12867_clexanekriha_english_b.indd

PRESCRIBING INFORMATION
Clexane
Pre-filled Syringes and Multidose Vial
1. NAME OF THE MEDICINAL PRODUCT
Clexane Syringes
Clexane Forte Syringes Clexane Multidose Vial 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Clexane Pre-filled Syringes (100 mg/ml)
Enoxaparin sodium 20 mg (equivalent to 2,000 IU anti-Xa activity)in 0.2 ml water for injections Enoxaparin sodium 40 mg (equivalent to 4,000 IU anti-Xa activity)in 0.4 ml water for injections Enoxaparin sodium 60 mg (equivalent to 6,000 IU anti-Xa activity)in 0.6 ml water for injections Enoxaparin sodium 80 mg (equivalent to 8,000 IU anti-Xa activity)in 0.8 ml water for injections Enoxaparin sodium 100 mg (equivalent to 10,000 IU anti-Xa activity) in 1.0 ml water for injections Clexane Forte Pre-filled Syringes (150 mg/ml)
Enoxaparin sodium 120 mg (equivalent to 12,000 IU anti-Xa activity) in 0.8 ml water for injections Enoxaparin sodium 150 mg (equivalent to 15,000 IU anti-Xa activity) in 1.0 ml water for injections Clexane Multidose Vial (100 mg/ml)
Vials containing 300 mg enoxaparin (equivalent to 30,000 IU anti-Xa activity) in 3.0 ml.
For a full list of the excipients see section 6.1.
3. PHARMACEUTICAL FORM
Pre-filled syringes: Solution for injection in pre-filled syringes.
Multidose vial: Sterile pyrogen-free solution for injection contained in a multidose vial for single patient use.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Enoxaparin is a low molecular weight heparin (LMWH).
Enoxaparin sodium is an anti-coagulant.
CLEXANE Solution for injection at 20 mg and 40 mg
- Prophylactic treatment of thromboembolic 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.
CLEXANE Solution for injection at 40 mg
- Prophylactic treatment of deep vein thrombosis (DVT) in patients who are bedridden due to an
acute medical 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.
CLEXANE 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.
CLEXANE FORTE Solution for injection at 120 mg and 150 mg
- Treatment of deep vein thrombosis (DVT) once daily.
- Treatment of pulmonary embolism once daily.
CLEXANE Multidose Vials 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.
4.2 Posology and method of administration
SUBCUTANEOUS ROUTE (except for patients undergoing hemodialysis and in patients with acute
ST-segment elevation myocardial infarction, in whom IV bolus administration is required).
This presentation is suitable for adults. This drug is not to be injected via the intramuscular route.
• Clexane 100 mg/ml - One milliliter of solution for injection is equivalent to approximately 10 000 anti-Xa IU of enoxaparin.
• Clexane Forte 150 mg/ml - One milliliter of solution for injection is equivalent to approximately 15 000 anti-Xa IU of enoxaparin.
Pre-filled Syringes
Subcutaneous injection technique
The pre-filled syringe is ready for immediate use; no air should be expelled before administering the injection.
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 forefinger. This skin fold should be held throughout the injection.
Regular monitoring of the platelet count is essential throughout the treatment due to the risk of heparin-induced thrombocytopenia (HIT) (see section 4.4).
Multidose Vial
The correct amount for injection should be withdrawn from the vial using a graduated syringe and
a needle adapted to the subcutaneous administration.
With multidose vials, it is recommended to use very fine-gauge needles (maximum diameter of 0.5 mm).
Intravenous (bolus) injection technique / Using the multidose vial of Clexane 300 mg (30 000
anti-Xa IU) /3 ml for the treatment of acute ST-segment elevation myocardial infarction
Treatment is initiated with an IV bolus injection, immediately followed by an SC injection.
The multidose vial should be used to allow the initial dose of 30 mg (3 000 IU), i.e. 0.3 ml
to be withdrawn using a graduated 1 ml syringe (insulin-type syringe).
