ENOXOL Enoxaparin Sodium Injection USP

20 mg/0.2 ml, 40 mg/0.4 ml
60 mg/0.6 ml, 80 mg/0.8 ml


For the use of a Registered Medical Practitioner or a Hospital or a Institution only. 

Treatment of Unstable Angina and Non-Q-Wave MI
Prevention of Thrombus Formation during PCI
Prophylaxis of DVT in Major Surgeries and in Bed Ridden Patients

Enoxaparin Sodium is a low molecular weight heparin (LMWH), with a mean molecular weight of approximately 4,500 daltons and low anti-thrombotic activity. 

Its structural formula is :



ENOXOL is a clear, colourless to pale yellow solution filled in a single dose ready to use prefilled graduated syringe.

(Low Molecular Weight Heparin
Enoxaparin Sodium Injection)
Each Pre-filled Syringe contains :
Enoxaparin Sodium Ph. Eur.      20 mg
Water for Injection I.P. q.s. to     0.2 ml

(Low Molecular Weight Heparin
Enoxaparin Sodium Injection)
Each Pre-filled Syringe contains :
Enoxaparin Sodium Ph. Eur.      40 mg
Water for Injection I.P. q.s. to     0.4 ml

(Low Molecular Weight Heparin
Enoxaparin Sodium Injection)
Each Pre-filled Syringe contains :
Enoxaparin Sodium Ph. Eur.      60 mg
Water for Injection I.P. q.s. to     0.6 ml

(Low Molecular Weight Heparin
Enoxaparin Sodium Injection)
Each Pre-filled Syringe contains :
Enoxaparin Sodium Ph. Eur.      80 mg
Water for Injection I.P. q.s. to     0.8 ml

ENOXOL - 100
(Low Molecular Weight Heparin
Enoxaparin Sodium Injection)
Each Pre-filled Syringe contains :
Enoxaparin Sodium Ph. Eur.    100 mg
Water for Injection I.P. q.s. to         1 ml

Enoxaparin is a low molecular weight heparin which has antithrombotic activity. It is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global clotting tests such as APTT and prothrombin time. 

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of 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).

Bioavailability and Absorption :
After subcutaneous injection of 20 to 80 mg and 1 or 2 mg/kg, enoxaparin sodium is rapidly and completely absorbed. The absorption is directly proportional to the dose administered indicating that, unlike unfractionated heparin, absorption of enoxaparin sodium is linear. 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 achieved 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. Enoxaparin pharmacokinetics appears 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.

Distribution :
The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 litres and is close to the blood volume.

Elimination and Metabolism :
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. Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower molecular weight species with much reduced biological potency. 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.

Characteristics in 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.

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. 

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 Cmax 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 50 % higher in low-weight women (< 45 kg) and 27 % higher in low-weight men (< 57 kg) when compared to normal weight control subjects.

ENOXOL is indicated for :

  • Prophylaxis of venous thromboembolic disease, in particular those which may be associated with orthopaedic, general, major colorectal or cancer surgery. 
  • Prophylaxis of venous thromboembolism in general medical patients bedridden due to acute illnesses including acute heart failure, respiratory failure, severe infections, rheumatic disease. 
  • Treatment of venous thromboembolic disease. 
  • Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin. 
  • Prevention of thrombus formation in the extra-corporeal circulation during haemodialysis. 

Administration :
Subcutaneous injection technique :
Patients should be lying down and ENOXOL 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. Administration should be alternated between the left and right anterolateral or posterolateral abdominal wall. ENOXOL contains no antimicrobial agent and should be used only once and then discarded.

