Intra-patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics. 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 and mean peak and trough levels of about 1.2 and 0.52 IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection and reaches 0.13 IU/ml and 0.19 IU/ml following repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.
Distribution: The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 liters and is close to the blood volume.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Elimination: Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h after a 1.5 mg/kg 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 4 hours after a single subcutaneous dose to about 7 hours after repeated dosing. 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.
Special Populations: Elderly: Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium 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 sodium (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration and Precautions).
Renal impairment: A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance <30 ml/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once daily doses (see Dosage & Administration and Precautions).
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control subjects, while Amax is not increased. There is a lower weight-adjusted clearance in obese subjects with subcutaneous dosing.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects (see Precautions).
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.50 mg/kg intravenous dose.
Pharmacokinetic Interactions: No pharmacokinetic interactions were observed between enoxaparin and thrombolytics when administered concomitantly.
Toxicology: Non-Clinical Safety Data: No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.
Pharmacology: Pharmacodynamics: Mechanism of action: Enoxaparin sodium is a Low Molecular Weight Heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is:
<2000 daltons ≤20%
2000 to 8000 daltons ≥68%
>8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or anti thrombin activity (approximately 28 IU/mg). These anticoagulant activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.
Beyond its anti-Xa/IIa activity, further anti-thrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall anti-thrombotic effect of enoxaparin.
Clinical Efficacy/Clinical Studies: Treatment of unstable angina and non-Q-wave myocardial infarction: In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave myocardial infarction were randomized to receive in association with aspirin (100 to 325 mg once daily), either subcutaneous enoxaparin sodium 1 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT). Patients had to be treated in hospital for a minimum of 2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be followed up to 30 days. Enoxaparin sodium compared to heparin significantly decreased the incidence of recurrent angina, myocardial infarction and death, with a relative risk reduction of 16.2% at Day 14, sustained over the 30 day period. Furthermore, fewer patients in the enoxaparin sodium group underwent revascularization with either percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) (15.8% relative risk reduction at Day 30).
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI): In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were randomized to receive either enoxaparin sodium in a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1.0 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT) for 48 hours. All patients were also treated with aspirin for a minimum of 30 days. The enoxaparin dosing strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded study drug. Therefore, for patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies i.e. no additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin, if the last SC administration given more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after randomization [9.9 percent in the enoxaparin group, as compared with 12.0 percent in the unfractionated heparin group] with a 17 percent relative risk reduction (P<0.001).
The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as compared with treatment with unfractionated heparin (P<0.001).
The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of fibrinolytic administered, and time to treatment with study drug.
There was a significant treatment benefit of enoxaparin, as compared with unfractionated heparin, in patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, P=0.27 for interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favor of treatment with Enoxaparin sodium (Clexane).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period.
Pharmacokinetics: General characteristics: The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated subcutaneous administration and after single intravenous administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods with specific substrates and an enoxaparin standard calibrated against the international standard for LMWHs (NIBSC).
Absorption: Bioavailability and Absorption: The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is close to 100%. Injection volume and dose concentration over the range 100-200 mg/ml does not affect pharmacokinetic parameters in healthy volunteers.
The mean maximum plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/ml following single-subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg doses, respectively.
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.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. Intra-patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics. 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 and mean peak and trough levels of about 1.2 and 0.52 IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection and reaches 0.13 IU/ml and 0.19 IU/ml following repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.
Distribution: The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 liters and is close to the blood volume.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Elimination: Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h after a 1.5 mg/kg 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 4 hours after a single subcutaneous dose to about 7 hours after repeated dosing. 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.
Special Populations: Elderly: Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium 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 sodium (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration and Precautions).
Renal impairment: A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance <30 ml/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once daily doses (see Dosage & Administration and Precautions).
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control subjects, while Amax is not increased. There is a lower weight-adjusted clearance in obese subjects with subcutaneous dosing.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects (see Precautions).
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.50 mg/kg intravenous dose.
Pharmacokinetic Interactions: No pharmacokinetic interactions were observed between enoxaparin and thrombolytics when administered concomitantly.
Toxicology: Non-Clinical Safety Data: No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.
MedsGo Class
Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)
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