This dose of enoxaparin should be injected into a venous line, and must not be mixed or administered with other medicinal products. To avoid any traces of other medicinal products and therefore to prevent them from mixing with enoxaparin, the injection line must be rinsed with a sufficient quantity of normal saline or glucose solution before and after IV bolus injection of enoxaparin. Enoxaparin can be safely administered with 0.9% normal saline solution or 5% glucose solution.
In the hospital setting, the multidose vial can be used to:
• obtain the required 1 mg (100 IU)/kg dose for the first SC injection, to be given along
with the IV bolus, and then the required 1 mg (100 IU)/kg doses for SC injection, repeated
every 12 hours,
• obtain the 0.3 mg (30 IU)/kg dose for IV bolus injection for patients undergoing subsequent
Dosage per indication
Prophylactic treatment of venous thromboembolic disease in surgery
As a general rule, these recommendations apply to surgical procedures carried out under general anesthesia. For spinal and epidural anesthesia techniques, the benefit of a pre-operative injection of enoxaparin should be weighed against the theoretically increased risk of spinal hematoma (see section 4.4). • Administration schedule One injection daily. The dose must be determined based on the individual risk related to the patient and the type • Surgery involving moderate thrombogenic risk 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 20 mg (2000 anti-Xa IU, 0.2 ml).
The studied dosage regimen involves administration of the first injection 2 hours before • Surgery involving high thrombogenic risk Hip and knee surgery: The dosage is 40 mg (4 000 anti-Xa IU, 0.4 ml) injected once daily. The studied dosage regimen involves either administration of the first injection of 40 mg (4 000 anti-Xa IU) (total dose) twelve hours before surgery, or a first injection of 20 mg (2 000 anti-Xa IU) (half dose) 2 hours before surgery. When there appears to be an increased risk of venous thromboembolism due to the type of surgery (particularly cancer surgery) and/or due to the patient (particularly history of venous thromboembolism), administering a prophylactic dose identical to that for high-risk orthopedic 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 of 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 section 4.4); • the therapeutic benefit of prophylactic treatment consisting of an injection of 40 mg (4 000 anti-Xa IU)/day of enoxaparin for 4 to 5 weeks after hip surgery has been established; • if the patient is still at risk of venous thromboembolism after the recommended treatment duration, continuing prophylactic therapy must be considered, particularly by administration of oral anticoagulants; 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 the extracorporeal circulation/hemodialysis INJECTION BY THE INTRAVASCULAR ROUTE (in the arterial line of the dialysis circuit). In patients undergoing repeated hemodialysis sessions, prevention of clotting in the extrarenal purification system is obtained by injecting an initial dose of 1 mg (100 anti-Xa IU)/kg in the arterial line of the dialysis circuit at the beginning of the session.
This dose, administered as a single intravascular bolus injection, is only suitable for hemodialysis sessions of 4 hours or less. It may be adjusted subsequently given high inter- and intra-individual variability.
The maximum recommended dose is 1 mg (100 anti-Xa IU)/kg. 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 0.5 mg (50 anti-Xa IU)/kg (double vascular access) or 0.75 mg (75 anti-Xa IU)/kg (single vascular access). Curative treatment of deep vein thrombosis (DVT), with or without pulmonary embolism, without signs of clinical severity Any suspected deep vein thrombosis should be quickly confirmed by the appropriate examinations. • Administration schedule Enoxaparin sodium can be administered subcutaneously either as a single injection of 1.5 mg/kg or as twice daily injections of 1 mg/kg.
The dose per injection is 1 mg (100 anti-Xa IU)/kg twice daily or 1.5 mg (150 anti-Xa IU)/kg as a single injection.