Pre-filled Syringes :
The pre-filled disposable syringe is ready for immediate use. The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and forefinger. The skin fold should not be released until the injection is complete.
Graduated Pre-filled Syringes :
When using the graduated prefilled syringes, the volume to be injected should be measured precisely according to the dosage recommended, without expelling the air bubble while adjusting dosage. If the dose required is exactly 60, 80 or 
100, 120 or 150 mg inject the full contents of the syringe. The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and forefinger. The skin fold should not be released until the injection is complete.
Dosage :
Adult dosage :
Prophylaxis of venous thrombosis in surgical patients :
Prophylaxis against thromboembolism should be tailored according to the patients risk. Risk factors include age over 
Dosage :
Adult dosage :
Prophylaxis of venous thrombosis in surgical patients :
Prophylaxis against thromboembolism should be tailored according to the patients risk. Risk factors include age over 40 years, history of deep vein thrombosis or pulmonary embolism, surgery and other trauma, prolonged immobilisation, cardiac disease, obesity, malignancy, varicose veins, hypercoagulable states, pregnancy and the puerperium, oral contraceptives, severe infection, inflammatory bowel disease.
a) High Risk Patients :
In patients with high risk of thromboembolism, a ENOXOL dosage of 40 mg (0.4 mL; anti-Xa : 4000 IU) should be administered subcutaneously once daily. In high risk patients undergoing surgery, the initial dose should be given approximately 12 hours preoperatively. The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed.
b) Moderate Risk Patients :
In patients with a moderate risk of thromboembolism, the recommended ENOXOL dosage is 20 mg (0.2 mL; anti-Xa : 2000 IU) subcutaneously once daily. In moderate risk patients undergoing surgery, the initial dose should be given approximately 2 hours preoperatively. The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed. 
c) Prolonged Thromboprophylaxis :
Therapy with 40 mg once daily for 30 post-operative days has been proven to be beneficial in total hip replacement surgery. Under normal conditions of use, ENOXOL does not modify global clotting tests and therefore there is no need to perform these tests in order to monitor therapy.
Elderly :
No dose reduction is necessary in the elderly, unless kidney function is impaired.
Children :
The safety and efficacy of ENOXOL in children has not been established.
Hepatic impairment :
In the absence of clinical studies, caution should be used in hepatically impaired patients.
Contraindicated in patients with acute bacterial endocarditis; major bleeding disorders; thrombocytopenia in patients with a positive in-vitro aggregation test in the presence of enoxaparin; active gastric or duodenal ulceration; hypersensitivity to enoxaparin; stroke (unless due to systemic emboli); other patients with an increased risk of haemorrhage; in patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated. 
As different low molecular weight heparins may not be equivalent, alternative products should not be substituted during a course of treatment. Enoxaparin is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis. As there is a risk of antibody-mediated heparin-induced thrombocytopenia also occurring with low molecular weight heparins, regular platelet count monitoring should be considered prior to and during therapy with these agents. Enoxaparin injection, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as : impaired haemostasis, history of peptic ulcer, recent ischaemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro- or ophthalmologic surgery. Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days. 
in long term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens 40 mg od or lower. The risk is greater with higher enoxaparin sodium dosage regimens, use of post-operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDs. The risk also appears to be increased by traumatic or repeated neuraxial puncture. To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered. Placement and removal of the catheter is best performed when the anticoagulation effect of enoxaparin is low. Placement or removal of a catheter should be delayed for 
10 - 12 hours after administration of DVT prophylactic doses of enoxaparin sodium, whereas patients receiving higher doses of enoxaparin sodium (1.5 mg/kg once daily) will require longer delays (24 hours). The subsequent enoxaparin sodium dose should be given no sooner than 4 hours after catheter removal.
Percutaneous coronary revascularisation procedures : 
To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, the vascular sheath should remain in place for 6 to 8 hours following a dose of enoxaparin sodium. 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 haematoma formation. For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment such as thrombolysis or surgery may be indicated. 
Prosthetic Heart Valves :
There have been no adequate studies to assess the safe and effective use of enoxaparin sodium in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of enoxaparin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses. The use of enoxaparin sodium cannot be recommended for this purpose. 
Haemorrhage in the elderly : 
No increased bleeding tendency is observed in the elderly within the prophylactic dosage ranges. Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised. 
Renal impairment : 
In patients with renal impairment, there is an increase in enoxaparin exposure which increases the risk of bleeding. Since enoxaparin exposure is significantly increased in patients with severe renal impairment (creatinine clearance < 30 ml/min) dosage adjustments are recommended in therapeutic and prophylactic dosage ranges. Although no dosage adjustments are 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. 
Low body weight : 
In low-weight women (< 45 kg) and low-weight men (< 57 kg), an increase in enoxaparin exposure has been observed within the prophylactic dosage ranges (non-weight adjusted), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients. 
Monitoring :
Risk assessment and clinical monitoring are the best predictors of the risk of potential bleeding. Routine anti-Xa activity monitoring is usually not required. However, anti-Xa activity monitoring might be considered in those patients treated with LMWH who also have either an increased risk of bleeding (such as those with renal impairment, elderly and extremes of weight) or are actively bleeding. 

