Clexane

Clexane

enoxaparin sodium

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Enoxaparin sodium.
Description
Clexane is a low-molecular weight heparin (MW approximately 4500 D) obtained by controlled depolymerisation of a benzyl ester of natural porcine heparin. In comparison with natural heparin, it is characterised by a clear increase in the ratio between anti-Xa and anti-IIa activities which is always >4.
As a result, antithrombotic activity is increased relative to the anticoagulant activity. It has a high affinity for antithrombin III and a dual action on the coagulation mechanism inhibiting prothrombinase activity (factor Xa, co-factor V, calcium and phospholipid) and inactivating thrombin. The antithrombotic activity is related to other factors in addition to anti-Xa activity.
Action
Pharmacology: In the experimental animal, Clexane was found to have potent antithrombotic properties with a minimum effect on bleeding.
In man, Clexane has prolonged antithrombotic properties at recommended dosages without any significant change in global blood clotting test (ie, prothrombin time or activated partial thromboplastin time). It does not modify platelet aggregation or the binding of fibrinogen to platelets.
Pharmacokinetics: The pharmacokinetic parameters of Clexane were studied from the changes in plasma anti-Xa activity.
After injection of Clexane by the SC route, it is rapidly and completely absorbed. The absolute bioavailability is >90%.
The maximum plasma activity is observed after 3 hrs and is, on average, 1.6 mcg/mL after the injection of a 20-mg dose and 3.8 mcg/mL after the injection of a 40-mg dose. The anti-Xa activity, measured like that of unfractionated heparin, gives values of approximately 0.16 and 0.38 IU/mL, respectively.
The elimination of enoxaparin is characterised by a half-life of approximately 4.4 hrs for a dose of 40 mg and circulating levels of anti-Xa activity are present in the plasma 24 hrs after injection.
Elimination of enoxaparin at prophylactic dosages is not significantly modified in patients with renal insufficiency. It is slightly reduced in the elderly (t½ = 6-7 hrs). This modification has no effect on the doses or the frequency of injections as there is no plasma accumulation in elderly subjects.
The anti-Xa activity generated by Clexane does not cross the placental barrier during the 2nd trimester of pregnancy.
Anti-Xa activity generated by Clexane is localised within the vascular space.
Metabolic breakdown of Clexane is slight and takes place mainly in the liver (desulfation and depolymerisation). Small amounts of the product are eliminated by the kidneys in an intact or slightly degraded form.
Indications/Uses
Prevention of thromboembolic disorders of venous origin in patients undergoing orthopaedic and general surgery. Prevention of thrombosis in extracorporeal circulation during haemodialysis. Treatment of established deep vein thrombosis. Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin. Treatment of acute ST-segment elevation.
Dosage/Direction for Use
Prophylaxis: Prophylaxis against thromboembolism should be tailored according to the patient's risk. Risk factors include age >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.
Patients with high risk of thromboembolism: Clexane dosage of 40 mg (0.4 mL; anti-Xa: 4000 IU) should be administered SC once daily. In high-risk patients undergoing surgery, the initial dose should be given approximately 12 hrs preoperatively.
Patients with a moderate risk of thromboembolism: The recommended Clexane dosage is 20 mg (0.2 mL; anti-Xa: 2000 IU) SC once daily. In moderate risk patients undergoing surgery, the initial dose should be given approximately 2 hrs preoperatively.
Prophylaxis should be continued for 7-10 days or until the risk of thromboembolism has diminished.
Under normal conditions of use, Clexane does not modify global clotting tests and therefore there is no need to perform these tests in order to monitor treatment.
Treatment of Deep Venous Thrombosis: The clinical trials which established the efficacy of Clexane in the treatment of deep venous thrombosis were conducted on patients who were initially treated with heparin and then changed to Clexane when a definitive diagnosis was established. However, the use of heparin prior to Clexane is not currently recommended. The average duration of therapy in the clinical trials was 10 days. No data are available on the safety of long-term treatment. Data on use in patients >65 years in these trials were limited.
Recommended Dosage: 1 mg/kg body weight (100 IU anti-Xa activity/kg body weight) twice daily SC.
Treatment of Unstable Angina and Non-Q-Wave Myocardial Infarction: Recommended Dose: 1 mg/kg (100 IU anti-Xa activity/kg) every 12 hrs by SC injection, administered concurrently with oral aspirin (100-325 mg once daily). Treatment with Clexane in these patients should be prescribed for a minimum of 2 days and a maximum of 8 days.