LMWH dosage has not been evaluated in terms of bodyweight in patients weighing more than 100 kg or less than 40 kg. The efficacy of LMWH treatment may be slightly lower in patients weighing more than 100 kg, and the risk of hemorrhage may be higher in patients weighing less than 40 kg. Specific clinical monitoring must be carried out in these patients. • DVT treatment duration Treatment with low-molecular-weight heparin should be quickly replaced by oral anticoagulant therapy, unless contraindicated. Treatment duration with LMWH should not exceed 10 days, including the time needed to reach the required oral anticoagulant effect, except when this is difficult to achieve (see section 4.4). Oral anticoagulant treatment should therefore be initiated as soon as possible. Curative treatment of unstable angina/non-Q-wave myocardial infarction A dose of 1 mg (100 anti-Xa IU)/kg of enoxaparin is administered by subcutaneous injection twice daily at 12-hour intervals, in combination with aspirin (recommended doses: 75 to 325 mg orally, following a minimum loading dose of 160 mg). The recommended duration of treatment is about 2 to 8 days, until the patient is clinically stable.
Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent in patients eligible or not for subsequent coronary angioplasty.
An initial IV bolus injection of 30 mg (3 000 anti-Xa IU) followed by an SC injection of 1 mg (100 anti-Xa IU)/kg within 15 minutes, then every 12 hours (a maximum of 100 mg (10 000 anti-Xa IU) for the first two SC doses).
The first dose of enoxaparin should be administered at any time between 15 minutes before and 30 minutes after the start of thrombolytic treatment (whether fibrin-specific or not).
The recommended duration of treatment is 8 days, or until the patient is discharged from hospital if the hospitalization period is less than 8 days.
Concomitant treatment: administration of aspirin must be instituted as soon as possible after symptoms appear, and maintained at a dosage of between 75 mg and 325 mg daily for at least 30 days, unless otherwise indicated.
Patients treated by coronary angioplasty: - if the last SC injection of enoxaparin was performed less than 8 hours before balloon inflation, no additional administration is necessary.
- if the last SC injection was performed more than 8 hours before balloon inflation, an IV bolus of 0.3 mg (30 anti-Xa IU)/kg of enoxaparin must be administered. In order to improve the accuracy of the volumes to be injected, it is recommended to dilute the drug to 3 mg (300 IU)/ml (i.e. 0.3 ml of enoxaparin diluted in 10 ml) (see table below).
Volumes to inject when dilution is performed for coronary angioplasty patients: Volume to inject when diluted to 3 mg (300 IU/ml) (i.e. 0.3 ml of enoxaparin diluted in 10 ml) 13.5 mg (1350 IU) 16.5 mg (1650 IU) 19.5 mg (1950 IU)) 22.5 mg (2250 IU) 25.5 mg (2550 IU) 28.5 mg (2850 IU) In patients aged 75 and over, treated for acute ST-segment elevation myocardial infarction: The initial IV bolus injection should not be administered. An SC dose of 0.75 mg (75 anti-Xa IU)/kg every 12 hours should be administered (maximum of 75 mg (7 500 anti-Xa IU) for the first two injections only).
For treatment of acute ST-segment Elevation Myocardial Infarction in elderly patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses; see Clinical Trials: Acute ST-segment Elevation Myocardial Infarction). No dose reduction is necessary in the elderly for other indications, unless renal function is impaired, however careful clinical observation is advised (see section 4.4). Not recommended, as dosage not established. Renal impairment (See also section 4.4 and 5.2) • Severe renal impairment: A dosage adjustment is required for patients with severe renal impairment (creatinine clearance < 30 ml/min), according to the following tables, since enoxaparin sodium exposure is significantly increased in this patient population: The following dosage adjustments are recommended for the prophylactic dosage ranges. Severe renal impairment 40 mg SC once daily 20 mg SC once daily 20 mg SC once daily 20 mg SC once daily The following dosage adjustments are recommended for the treatment dosage ranges. Severe renal impairment 1 mg/kg SC twice daily 1 mg/kg SC once daily 1.5 mg/kg SC once daily 1 mg/kg SC once daily Acute STEMI patients < 75 years of age 30 mg-single IV bolus plus a 1 mg/kg SC 30 mg-single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC twice daily dose followed by 1 mg/kg SC once daily Acute STEMI patients ≥ 75 years of age 0.75 mg/kg SC twice daily without initial 1 mg/kg SC once daily without initial bolus The recommended dosage adjustments do not apply to the hemodialysis indication.
