Each composition per syringe: Enoxaparin Sodium USP 20/40/60/80 mg and Water for Injection USP q.s. to 0.2/0.4/0.6/0.8 ml.
It is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5.
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. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is: <2000 daltons ≤20%, 2000 to 8000 ≥68%, >8000 daltons ≤18%.
The mass-average relative molecular mass ranges between 3800 and 5000. The mass percentage of chains lower than 2000 ranges between 12.0 percent and 20.0 percent. The mass percentage of chains between 2000 and 8000 ranges between 68.0 percent and 82.0 percent.
The potency is not less than 90 IU and not more than 125 IU of anti-factor Xa activity per milligram, calculated with reference to the dried substance. The ratio of anti-factor Xa activity to anti-factor IIa activity is between 3.3 and 5.3.
Enoxaparin sodium is available as white or almost white powder, hygroscopic.
Enoxaparin sodium injection is available as a clear, colourless to pale yellow solution and free from any visible particles.
Excipients/Inactive Ingredients: Water for injection USP.
Pharmacology: Pharmacodynamics: Enoxaparin is a low molecular weight heparin with high anti Xa activity (100 I.U./mg) and with a low anti II or anti thrombotic activity (28 IU/mg). At doses required for various indications, enoxaparin does not increase bleeding time. At preventive doses, Enoxaparin causes no notable modification of APTT. It neither influences platelet aggregation nor binding of fibrinogen to platelets.
Mechanism of Action: Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
Pharmacokinetics: The pharmacokinetic parameters have been studied in terms of the time course of plasma anti-Xa activity.
Bioavailability: After subcutaneous injection, enoxaparin is rapidly and completely absorbed. The bioavailability of enoxaparin is close to 95%.
Distribution: After subcutaneous injection, the maximum plasma activity is obtained 3 hours after the administration.
The anti-Xa activity is located in the vascular space.
Biotransformation: Enoxaparin is primarily metabolized in the liver.
Elimination: The elimination half-life of anti-Xa activity is approximately 4.4 hours after administration of 40 mg of enoxaparin and 4 hours for an administration of 60 mg or 80 mg of enoxaparin.
Excretion: Enoxaparin is eliminated in the urine. In the elderly, the elimination is slightly decreased.
Enoxaparin is a low molecular weight heparin [LMWH] indicated for: Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness.
Inpatient treatment of acute DVT with or without pulmonary embolism.
Outpatient treatment of acute DVT without pulmonary embolism.
Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI].
Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI].
Method of administration: 1 mg (0.01 mL) of Enoxaparin corresponds approximately to 100 anti-Xa I.U. Enoxaparin should be injected by deep SUBCUTANEOUS ROUTE in prophylactic and curative treatment and by INTRAVENOUS ROUTE during haemodialysis. Do not inject intramuscularly.
Subcutaneous administration technique: The prefilled syringes are ready-to-use. The air bubble from the syringe should not be expelled before the injection. The subcutaneous injection should preferably be made when the patient is lying down. Enoxaparin is administered in the subcutaneous cellular tissue of the anterolateral or posterolateral abdominal wall, alternately on the left and the right side.
The injection itself consists in introducing the needle perpendicularly and not tangentially, throughout its entire length into a fold skin held between the thumb and index finger. The skin fold should be held throughout the injection.
Prophylaxis of venous thrombosis: In the case of a surgery with a moderate thrombogenic risk and when patients do not present high thrombo-embolism risk, the recommended dosage is 20 mg (0.2 mL) once daily by a single subcutaneous injection. In the case of a surgery with a high thrombogenic risk (hip and knee surgery) and/or patients with a high risk of thromboembolism, the dosage should be 40 mg (0.4 ml)-once daily by a single subcutaneous injection. In general surgery, the first injection should be given 2 hours before the surgical procedure. In orthopaedic surgery, the first injection is to be given 12 hours preoperatively. A higher prophylactic dosage may be envisaged when the risk of thrombo-embolism linked to the type of surgery and/or to the patient's history is increased.
Enoxaparin treatment is usually prescribed for an average period of 7 to 10 days. Longer treatment duration may be appropriate in certain cases and the treatment should be continued for as long as there is a risk of venous thrombo-embolism and until the patient is ambulatory.
