THERAPEUTIC INDICATIONS

This heparin is a low molecular weight heparin(LMWH). Prophylactic treatment of venous thromboembolic disease in moderate or high risk surgery. Prevention of clotting in the extracorporeal circulating during hemodialisis (generally a session of 4 hours or less).

POSOLOGY AND METHOD OF ADMINISTRATION

Subcutaneous injection method: The pre- filled syringe is ready for immediate use; do not press on the plunger to expel any air bubbles before injecting the drug. Enoxaparin should be administered by injection into the subcutaneous tissue preferably with the patient supine. Administration should be alternated between the left and right anterolateral and posterolateral abdominal walls. The whole length of the needle should be inserted perpendicularly, not from the side, into a skin fold held between the thumb and index finger. This skin fold should be held throughout the injection. Prophylactic treatment of venous thromboembolic disease in surgery: Generally this apply to surgical procedures carried out under general anesthesia. For spinal and epidural anesthesia techniques, risk and benefit of pre-operative injection should be weighed (see “Precautions for use”). Administration schedule: One injection per day. Dosage: In surgery involving moderate thrombogenic risk and in patients who are not at high risk of thromboembolism, effective prevention is achieved by daily injection of 2,000 anti-Xa IU (0.2 ml). The studied dosage regimen involves administration of the first injection approximately 2 hours before surgery. Surgery involving high thrombogenic risk: • Hip and knee surgery: The dosage is 4,000 anti-Xa IU (0.4 ml) injected once daily. The studied dosage regimen involves either administration of the first injection of 4,000 anti-Xa IU (total dose) 12 hours before surgery, or a first injection of 2,000 anti-Xa IU (half dose) 2 hours before surgery. • Other situations: When there appears to be an increased risk of venous thromboembolism related to the type of surgery (particularly cancer surgery) and/or related to the patient (particularly history of venous thromboembolism), administering a prophylactic dose identical to that for high risk surgery, such as hip or knee surgery, can be considered. Duration of treatment: Treatment with LMWH should be maintained, along with the usual methods of elastic support for the legs, until the patient is fully and actively ambulatory. - In general surgery, the duration of LMWH treatment must be less than 10 days unless there is a patient-specific risk of venous thromboembolism (see “Precautions for use”, platelet monitoring). - The therapeutic benefit of prophylactic treatment consisting of a daily injection of 4000 anti-Xa IU/day of enoxaparin for 4 to 5 weeks after hip surgery has been established. However, the clinical benefit of long term treatment with low molecular weight heparins or oral anticoagulants has not yet been evaluated. Prevention of clotting in extracorporeal circulation/hemodialysis: Inject by the intravascular route (in the arterial line of the dialysis circuit). In patients undergoing repeated hemodialysis sessions, preventing of clotting in the extrarenal purification system is obtained by injecting an initial dose of 100 anti-Xa IU/kg in the arterial line of the dialysis circuit at the beginning of session. This dose, administered as a single intravascular bolus injection, is only suitable for hemodialysis sessions of 4 hours or less. If fibrin rings are found in the dialysis device, an additional dose of 50 to 100 anti-Xa IU/kg may be injected, depending on the time to the end of dialysis. In hemodialysis patients at high risk of hemorrhage (particularly pre- and post-operative dialysis) or with active hemorrhage, dialysis sessions may be carried out using a dose of 50 anti-Xa IU/kg (double vascular access) or 75 anti-Xa IU/kg (single vascular access).