• Moderate and mild renal impairment: Although no dosage adjustment are recommended in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) or mild renal impairment (creatinine clearance 50-80 ml/min), careful clinical monitoring is advised. In the absence of clinical studies, caution should be exercised.
Body weight No dosage adjustments are recommended in obesity or low body weight (see also section 4.4 Special warnings and special precautions for use: Low body weight and Monitoring; section 5.2 Pharmacokinetic properties).
4.3 Contraindications
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 (see section 4.4) • 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 (see section 4.4) • Organic lesion likely to bleed • Clinically significant active bleeding • For the Multidose Vial presentation: Premature and full-term neonates, due to the benzyl alcohol At curative doses, this medicinal product MUST NOT BE USED in the following situations:
• Intracerebral hemorrhage
• Spinal or epidural anesthesia must never be performed in patients under curative LMWH At curative doses, this medicinal product is GENERALLY NOT RECOMMENDED in the following
cases:
• Acute extensive ischemic stroke, with or without impaired consciousness.
If the stroke is caused by embolism, enoxaparin must not be administered for 72 hours following
The efficacy of curative doses of LMWH has however not yet been established, regardless of the cause, extent or clinical severity of cerebral infarction. • Acute infectious endocarditis (except for some emboligenic cardiac conditions) In addition, at curative doses, this drug should preferably not be used in all subjects, regardless
of age, when combined with the following (see section 4.5):
1. Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses,
2. NSAIDs (systemic use),
3. Dextran 40 (parenteral use).
At prophylactic doses, this medicinal product is GENERALLY NOT RECOMMENDED in the
following situations:
• during the first 24 hours following intracerebral hemorrhage.
In addition, at prophylactic doses, this drug should preferably not be used in subjects over 65
years of age when used in combination with (see section 4.5):
1. Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses,
2. NSAIDs (systemic use),
3. Dextran 40 (parenteral use).
4.4 Special warnings and special precautions for use
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 Multidose 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. Special warnings
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 high-risk 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 (see section 4.5). 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. 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, • 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 1 mg (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. Precautions for use
Hemorrhage
As with all anticoagulants, bleeding can occur (see section 4.8). If bleeding occurs, the origin of the hemorrhage must be investigated and appropriate treatment instituted. 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), using the Cockcroft formula and based on a recent bodyweight measurement: In male patients: Clcr = (140-age) × weight / (0.814 × serum creatinine) where age is expressed in years, weight in kg and serum creatinine in μmol/l. This formula must be adjusted for female patients by multiplying the result by 0.85. When serum creatinine is expressed in mg/l, the value should be multiplied by a factor of 8.8. Laboratory tests • Platelet monitoring
Heparin-induced thrombocytopenia (HIT)
There is a risk of serious, occasionally thrombogenic, heparin-induced thrombocytopenia (reported with unfractionated heparin and less often with LMWH) of immunologic origin, called type II HIT (see also section 4.8). 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 in certain specific cases (i.e. hip surgery, second and third trimesters of high-risk pregnancy (see section 4.6)), the platelet counts should be performed twice a week during the first month of treatment (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. HIT mainly develops 5 to 21 days after heparin treatment is instituted (with a peak incidence after about 10 days).