Treatment of established deep vein thrombosis: A dose of 1 mg/kg should be given subcutaneously every 12 hours. The duration of the treatment should not exceed a period of 10 days.
Treatment of unstable angina and non-Q-wave myocardial infarction: A dose of 1 mg/kg should be given subcutaneously every 12 hours. The recommended treatment should be prescribed for a period of 2 to 8 days, until clinical stabilization of the patient. Enoxaparin should be administered concurrently with aspirin (100 to 325 mg daily per oral route).
Elderly: No dosage adjustment is necessary in preventive therapy. In curative therapy measurement of anti-Xa activity is recommended.
Children: Enoxaparin is not recommended for children.
Renal impairment: No dosage adjustment is necessary at prophylactic doses whereas dosage adjustment is necessary and the monitoring of anti-Xa activity is recommended at curative doses.
Patients under 40 kg and over 100 kg weight: Particular clinical surveillance is necessary in order to adjust dosage if necessary. In all cases, strictly follow the physician's prescription.
Accidental over dosage after subcutaneous injection of massive doses of enoxaparin could lead to bleeding complications. Neutralization can be obtained by slow intravenous injection of protamine. (1 mg protamine can be used to neutralize the anticoagulant effect of about 1 mg enoxaparin).
In case of over dosage or accidental intoxication the patient must notify to a physician.
Active major bleeding; Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium; Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions); Known hypersensitivity to heparin or pork products.
Increased Risk of Hemorrhage: Cases of epidural or spinal hematomas have been reported with the associated use of enoxaparin and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
Enoxaparin should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.
Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal.
Bleeding can occur at any site during therapy with enoxaparin. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.
Percutaneous Coronary Revascularization 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 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. 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.
Use of enoxaparin with Concomitant Medical Conditions: Enoxaparin should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.
History of Heparin-Induced Thrombocytopenia: Enoxaparin should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.
Thrombocytopenia: Thrombocytopenia can occur with the administration of enoxaparin.
Interchangeability with Other Heparins: Enoxaparin cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.
Pregnant Women with Mechanical Prosthetic Heart Valves: The use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied.
Laboratory Tests: Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of enoxaparin activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin in patients with significant renal impairment. If during enoxaparin therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin.
Effects on ability to drive and use machines: Enoxaparin has no effect on the ability to drive and operate machines.
Renal Impairment: In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because 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. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia.
Hepatic Impairment: The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.
Low Weight Patients: 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). All such patients should be observed carefully for signs and symptoms of bleeding.
Pediatric Use: Safety and effectiveness of Enoxaparin in pediatric patients have not been established.
Geriatric Use: Enoxaparin should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.
In case of pregnancy or lactation the patient always have to ask the physician or pharmacist for advice before the beginning of the treatment. As a precautionary measure, enoxaparin should not be used during pregnancy and lactation.
Like any active product, this drug may induce undesirable effects to a greater or lesser degree.
Hemorrhage (bleeding): this may occur during treatment with any anticoagulant: the physician should be informed immediately.
Bluish marks at injection sites.
Localized or general allergic reactions.
Thrombocytopenia (abnormally low platelet count level): the physician should be informed immediately.
Rare incidences of severe skin rash at injection sites: consult the physician.
Risk of osteoporosis (bone demineralization leading to bone fragility).
Increased blood level of certain enzymes.
Cases of neuraxial hematomas with the concurrent use of enoxaparin and spinal/epidural anesthesia or spinal puncture which may have resulted in varying degrees of neurological injuries including long term or permanent paralysis have been reported (see Precautions).
Do not hesitate to ask the physician or pharmacist for advice and to report any undesirable effect not mentioned in this monograph.
Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring.
Protect from light and moisture.
Store below 30°C in a dry place.
Do not freeze.
Shelf Life: 36 months from date of manufacture.
B01AB05 - enoxaparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.
Soln for inj (Clear glass Pre-Filled Syringe) 20 mg/0.2 mL x 1's. 40 mg/0.4 mL x 1's. 60 mg/0.6 mL x 1's. 80 mg/0.8 mL x 1's.