Active ingredients: Heparin (Enoxaparin sodium)
Clexane 2,000 I.U. aXa / 0.2 ml solution for injection
Clexane 4,000 I.U. aXa / 0.4 ml solution for injection
Why is Clexane used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Clexane (enoxaparin) is a "low molecular weight heparin with a" high antithrombotic activity.
THERAPEUTIC INDICATIONS
- Prophylaxis of deep vein thrombosis (DVT) in general surgery, in orthopedic surgery and in bedridden non-surgical patients at risk of DVT.
- Treatment of deep vein thrombosis with or without pulmonary embolism.
- Treatment of unstable angina and non-Q myocardial infarction in combination with acetylsalicylic acid.
- Prevention of coagulation during hemodialysis.
Contraindications When Clexane should not be used
- Hypersensitivity to the active substance, to heparin or its derivatives including other low molecular weight heparins or to any of the excipients listed in the "Composition" section.
- History of thrombocytopenia with enoxaparin (see also section "Special warnings").
- Hemorrhagic manifestations or tendencies related to haemostatic disorders, with the exception of consumption coagulopathies not related to heparin.
- Organic lesions at risk of bleeding.
- Acute infective endocarditis (except those related to mechanical prostheses).
- Hemorrhagic cerebrovascular accidents.
- Locoregional anesthesia for elective surgical procedures is contraindicated in those patients who receive heparin for reasons other than prophylaxis.
- Relative contraindications: association with ticlopidine, with salicylates or NSAIDs, with antiplatelet agents (dipyridamole, sulfinpyrazone, etc.).
Precautions for use What you need to know before taking Clexane
- Do not administer intramuscularly
- Hemorrhages. As with other anticoagulants, bleeding can occur at any site (see section "Undesirable effects"). If bleeding occurs, the origin of the bleeding should be sought and appropriate treatment instituted.
- As with other anticoagulant therapies, enoxaparin sodium should be used with caution in conditions of potentially increased bleeding, such as: - haemostatic disorders; - history of peptic ulcer; - recent ischemic stroke; - severe uncontrolled arterial hypertension; - diabetic retinopathy; - recent neurological or ophthalmological surgery; - concomitant use of drugs that affect haemostasis (see section "Interactions").
Mechanical heart valve prostheses
The use of Clexane for thromboprophylaxis in patients with mechanical heart valve prostheses has not been adequately investigated. There have been isolated reports of valve thrombosis in patients with mechanical heart valve prostheses while on enoxaparin therapy for thromboprophylaxis. Confounding factors including underlying disease, as well as insufficient clinical data limit the assessment of these cases. Some of these cases were pregnant women in whom thrombosis has led to maternal and fetal death. Pregnant women with mechanical heart valve prostheses may have increased risk of thromboembolic events (see section "Warnings: Pregnant women with mechanical heart valve prostheses").
Hemorrhage in elderly patients
With the doses used in the prophylaxis of venous thromboembolism in elderly patients, no increased tendency for bleeding has been observed. Elderly patients (especially 80 years of age or older) may have an increased risk of bleeding complications with therapeutic doses. Close clinical monitoring is recommended.
Kidney failure
In patients with renal insufficiency there is a risk of increased levels of enoxaparin sodium which could lead to an increased risk of bleeding. Since the levels of enoxaparin sodium are significantly increased in patients with severe renal insufficiency (creatinine clearance <30 ml / min), a dose adjustment is necessary in both prophylaxis and treatment of venous thromboembolism. Although dose adjustment is not recommended in patients with moderate (creatinine clearance 30-50 mL / min) and mild (creatinine clearance 50-80 mL / min) renal impairment, close clinical monitoring is advisable. Hemodialysis: the doses will have to be adjusted if the anti-Xa activity is lower than 0.4 IU / ml or higher than 1.2 IU / ml.
Low body weight patients
In women with low body weight (<45 kg) and in men with low body weight (<57 kg) an increase in the levels of enoxaparin sodium was observed, at the doses used in the prophylaxis of venous thromboembolism (not adapted to body weight); this could lead to an increased risk of bleeding. However, careful clinical monitoring is advisable in these patients.