This complication can however occur much earlier in patients with a history of heparin-induced thrombocytopenia, and isolated cases have been reported after 21 days. This type of patient history must therefore be systematically investigated by means of an in-depth interview before starting treatment. Furthermore, the risk of recurrence when reinstituting heparin may remain for several years or even indefinitely (see section 4.3). In all cases, the occurrence of HIT constitutes an emergency situation and requires a specialist Any significant drop in the platelet count (30% to 50% versus baseline) is a warning sign even before values reach a critical level. Should a decrease in platelets be observed, the following must be performed in all cases: 1) an immediate platelet count for verification,2) discontinuation of heparin treatment, if the drop is confirmed or even increased based on these results and when no other obvious cause is identified. A sample must be taken using a citrate tube in order to perform in vitro platelet aggregation and immunological tests. However, under these conditions, the immediate measures to be taken are not based on in vitro platelet aggregation or immunological test results as only a few specialized laboratories perform these tests routinely and the results are available at best after several hours. These tests are however necessary to assist in diagnosis of the complication as the risk of thrombosis is very high if heparin treatment is continued. 3) prevention or treatment of HIT-related thrombotic complications. If continued anticoagulant therapy appears to be essential, heparin must be replaced by an antithrombotic agent of a different group such as sodium danaparoid or hirudin, 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 (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 reaches its maximum effect, heparin therapy should be continued at a constant dose for as long as necessary in order to maintain INR within the desired therapeutic range, for the indication in two successive tests. • Monitoring of anti-factor Xa activity
As most of the clinical studies which demonstrated the efficacy of LMWH were conducted using a
dose based on bodyweight without specific laboratory monitoring, the usefulness of laboratory tests for assessing the efficacy of LMWH treatment has not been established. However, laboratory tests, i.e. 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 involve the curative indications of LMWH, due to the doses administered, in patients with: • severe and mild to moderate renal failure (creatinine clearance of approximately 30 ml/min to 60 ml/min calculated using the Cockroft formula). As LMWH is primarily eliminated by the renal route, unlike standard unfractionated heparin, any renal failure can result in relative overdose. • extreme high or low bodyweight (thinness or even cachexia, obesity); • unexplained bleeding. In contrast, laboratory monitoring is not recommended at prophylactic doses if the LMWH treatment complies with the therapeutic recommendations (particularly treatment duration), nor during hemodialysis. To detect possible heparin accumulation following repeated administration, it is recommended, if necessary, to collect a blood sample at peak activity (based on available data), 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, for example every 2 to 3 days, should be decided on a case-by-case basis, depending on the results of the preceding assay, and a possible LMWH dose adjustment should be considered. The anti-Xa activity observed varies for each LMWH and each dosage regimen. For information, based on available data, the mean value (± standard deviation) observed 4 hours after the 7th injection of enoxaparin given at a dose of 1 mg (100 anti-Xa IU)/kg/injection
b.i.d. was 1.20 ± 0.17 anti-Xa IU/ml.
This mean value was observed during clinical trials for anti-Xa activity assays carried out by a chromogenic method (amidolytic). • Activated partial thromboplastin time (aPTT)
Some LMWHs moderately increase aPTT. As no clinical relevance has been established, monitoring
of treatment using this test is of no use. Spinal/epidural anesthesia in patients given preventive treatment with LMWH • As with other anticoagulants, rare cases of spinal hematomas have been reported with LMWHs during spinal/epidural anesthesia, resulting in long-term or permanent paralysis. The risk of spinal hematoma appears to be higher in epidural anesthesia with a catheter than spinal anesthesia. The risk of these rare events may be increased by prolonged post-operative use of epidural • 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. Close neurological monitoring is recommended due to the risk of spinal 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. Particular caution should be exercised during co-administration with other drugs that 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, • chorioretinal vascular disease, • post-operatively, following cerebral or spinal cord surgery, • lumbar puncture: this should only be considered taking into account the risk of intra-spinal bleeding and should be postponed whenever possible, • concomitant use of medicinal products affecting hemostasis (see section 4.5). Coronary angioplasty revascularization procedure To minimize the risk of hemorrhage during coronary angioplasty for unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, it is recommended that the advised intervals between enoxaparin injections be strictly complied with. It is important to perform hemostasis at the vascular puncture site following coronary angioplasty. If an occlusion device is used, the introducer can be removed immediately. If manual compression is performed, the introducer must be removed 6 hours after the last SC/IV injection of enoxaparin. If enoxaparin treatment is continued, the following injection must be performed at the earliest 6 to 8 hours after removal of the introducer. The puncture site must be monitored to detect any signs of bleeding or hematoma. 4.5 Interactions with other medicinal products and other forms of interaction
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-administered.