Acute ST-Segment Elevation Myocardial Infarction (STEMI): With a thrombolytic agent, an initial IV bolus injection of 30 mg followed by an SC injection of 1mg/kg within 15 min, then every 12 hrs (a maximum of 10,000 anti-Xa IU for the first 2 SC doses) for 8 days or until discharged. In patients ≥75 years, the initial IV bolus injection should not be administered. An SC dose of 0.75 mg/kg every 12 hrs should be administered (maximum of 7500 anti-Xa IU for the first 2 injections only).
Haemodialysis: In patients undergoing repeated sessions of haemodialysis, the prevention of thrombosis in the extracorporeal blood circuit is obtained by injection of a dose of 1 mg/kg (100 IU anti-Xa activity/kg) into the arterial line of the dialysis circuit at the start of the session. This dose is usually sufficient for a 4-hr haemodialysis session. If fibrin rings are formed, a fresh injection of 0.5-1 mg/kg (50-100 IU anti-Xa activity/kg) should be made depending on the time before the end of the dialysis. In haemodialysis patients with a high risk of haemorrhage (in particular, in pre- or postoperative dialysed patients) or with a progressive haemorrhagic disorder, the dialysis sessions may be carried out by using a dose of 0.5 mg/kg (50 IU anti-Xa activity/kg) (double vascular access) or 0.75 mg/kg (75 IU anti-Xa activity/kg) (single vascular access).
SC Injection Technique: The SC injection of Clexane should be alternated between the left and right anterolateral abdominal wall using a different site for each injection.
The pre-filled syringes are ready for use and no attempt to expel air should be made before injection.
The whole length of the needle should be introduced vertically into the thickness of a skin fold gently held between the operator's thumb and finger. This skin fold should be held throughout the duration of the injection. When using the ampoules of enoxaparin, the volume should be measured precisely with a graduated syringe fitted with an appropriate needle for the SC injection.
Do not mix Clexane with other injections or infusions.
Overdosage
Oral ingestion of Clexane (no reported cases) should lead to no serious consequences, taking into account the very low gastric and intestinal absorption of Clexane. This may be checked by carrying on a plasma assay of the anti-Xa activity.
Accidental overdosage after IV, extracorporeal or SC administration of massive doses of enoxaparin sodium may lead to bleeding complications. Neutralization can be obtained by slow IV injection of protamine; however, the anti-Xa activity of enoxaparin sodium is never completely neutralized (maximum about 60%). Protamine 1 mg can be used to neutralize the anticoagulant effect of about enoxaparin sodium 1 mg, if enoxaparin sodium was administered in the previous 8 hrs. An infusion of 0.5-mg protamine per 1 mg of enoxaparin sodium may be administered >8 hrs previous to the protamine administration, or if it has been determined that a 2nd dose of protamine is required. After 12 hrs of the enoxaparin sodium injection, protamine administration may not be required.
Contraindications
Allergy to Clexane, heparin or its derivatives including other low-molecular weight heparins. Acute bacterial endocarditis. Conditions with a high risk of uncontrolled haemorrhage including major bleeding disorders, focal lesions, haemorrhagic stroke, active ulcerative conditions showing a tendency to haemorrhage (eg, peptic ulcer, ulcerative colitis).
Special Precautions
Low-molecular weight heparin products are not clinically interchangeable.
The biological activity of different low-molecular weight heparin cannot be expressed in a test allowing for a simple dose comparison. Different low-molecular weight heparin may not be bioequivalent in terms of their labelled anti-Xa activities and alternative products should not be introduced nor interchanged during a course of treatment.
Enoxaparin is to be used with extreme care in patients with a history of heparin-induced (including low-molecular weight heparins) thrombocytopaenia with or without thrombosis. The risk of heparin-induced thrombocytopaenia may persist for several years. If history of heparin-induced thrombocytopaenia is suspected, in vitro platelet aggregation tests have limited predictive value. The decision to use enoxaparin in such a case must be made only in consultation with an expert in the field.
Not to be administered by IM route.
Clexane should be used with care in patients with the following conditions: Hepatic insufficiency, uncontrolled arterial hypertension, a history of gastrointestinal ulceration, impaired haemostasis, recent ischaemic stroke, diabetic retinopathy and recent neuro- or ophthalmologic surgery.
In severe renal failure, despite evidence that the pharmacokinetics of Clexane is unchanged, the extent to which the platelet function defect in severe renal failure might contribute to bleeding risk during long-term therapy is unknown.
If a transmural myocardial infarction occurs in a patient being treated with enoxaparin for unstable angina or non-Q-wave myocardial infarction, thrombolytic treatment may be appropriate.
Use in Pregnancy: Pregnancy Category C: Animal toxicity studies have shown that enoxaparin may have some effect on rat and rabbit reproduction.
There is no information available concerning the use of Clexane during the 1st and 3rd 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.
