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  • Clexane Forte
    / Sanofi


    Active Ingredient
    Enoxaparin (as sodium) 150 mg/ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Pre-filled Syringe (solution for injection)

    10 X 120 mg / 0.8 ml

    partial basket chart 22699 12436

    Pre-filled Syringe (solution for injection)

    10 X 150 mg/1 ml

    partial basket chart 22716 12437

    Dosage

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


    Indications

    Solution for injection at 20 mg and 40 mg: Prophylactic treatment of thrombo-embolic disorders of venous origin and in particular in orthopedic surgery or in general surgery. Prevention of thrombus formation in the extra-corporeal circulation during hemodialysis. Solution for injection at 40 mg: Prophylactic treatment of deep vein thrombosis (DVT) in patients who are bedridden due to an acute medicdbal disorder: Heart failure (NYHA class III or IV ); acute respiratory failure; episode of acute infection or acute rheumatic disorder combined with at least one other venous thromboembolic risk factor.Solution for injection at 60 mg, 80 mg and 100 mg: Treatment of deep vein thrombosis (DVT). Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin. Treatment of pulmonary embolism. Treatment of acute ST-segment elevation myocardial infarction, in combination with a thrombolytic agent in patients eligible or not for subsequent coronary angioplasty.Forte solution for injection at 120 mg and 150 mg: Treatment of deep vein thrombosis (DVT) once daily. Treatment of pulmonary embolism once daily. Multidose vials at 100 mg/ml: Treatment of acute ST-segment elevation myocardial infarction, in combination with a thrombolytic agent in patients eligible or not for subsequent coronary angioplasty.


    Contra-Indications

    Regardless of the dose (curative or preventive), this medicinal product MUST NOT BE USED in the following situations:  Hypersensitivity to enoxaparin, heparin or its derivatives, including the other LMWHs
    History of serious type II heparin-induced thrombocytopenia (HIT), whether caused by unfractionated or low-  molecular-weight heparin  Bleeding or tendency to bleed related to impaired hemostasis (a possible exception to  this contraindication may  be disseminated intravascular coagulation, when not related to heparin treatment
    Organic lesion likely to bleed  Clinically significant active bleeding  For the Multi Dose Vial presentation: Premature and full-term neonates, due to the benzyl alcohol content.
    See prescribing information for full details.


    Special Precautions

    General: Although the concentrations of the various low-molecular-weight heparins are all expressed in anti-Xa international units (IU), their efficacy is not only related to their anti-Xa activity. It would be dangerous to replace one LMWH dosage regimen by another as each regimen has been validated by specific clinical studies. Particular care is therefore required and the specific instructions for use of each drug must be followed. For the Multi Dose Vial presentation:
    – As this medicinal product contains 15 mg/ml benzyl alcohol, it may cause toxic or anaphylactoid reactions in infants and children under 3 years of age.
    – The administration of medications containing benzyl alcohol to newborns or premature neonates has been associated with a fatal “Gasping Syndrome” (symptoms include a striking onset of gasping syndrome, hypotension, bradycardia, and cardio-vascular collapse). As benzyl alcohol may cross the placenta, solution for injection should be used with caution in pregnancy.
    Special notes: Risk of hemorrhage The recommended dosage regimens must be respected (dosage and duration of treatment). Failure to comply with these recommendations can lead to hemorrhage, particularly in highrisk patients (the elderly, patients with renal failure, etc.) Serious hemorrhagic events have been reported in the following situations:
    – elderly subjects, particularly due to age-related renal impairment,
    – patients with renal failure,
    – bodyweight below 40 kg,
    – treatment lasting longer than the recommended mean duration of ten days,
    – non-compliance with treatment recommendations (particularly treatment duration and dose adjustment based on bodyweight in curative treatment).
    – co-administration with drugs increasing the risk of hemorrhage. In any event, special monitoring is essential in the elderly and/or patients with renal failure, as well as during treatment prolonged beyond ten days. Assay of anti-Xa activity may in certain cases be useful in detecting drug accumulation. 9 Risk of heparin-induced thrombocytopenia (HIT) Should a patient treated with LMWH (at curative or preventive doses) develop thrombotic complications such as:
    – exacerbation of the thrombosis being treated,
    – phlebitis,
    – pulmonary embolism,
    – acute ischemia of the lower limbs,
    – or even myocardial infarction or ischemic stroke, HIT should systematically be suspected and a platelet count performed urgently.
    Use in children: As no relevant data are available, use of LMWH is not recommended in children.
    Mechanical prosthetic heart valves: Use of enoxaparin in the prevention of thromboembolic complications in patients with mechanical prosthetic heart valves has not specifically been studied. Nevertheless, some isolated cases of thrombosis have been reported in patients with mechanical prosthetic heart valves receiving enoxaparin for the prevention of thromboembolic complications.
    Pregnant women: In a clinical study in pregnant women with mechanical prosthetic heart valves who received 1mg (100 anti-Xa IU)/kg enoxaparin b.i.d. to reduce the risk of thromboembolic complications, 2 of 8 women developed thrombosis causing valve obstruction leading to maternal and fetal death. Moreover, isolated cases of thrombosis in pregnant women with mechanical prosthetic heart valves receiving enoxaparin for the prevention of thromboembolic complications have been reported as part of post-marketing surveillance of the drug. Therefore, the risk of thromboembolic complications in these patients could be higher.
    Hyperkalemia: Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalemia 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.
    See prescribing information for full details.