• Patients under 65 years of age receiving curative LMWH doses and elderly patients (more
than 65 years) regardless of the LMWH dose
Inadvisable + 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, anti-pyretic
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
Combinations to be taken into consideration Combined use of drugs affecting various stages of hemostasis potentiates the risk of bleeding. Therefore, regardless of patient age, continued clinical monitoring and, if necessary, laboratory tests must be performed when co-administering LMWHs at prophylactic doses with oral anti-coagulants, platelet aggregation inhibitors (abciximab, NSAIDs, acetylsalicylic acid at any dose, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban) and thrombolytic agents. 4.6 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.
4.7 Effects on ability to drive and operate machines
Not applicable.
4.8 Undesirable effects
• Hemorrhagic manifestations
This are mainly related to: • Associated risk factors: organic lesions likely to bleed and certain drug combinations (see sections 4.3 and 4.5), age, renal failure, low bodyweight.
• Failure to comply with therapeutic recommendations, particularly treatment duration and dose adjustment based on bodyweight (see section 4.4).
Rare cases of spinal hematoma have been reported following administration of low-molecular- weight heparin during spinal anesthesia, analgesia or epidural anesthesia.
These adverse events have produced varying degrees of neurological injury, including long-term or permanent paralysis (see section 4.4).
• Possible hematomas at the injection site after subcutaneous administration. This risk is increased if the recommended injection technique is not respected or if inappropriate injection material is used. Hard nodules which disappear within a few days may develop as a result of an inflammatory reaction and do not require discontinuation of therapy.
• Thrombocytopenia has been reported. There are two types: • Type I, i.e. the most common cases, usually moderate (more than 100 000/mm3), of early onset (before the fifth day) which do not require discontinuation of treatment, • Type II, i.e. rare serious immunoallergic thrombocytopenia (HIT). The incidence remains poorly evaluated (see section 4.4).
• Possible asymptomatic and reversible elevation of the platelet count.
• Rare skin necrosis observed in most cases at the injection site has been reported with heparins. These reactions may be preceded by purpura or by infiltrated and painful erythematous plaques. Treatment must be discontinued immediately in these cases.
• Rare skin or systemic allergic manifestations have occurred, possibly leading to treatment discontinuation in certain cases.
• As with unfractionated heparins, the risk of osteoporosis cannot be ruled out if treatment is • Transient elevation of transaminase levels.
• A few cases of hyperkalemia have been reported.
• In very rare cases, vasculitis due to skin hypersensitivity • Very rarely, hypereosinophilia, occurring in isolated cases or along with skin reactions, resolving on treatment discontinuation. 4.9 Overdose
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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ANTITHROMBOTIC AGENT, ATC code: B01 AB 05
Enoxaparin is a low-molecular-weight heparin in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated.
It is characterized by higher anti-Xa activity than anti-IIa or antithrombin activity.
For enoxaparin, the ratio between these two activities is 3.6.
At prophylactic doses, it does not significantly affect the aPTT.
At curative doses, aPTT can be prolonged by 1.5 to 2.2 times the control time at peak activity. This prolongation reflects the residual antithrombin activity.
Treatment of acute ST-segment elevation myocardial infarction, in combination with
a thrombolytic agent in patients who are eligible or not for subsequent coronary
angioplasty.
In a large multicenter study, 20 479 patients with acute ST-segment elevation myocardial infarction having received fibrinolytic treatment were randomized to receive either: enoxaparin as an IV bolus injection of 30 mg (3 000 anti-Xa IU) immediately followed by a dose of 1 mg (100 anti-Xa IU)/kg SC, then by an SC injection of 1 mg (100 anti-Xa IU)/kg every 12 hours, or unfractionated heparin by the IV route as a bolus injection of 60 IU/kg (maximum 4 000 IU) followed by a continuous infusion at a dose adjusted to the activated partial thromboplastin time. The SC injections of enoxaparin were administered until discharge from hospital or for a maximum period of 8 days (in 75% of cases for at least 6 days). Half the patients receiving heparin were administered the drug for less than 48 hours (in 89.5% of cases ≥ 36 hours). All the patients were also treated with aspirin for at least 30 days. The enoxaparin dosage was adjusted for patients aged 75 years or more: 0.75 mg (75 IU)/kg as an SC injection every 12 hours, without an initial IV bolus injection.