CONTRA-INDICATIONS

Hypersensitivity to enoxaparin, heparin or heparin derivatives, including other LMWHs; History of thrombocytopenia with enoxaparin or any other heparin, whether caused by unfractionated or low molecular weight heparin (see “Precautions for use”); Hemorrhagic manisfestations or tendency to bleed related to impaired hemostasis (a possible exception to this contraindication may be disseminated intravascular coagulation, when it is not related to heparin therapy (see “Precaution for use”); History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies; Organic lesion likely to bleed; Clinically significant active bleeding; Acute infectious endocarditis (except when occurring on a mechanical prosthesis); In the absence of data, severe renal failure, except in dialysis which is a special case. In these cases, use unfractionated heparin. This medicinal product is generally not recommended in cases of: mild to moderate renal failure, haemorrhagic stroke, uncontrolled arterial hypertension, or in combination with acetylsalicylic acid (for analgesia and antipyretic therapy), NSAIDs, dextran, ticlopidine

SPECIAL WARNINGS

Warnings: Spinal/epidural anesthesia: As with other anticoagulants, there have been rare reports of spinal haematomas following the administration of enoxaparin during spinal/epidural anesthesia, resulting in long-term or permanent paralysis. The risk of these rare events may be increased by prolonged use of postoperative indwelling epidural catheters. Risk of hemorrhage: The recommended dosage regimens must be respected (dosage and duration of treatment). Serious hemorrhage 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 recommended mean duration of ten days, non-compliance with therapeutic recommendations, co- administration with drug increasing the risk of hemorrhage. Assay of anti-Xa activity may in certain cases be useful in detecting accumulation. Risk of heparin-induced thrombocytopenia (HIT): Should a patient treated with LMWH (curative or preventive dose) develop thromboembolic 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 LHWH is not recommended in children. Mechanical prosthetic heart valves: Enoxaparin in the prevention of thromboembolic events in patients with mechanical prosthetic heart has not been specifically investigated. However, some isolated cases of thrombosis have been reported in patients with this devise who received enoxaparin as prophylactic treatment of thromboembolic events. Pregnant women: During a clinical study in pregnant women with mechanical prosthetic heart valves receiving 100 anti-Xa IU/kg bodyweight of enoxaparin twice daily to reduce the risk of thromboembolic events, two of eight women developed thrombosis which led to an obstructed valve with fatal outcome for both the woman and the fetus. In addition, other isolated post-marketing cases of thrombosis have been reported in pregnant women with mechanical prosthetic heart valves who received thromboembolic prophylaxis with enoxaparin. Therefore, the risk of thromboembolic events in this population might be higher.

PRECAUTION FOR USE

Hemorrhage: As with all anticoagulants, bleeding may occur (see “Adverse effects”). Renal function: Before low molecular weight heparin treatment is initiated, it is essential to evaluate renal function, particularly in subjects 75 years or older by determining creatinine clearance (Clcr). In patients diagnosed with severe renal insufficiency (creatinine clearance of about 30 ml/min) the use of LMWH as curative intent is contraindicated (see Contraindications). Obese patients: Obese patients are at higher risk for thromboembolism. These patients should be observed carefully for signs and symptoms of thromboembolism. History of HIT (>100 days): Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or several years. Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies.

Laboratory tests: Platelet monitoring: Heparin-induced thrombocytopenia (HIT). There is a risk of serious, occasionally thrombogenic, heparin-induced thrombocytopenia of immunologic origin (type II HIT). As a result of this risk, platelet counts must be performed regardless of the therapeutic indication and the dose administered. Platelet counts must be performed before administration or at the latest within 24 hours of initiating treatment, then twice a week during the usual treatment duration. Should long-term treatment prove necessary, the schedule for platelet counts is twice a week during the first month (highest risk period) and then once a week until treatment discontinuation. HIT should be suspected when the platelet count is below 100,000/mm3 and/or when there is a drop of 30% to 50% between two successive platelet counts. Should a decrease in platelets be observed, a certain procedure should be followed (see full prescribing information). If continued anticoagulant therapy appears to be essential, heparin must be replaced by an antithrombotic agent of a different chemical group of such as sodium danaparoid or hirudine, prescribed at curative or preventive doses on a case-by-case basis. Replacement by oral anticoagulants can only take place after the platelet count has reverted to normal due to the risk of exacerbation of thrombosis by oral anticoagulants. Replacement of heparin by oral anticoagulants Clinical monitoring and laboratory tests (one stage prothrombin time expressed as the INR) must be intensified to monitor the effect of oral anticoagulants. As there is an interval before the oral anticoagulant has reached its maximum effect, heparin therapy should be maintained at an equivalent dose so that the INR remains within the desired therapeutic range for the indication in two successive tests.