    Side Effects

    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 patients1 ). Some of these cases have been fatal. As with other anticoagulants, haemorrhage may occur during enoxaparin therapy in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis. The origin of the bleeding should be investigated and appropriate treatment instituted.
    Rare: 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 and post operative indwelling catheters. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis. 1 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.
    Immune system disorders: Common: Allergic reaction
    Hepatobilary disorders: Very common: Hepatic enzymes increase (mainly transaminases)
    Skin and subcutaneous tissue disorders: Common: Urticaria, pruritus, erythema.
    General disorders and administration site conditions: Common: Injection site haematoma, injection site pain, other injection site reaction.
    See prescribing information for full details.


    Drug interactions

    Certain drugs or therapeutic classes may promote the occurrence of hyperkalemia: potassium salts, potassium-sparing diuretics, conversion enzyme inhibitors, angiotensin II inhibitors, non-steroidal anti-inflammatory drugs, heparins (low-molecular-weight or unfractionated heparin), ciclosporin and tacrolimus, trimethoprim.
    Occurrence of hyperkalemia may depend on possible related risk factors. This risk is potentiated when the above-mentioned drugs are co-administere.
    Patients under 65 years of age receiving curative LMWH doses and elderly patients (more than 65 years) regardless of the LMWH dose:
    Inadvisable combinations:

    Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses (and, by extrapolation, other salicylates): Increased risk of bleeding (salicylate-induced platelet function inhibition and gastroduodenal mucosal damage). Use a non-salicylate antipyretic analgesic (such as paracetamol).
    NSAIDs (systemic use): Increased risk of bleeding (NSAID-induced platelet function inhibition and gastroduodenal mucosal damage). If co-administration cannot be avoided, close clinical monitoring is required.
    Dextran 40 (parenteral use) : Increased risk of bleeding (inhibition of platelet function by dextran 40).
    Combinations requiring precautions for use
    Oral anticoagulants Potentiation of the anticoagulant effect. When heparin is replaced by an oral anticoagulant, clinical monitoring must be intensified.
    Combinations to take into consideration
    – Platelet aggregation inhibitors (other than acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses; NSAIDs): abciximab, acetylsalicylic acid at antiaggregant doses in cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban. Increased risk of bleeding.
    – Patients under 65 years of age receiving prophylactic LMWH doses.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: There is no evidence from animal studies that enoxaparin has teratogenic effects. In the absence of any teratogenic effect in animals, no such effect is expected in man. To date, substances responsible for malformation in humans have proved to be teratogenic in animals during well-conducted studies in two species. Prophylactic treatment during the first trimester and curative treatment There are currently not enough relevant clinical data to evaluate possible teratogenic or fetotoxic effects of enoxaparain when the drug is administered prophylactically during the first trimester or at curative doses throughout pregnancy.
    Consequently, as a precautionary measure, enoxaparin should preferably not be administered prophylactically during the first trimester, nor at curative doses throughout pregnancy. If epidural anesthesia is planned, prophylactic heparin treatment should be interrupted whenever possible at the latest within 12 hours before anesthesia. Epidural or spinal anesthesia should never be performed during curative treatment with LMWH. Prophylactic treatment during the second and third trimesters To date, there seems to be no evidence from clinical use of enoxaparin in a limited number of pregnancies during the second and third trimesters, that the drug administered at prophylactic doses has any particular teratogenic or fetotoxic effects. However, additional studies are needed to evaluate the effects of exposure under these conditions. Therefore, prophylactic enoxaparin treatment during the second and third trimesters should only be considered if necessary.
    If epidural anesthesia is planned, prophylactic heparin treatment should be interrupted whenever possible at the latest within 12 hours before anesthesia.
    Lactation: Since gastro-intestinal absorption by neonates is unlikely in principle, treatment with enoxaparin is not contraindicated in breast-feeding women.


    Manufacturer
    Sanofi Winthrop Industrie, France
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