During the study, 4 716 (23%) patients underwent coronary angioplasty under antithrombotic treatment using blinded study drugs. Patients did not receive an additional dose if the last SC injection of enoxaparin had been given less than 8 hours before balloon inflation, or, received an IV bolus injection of 0.3 mg (30 anti-Xa IU)/kg if the last SC injection of enoxaparin had been given more than 8 hours before balloon inflation.
Enoxaparin significantly reduced the incidence of primary end point events (composite end point consisting of myocardial infarction relapse and all-cause mortality within 30 days after inclusion: 9.9% in the enoxaparin group versus 12.0% in the unfractionated heparin group (relative risk reduction of 17% (p<0.001)). The incidence of myocardial infarction relapse was significantly lower in the enoxaparin group (3.4% versus 5%, p<0.001, relative risk reduction 31%). The incidence of deaths was lower in the enoxaparin group, with no statistically significant difference between the groups (6.9% versus 7.5%, p=0.11).
The benefit of enoxaparin in terms of the primary endpoint was consistent, irrespective of sub-group: age, sex, location of myocardial infarction, history of diabetes or myocardial infarction, type of thrombolytic administered and interval between the first clinical signs and treatment initiation.
Enoxaparin demonstrated a significant benefit versus unfractionated heparin in terms of the primary efficacy criterion, both in patients who had undergone coronary angioplasty within 30 days after inclusion (10.8% versus 13.9%, 23% reduction in relative risk) and in patients who did not have coronary angioplasty (9.7% versus 11.4%, 15% reduction in relative risk).
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the enoxaparin group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial bleeding was similar in both groups (0.8% with enoxaparin versus 0.7% with heparin).
The analysis of the composite criteria measuring overall clinical benefit showed statistically significant superiority (p<0.0001) for enoxaparin versus unfractionated heparin: a relative risk reduction of 14% in favor of enoxaparin (11.0% versus 12.8%) for the composite criteria consisting of death, myocardial infarction relapse, or major bleeding (TIMI criteria) at 30 days, and of 17% (10.1% versus 12.2%) for the composite criteria consisting of death, myocardial infarction relapse or intracranial bleeding at 30 days. 5.2 Pharmacokinetic properties
The pharmacokinetic parameters of enoxaparin have been evaluated based on the time course
of plasma anti-Xa and anti-IIa activity at the recommended doses (validated amidolytic methods)
following single and repeated sub-cutaneous administration, and following single intravenous
injection.
Bioavailability
Subcutaneously administered enoxaparin is rapidly and almost completely absorbed (nearly 100%).
Peak plasma activity is observed between 3 and 4 hours after administration.
This peak activity (expressed as anti-Xa IU) is 0.18 ± 0.04 (after 2 000 anti-Xa IU), 0.43 ± 0.11 (after 4 000 anti-Xa IU) in prophylactic treatment, and 1.01 ± 0.14 (after 10 000 anti-Xa IU) in curative treatment.
An IV bolus injection of 3 000 anti-Xa IU followed by 100 anti-Xa IU/kg by the SC route every 12 hours leads to a first peak in anti-Factor Xa levels of 1.16 IU/ml (n=16) and a mean exposure corresponding to 88% of the steady state level. Steady state is reached as of the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dose ranges. Intra-patient and inter-patient variability is low. After repeated subcutaneous administration of 4000 anti-Xa IU once daily in healthy volunteers, the steady state is reached on day 2 with mean enoxaparin activity of approximately 15% higher than that obtained after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics. After repeated subcutaneous administration of 100 anti-Xa IU/kg b.i.d., the steady state is reached between day 3 and 4 with mean exposure about 65% higher than after a single dose, and with maximum and minimum anti-Xa activity of about 1.2 and 0.52 anti-Xa IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and is within the therapeutic range.
Plasma anti-IIa activity after subcutaneous administration is about 10-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection, and reaches 0.13 anti-IIa IU/ml following repeated administration of a 100 anti-Xa IU/kg dose b.i.d.