Monitoring of anti-factor Xa activity: Monitoring of anti-Xa activity may be useful in managing the risk of bleeding in certain clinical conditions often associated with a risk of overdose. These situations mainly concern the curative indications of LMWH, due to the doses administered, in patients with: -mild to moderate renal insufficiency (creatinine clearance of approximately 30 ml/min to 60 ml/min calculated using the Cockcroft formula). As LMWH is primarily eliminated by the renal route, unlike standard unfractionated heparin, any renal insufficiency can result in relative overdose. Extreme bodyweight (thinness or even cachexia, obesity); unexplained bleeding. In contrast, laboratory monitoring is not recommended at prophylactic doses if the LMWH treatment is consistent with the therapeutic recommendations (particularly treatment duration), nor during hemodialysis. To detect possible heparin accumulation, it is recommended, to collect a blood sample at peak activity, i.e. approximately 4 hours after the third injection when the drug is given as 2 subcutaneous injections per day. Repeating anti-Xa activity assays to determine blood heparin levels, should be decided on a case-by-case basis. Activated partial thromboplastin time (aPTT) Some LMWHs moderately increase aPTT. Spinal/epidural anesthesia in patients given preventive treatment with LMWH: - Epidural or spinal anesthesia must never be performed in patients under curative LMWH treatment. - As with other anticoagulants, there have been rare reports of spinal hematomas following administration of LMWH during spinal/epidural anesthesia, resulting in long-term or permanent paralysis. The risk of intra-spinal hematoma appears to be higher in epidural anesthesia with a catheter than in spinal anesthesia. The risk of these rare events may be increased by prolonged post-operative use of indwelling epidural catheters and in patients who have undergone spinal surgery or have spinal deformities (e.g. ankylosing spondylitis). - Placement or 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. - If pre-operative LMWH treatment is required (long term bedridden patients, trauma) and if the benefit of local/regional spinal anesthesia has been carefully weighed, patients who received a pre-operative injection of LMWH can be anesthetized provided that an interval of at least 12 hours is respected between the heparin injection and the spinal anesthesia. Since anti-Xa levels are, however, still detectable after this 12-hour interval, a neuraxial hematoma can still occur. Close neurological monitoring is recommended due to the risk of intraspinal hematoma. In almost all patients, prophylactic treatment with LMWH can be initiated within 6 to 8 hours after the anesthesia or removal of the catheter, under neurological monitoring. Extra caution should be exercised during co- administration with other drugs which affect hemostasis (specifically non-steroidal anti-inflammatory drugs, aspirin).In almost all patients, prophylactic treatment with LMWH can be initiated within 6 to 8 hours after the anesthesia or removal of the catheter, under neurological monitoring. Extra caution should be exercised during co-administration with other drugs which affect hemostasis (specifically non-steroidal anti-inflammatory drugs, aspirin).

Situations involving particular risk: Monitoring of treatment should be intensified in the following cases: hepatic insufficiency, history of gastro-intestinal ulcers or any other organic lesion likely to bleed, vascular chorioretinal di sease, post-operatively, following cerebral or spinal cord surgery, lumbar puncture (risk of intraspinal bleeding).

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 and 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-administered. Inadvisable combinations Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses (and,by extrapolation, other salicylates): Increased risk of hemorrhage (salicylate-induced platelet function inhibition and gastroduodenal mucosal damage).Use a non-salicylate antipyretic analgesic (such as paracetamol) NSAIDs (systemic use): Increased risk of hemorrhage (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 hemorrhage (inhibition of platelet function by dextran 40). Adjust heparin dosage so that the coagulation test performed as a measure of hypocoagulability does not exceed 1.5 times the control value during co administration and after discontinuation of dextran 40. Ticlodipine: Increased risk of haemorrhage (inhibition of platelet function by ticlodipine) Combinations requiring precautions for use Corticoids (glucocorticoids) (except for hydrocortisone used as replacement therapy in Addison’s disesase) (systemic use and, in certain cases local uses, i.e. intramuscular, intraarticular or cutaneous use of rectal washout). Heparin- related increase in the risk of haemorrhage specific to corticoid therapy (gastric mucosa, vascular fragility), at high doses or during prolonged treatment lasting more than ten days. If the combination cannot be avoided clinical monitoring must be intensified. + 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 atanalgesic, antipyretic and anti-inflammatory doses; NSAIDs): abciximab, acetylsalicylic acid at antiaggregant doses in cardiological and neurological indications, baraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban. Increased risk of hemorrhage.