Use in Lactation: Studies performed in female rats demonstrated that enoxaparin had no effect on lactation or milk composition. Effects of Clexane on lactating women have not been studied.
As a precaution, women should be advised not to breastfeed while using Clexane.
Use In Pregnancy & Lactation
Use in Pregnancy: Pregnancy Category C: Animal toxicity studies have shown that enoxaparin may have some effect on rat and rabbit reproduction.
There is no information available concerning the use of Clexane during the 1st and 3rd 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.
Use in Lactation: Studies performed in female rats demonstrated that enoxaparin had no effect on lactation or milk composition. Effects of Clexane on lactating women have not been studied.
As a precaution, women should be advised not to breastfeed while using Clexane.
Adverse Reactions
Clinical Trial Data: The following information relates to adverse events observed in controlled clinical trials with patients given enoxaparin sodium prophylactically or for the treatment of deep vein thrombosis (n=1170) or with patients given enoxaparin sodium for the treatment of unstable angina or non-Q-wave myocardial infarction, administered concurrently with aspirin (n=1578).
Haematological: Common: Haemorrhage. During enoxaparin therapy, bleeding may occur in the presence of associated risk factors eg, organic lesions liable to bleed, invasive procedures or the use of medications affecting haemostasis (see Interactions). The origin of the bleeding should be investigated and appropriate treatment instituted.
Blood Disorders: Uncommon: Thrombocytopaenia. Mild, transient, asymptomatic thrombocytopaenia has been reported during the 1st days of therapy.
Hepatic: Uncommon: Asymptomatic and reversible increase in liver enzymes (eg, transaminases) levels have been reported (Note: Liver enzymes were not assessed in the unstable angina population).
Post-Marketing Data: The following information relates to events observed following the marketing of enoxaparin sodium. Voluntary reports of adverse events that have been received since market introduction (without causal relationship) that are not listed previously are cited as follows:
Haematological: Very Rare: There have been rare reports of intraspinal haematomas with the concurrent use of enoxaparin and spine/epidural anaesthesia and postoperative indwelling catheters. These events have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see Precautions).
Rare cases of immunoallergic thrombocytopaenia with or without thrombosis have been reported (see Precautions).
Asymptomatic and reversible increases in platelet counts levels have been reported.
Hypersensitivity and Skin: Injection Site: Very Rare: Pain, haematoma and mild local irritation may follow the SC injection of enoxaparin.
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 treatment discontinuation.
Cases of skin necrosis at the injection site have been reported with both unfractionated and low-molecular weight heparins. These phenomena are usually preceded by purpura or erythematous plaques, infiltrated and painful. Treatment must be discontinued immediately.
Systemic Allergic Reactions: Very Rare: Cutaneous (bullous) or systemic allergic reactions (eg, pruritus, rash and urticaria) including anaphylactoid reaction, may occur. In some cases, discontinuation of the treatment may be necessary.
Drug Interactions
Clinical trials revealed no adverse effects that could be caused by drug interactions.
It is recommended that agents which affect haemostasis should be discontinued prior to enoxaparin therapy unless strictly indicated. These agents include medications eg, anticoagulants, thrombolytics, nonsteroidal anti-inflammatory agents (including ketorolac), preparations containing acetylsalicylic acid, systemic salicylates, ticlopidine, dextran 40, or systemic glucocorticoids. If the combination is indicated, Clexane should be used with careful clinical and laboratory monitoring of the haemostatic factors, when appropriate.
Spinal/Epidural Anaesthesia: As with other anticoagulants, there have been rare cases of intraspinal haematomas reported with the concurrent use of enoxaparin and spinal/epidural anaesthesia resulting in long-term or permanent paralysis. The risk of these rare events may be higher with the use of postoperative indwelling epidural catheters.
Monitoring of Platelet Count: The risk of antibody-mediated heparin-induced thrombocytopaenia also exists with low molecular weight heparins. Should thrombocytopaenia occur, it usually appears between the 5th and the 21st day following the beginning of enoxaparin treatment. Therefore, it is recommended that the platelet counts be measured before initiation of therapy with enoxaparin and then regularly thereafter during the treatment. In practice, if a confirmed significant decrease of the platelet count is observed (30-50% of the initial value), enoxaparin treatment must be immediately discontinued and the patient switched to another therapy.
Storage
Store below 25°C.
Shelf-Life: 2 years.
ATC Classification
B01AB05 - enoxaparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.
Presentation/Packing
Pre-filled syringe with safety device (ready-to-use) 40 mg/0.4 mL x 2's. 60 mg/0.6 mL x 2's. 80 mg/0.8 mL x 2's.
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