Pregnancy : Pregnancy Category C
Animal studies have not shown any evidence of foetotoxicity or teratogenicity. In the pregnant rat, the transfer of 35S-enoxaparin across the maternal placenta to the foetus is minimal. In humans, there is no evidence that enoxaparin 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 not be used in pregnant patients unless no safer alternative is available. 

Lactation :
In lactating rats, the concentration of 35S-enoxaparin or its labelled metabolites in milk is very low. It is not known whether unchanged enoxaparin is excreted in human breast milk. The oral absorption of enoxaparin is unlikely. However, as a precaution, lactating mothers receiving enoxaparin should be advised to avoid breast-feeding.

Interactions :
It is recommended that agents which affect haemostasis should be discontinued prior to ENOXOL 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 anticoagulants

If the combination is indicated, ENOXOL should be used with careful clinical and laboratory monitoring when appropriate.

As with other anticoagulants bleeding may occur during enoxaparin therapy in the presence of associated risk factors such as : organic lesions liable to bleed or the use of medications affecting haemostasis. The origin of the bleeding should be investigated and appropriate treatment instituted. Major haemorrhage including retroperitoneal and intracranial bleeding have been reported, in rare instances these have been fatal. Mild, transient, asymptomatic thrombocytopenia has been reported during the first days of therapy. Immuno-allergic thrombocytopenia, with or without thrombosis, has rarely been reported. Pain, haematoma and mild local irritation may follow the subcutaneous injection of enoxaparin. Rarely, hard inflammatory nodules which are not cystic enclosures of enoxaparin, have been observed at the injection site. They resolve after a few days and should not cause therapy discontinuation. Exceptional cases of skin necrosis at the injection site have been reported with heparins and low molecular weight heparins. These phenomena are usually preceded by purpura or erythematous plaques, infiltrated and painful. Enoxaparin must be discontinued. 

Accidental overdosage with ENOXOL after intravenous, extracorporeal or subcutaneous administration may lead to haemorrhagic complications. Following oral administration of even large doses, it is unlikely that ENOXOL will be absorbed.

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose of protamine depends on the dose of ENOXOL injected, 1 mg protamine neutralises the anticoagulant effect of 1 mg of ENOXOL, if ENOXOL was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of ENOXOL may be administered if ENOXOL was administered greater than 8 hours previously, or if it has been determined that a second dose of protamine is required. Protamine administration may not be required 12 hours after the ENOXOL injection. However, depending on the clinical circumstances, eg the size of the dose of ENOXOL, whether or not a therapeutic level of anticoagulation needs to be retained and whether or not the patient is actively bleeding, the administration of a reduced dose of protamine may not be advisable.

ENOXOL prefilled syringes are single dose containers; Discard any unused Product.

Store below 30°C, protected from light.
Do not refrigerate.

24 months from the date of manufacture.

ENOXOL contains Enoxaparin 
20 mg/0.2 ml, 
40 mg/0.4 ml, 
60 mg/0.6 ml, 
80 mg/0.8 ml and 
100 mg/1 ml
solution filled in ready to use prefilled syringe. Each syringe is packed in a blister. Each blister is packed in a printed carton with package insert. Such 5 cartons are packed in a printed outer carton.

Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.
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