Patients under 65 years of age Combinations to take into consideration Combined use of drugs which variably affect hemostasis potentiate the risk of bleeding. Therefore, regardless of the age of the patients, co-administration of LMWH at preventive doses with the following drugs must be taken into consideration by means of continued clinical monitoring and possible laboratory tests: oral anticoagulants, platelet aggregation inhibitors (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticloprost, ticlopidine, tirofiban) and thrombolytic agents.

PREGNANCY AND LACTATION

Pregnancy: There is no evidence from animal studies that enoxaparin has teratogenic potential. Prophylactic treatment during the first trimester: As a precautionary measure, enoxaparin prophylaxis should not be administered during the first trimester. If epidural anesthesia is planned, prevented heparin treatment should be interrupted whenever possible within 12 hours before anesthesia at the latest. Prophylactic treatment during the second and third trimesters: Administration of prophylactic doses of enoxaparin to women during the second and third trimesters in a limited number of pregnancies has apparently not resulted in any particular teratogenic or fetotoxic effects. However, additional studies are needed to evaluate the effects of exposure under these conditions. Therefore, enoxaparin prophylaxis during the second and third trimesters should only be administered if necessary. If epidural anesthesia is planned, preventive heparin treatment should be interrupted whenever possible within 12 hours before anesthesia at the latest. Lactation: Since in principle gastro-intestinal absorption by neonates is unlikely in principle, treatment with enoxaparin, is not contraindicated in breast-feeding.

UNDESIRABLE EFFECTS

Hemorrhage : In clinical studies, hemorrhages were the most commonly reported reaction. These included major hemorrhages, reported in 4.2 % of patients (surgical patients). Some of these cases were fatal. Bleeding complications were considered major in the following cases: If the hemorrhage caused a significant clinical event; If accompanied by a hemoglobin decrease of ≥ 2 g/dl or transfusion of 2 or more units of blood products; Retroperitoneal and intracranial hemorrhages were always considered major. As with other anticoagulants, hemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or concomitant use of medications affecting hemostasis. Thrombocytopenia and thrombocytosis. Blood and lymphatic system disorders: Thrombocytosis, thrombocytopenia. Other adverse reaction observed in clinical studies: - Immune system disorders : Allergic reaction which may lead to treatment discontinuation in some cases (common), anaphylactic reaction(rare); - Hepatobilary disorders : Hepatic enzymes increase (very common); - Skin and subcutaneous tissue disorders : urticaria, pruritus, erythema (common); - General disorders and administration site conditions: injection site hematoma*, injection site pain, other injection site reaction (e.g. edema, hemorrhage, allergic reaction, inflammation, nodules, other reactions).

OVERDOSAGE

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 considering its efficacy is far lower than that reported in overdoses with unfractionated heparin; and 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 and the time since the heparin injection. The above recommendations are intended for patients with normal renal function receiving repeated doses. Nevertheless, the anti-Xa activity of enoxaparin cannot be completely neutralized. Furthermore, the neutralization may only be transient due to the absorption pharmacokinetics of low molecular weight heparin. This may require dividing the total calculated dose of protamine into several injections (2 to 4) given over 24 hours. Serious consequences are likely after ingestion of low molecular weight heparin, even in massive quantities (no cases reported), due to the low gastric and intestinal absorption of the drug.

PHARMACOLOGICAL PROPERTIES

ATC Code: B01AB05.

Based on approval 31 December 2018 - CCDS v13 Revision on date January 2019

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