No pharmacokinetic interaction has been observed between enoxaparin and the thrombolytic agent when co-administered.
Distribution
The volume of distribution of enoxaparin anti-Xa activity is about 5 liters and is close to the blood
volume.
Metabolism
Enoxaparin is metabolized mainly in the liver (desulfation, depolymerization).
Elimination
Following subcutaneous injection, the apparent anti-Xa activity elimination half-life is higher for
low-molecular-weight heparins than for unfractionated heparins.
Enoxaparin exhibits a monophasic elimination pattern with a half-life of about 4 hours after a single subcutaneous dose to about 7 hours after repeated dosing.
With low-molecular-weight heparin, plasma decay occurs more quickly for anti-IIa activity than for anti-Xa activity.
Enoxaparin and its metabolites are eliminated via the renal route (nonsaturable mechanism) and by the biliary route.
Renal clearance of fragments with anti-Xa activity accounts for about 10% of the administered dose, and total renal excretion of active and non-active compounds for 40% of the dose.
5.3 Preclinical safety data
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, the forward mutation test at the thymidine kinase (TK) locus of L5178Y mouse lymphoma cells, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses less than 20 mg/kg/day. Teratogenicity studies have been conducted in gravid rats and rabbits at SC doses of enoxaparin less than 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects during the following toxicity studies: • 15 mg/kg/day in 13-week subcutaneous toxicity studies in rats and dogs • 10 mg/kg/day in 26-week subcutaneous and intravenous toxicity studies in rats and monkeys. 6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Pre-filled syringes : Water for injection.
Multidose Vials : Benzyl alcohol, water for injection 6.2 Special precautions for storage
Do not store above 25°C. Do not refrigerate or freeze.
To be stored in the original packaging.
6.3 Shelf-life
Multidose Vials: after use for the first time, to be stored at a temperature not exceeding 25°C for
a maximum of 28 days.
6.4 Nature and contents of outer packaging
Clexane Pre-filled Syringes (100 mg/ml)
0.2 ml solution for injection in pre-filled (glass) syringes
0.2 ml solution for injection in pre-filled (glass) syringes with safety system 0.4 ml solution for injection in pre-filled (glass) syringes 0.4 ml solution for injection in pre-filled (glass) syringes with safety system 0.6 ml solution for injection in pre-filled (glass) syringes 0.6 ml solution for injection in pre-filled (glass) syringes with safety system 0.8 ml solution for injection in pre-filled (glass) syringes 0.8 ml solution for injection in pre-filled (glass) syringes with safety system 1.0 ml solution for injection in pre-filled (glass) syringes 1.0 ml solution for injection in pre-filled (glass) syringes with safety system Clexane Forte Pre-filled Syringes (150 mg/ml)
0.8 ml solution for injection in pre-filled (glass) syringes
0.8 ml solution for injection in pre-filled (glass) syringes with safety system 1.0 ml solution for injection in pre-filled (glass) syringes 1.0 ml solution for injection in pre-filled (glass) syringes with safety system Clexane Multidose Vial (100 mg/ml)
3 ml injection for solution in multidose vials – box of 1 vial
6.5 Special precautions for disposal and handling
Dispose of the product safely as instructed by your healthcare professional.
For pre-filled syringes with a safety system: Clexane/Clexane Forte is a solution for injection in pre-filled syringes with an automatic safety system intended to prevent accidental needle sticks after injection. Instructions on how to use the device are provided in the Package Leaflet. 7. MANUFACTURER
Clexane Pre-filled Syringes (100 mg/ml):
Sanofi Winthrop Industrie France
Clexane Forte Pre-filled Syringes (150 mg/ml):Sanofi Winthrop Industrie France Clexane Multidose Vials:Sanofi-aventis Spain 8. MARKETING AUTHORIZATION HOLDER
sanofi-aventis Israel ltd., P.O.B. 8090 Netanya 42504
The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in May 2010. CLEX INJ PHY SH 130410

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