Obese patients
Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI> 30 kg / m 2) have not been fully established and there is no consensus for dose adjustment. These patients should be carefully observed for signs and symptoms of thrombus embolism
Interactions Which drugs or foods can modify the effect of Clexane
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Associations not recommended:
- Acetylsalicylic acid and other salicylates (by general route): Increased risk of haemorrhage (inhibition of platelet function and aggression of the gastroduodenal mucosa by salicylates). Use other substances for an analgesic or antipyretic effect.
- NSAIDs (by the general route) Increased risk of bleeding (inhibition of platelet function and aggression of the gastroduodenal mucosa by non-steroidal anti-inflammatory drugs). If the association cannot be avoided, institute careful clinical and biological surveillance.
- Ticlopidine Increased risk of bleeding (inhibition of platelet function by ticlopidine). The combination with high doses of heparin is not recommended. The combination with low doses of heparin (preventive heparinotherapy) requires careful clinical and biological surveillance.
- Other antiplatelet agents (clopidogrel, dipyridamole, sulfinpyrazone, etc ....) Increased risk of bleeding (inhibition of platelet function).
Associations requiring use precautions:
- Oral anticoagulants Enhancement of anticoagulant action. Heparin distorts the prothrombin rate. When replacing heparin with oral anticoagulants: a. Reinforce clinical surveillance b. To check the effect of oral anticoagulants, take the sample before heparin administration, if this is discontinuous or, preferably, use a reagent not sensitive to heparin.
- Glucocorticoids (general route) Worsening of the haemorrhagic risk typical of therapy with glucocorticoids (gastric mucosa, vascular fragility), at high doses or in prolonged treatment for more than ten days. The association must be justified; enhance clinical surveillance.
- Dextran (parenteral route) Increased risk of bleeding (inhibition of platelet function). Adjust the dosage of heparin so as not to exceed a hypocoagulability greater than 1.5 times the reference value, during the combination and after the suspension of dextran.
Warnings It is important to know that:
The low molecular weight heparins differ in the method used in the production, in the molecular weight and in the specific anti-Xa activity, unit and dosage; therefore it is not necessary to switch from one active ingredient to another.
This results in differences in pharmacokinetics and associated biological activities (e.g. antithrombin activity and platelet interactions). Special attention is therefore required and compliance with the instructions for use of each individual medicinal product is required.
Spinal / epidural anesthesia
In patients undergoing spinal or epidural anesthesia, epidural analgesia or lumbar puncture, low-dose low-molecular-weight heparin prophylaxis may rarely be associated with spinal or epidural hematomas that can lead to prolonged or permanent paralysis. The risk is increased by the use of indwelling peridural catheters for continuous infusion, by the concomitant intake of drugs that affect haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors or anticoagulants, from trauma or from repeated spinal puncture, from the presence of an underlying haemostatic disorder and from old age, or in patients with a history of spinal surgery or spinal deformity. The presence of one or more of these risk factors must be carefully evaluated before proceeding with this type of anesthesia / analgesia, during prophylaxis with low molecular weight heparins.
As a rule, the insertion of the spinal catheter must be carried out at least 8-12 hours after the last administration of low molecular weight heparin at prophylactic doses. Subsequent doses should not be administered until at least 2-4 hours have elapsed after catheter insertion or removal, or further delayed or not administered in the case of hemorrhagic aspirate during initial spinal or epidural needle placement. Removal of an "indwelling" epidural catheter should be done as far away as possible from the last prophylactic heparin dose (approximately 8-12 hours) performed under anesthesia.
If it is decided to administer low molecular weight heparin before or after a "epidural or spinal anesthesia, extreme caution and frequent monitoring should be performed to identify signs and symptoms of neurological alterations such as: lumbar pain, sensory and motor deficit (numbness and weakness of the lower limbs), changes in bladder or bowel function. Nursing staff should be instructed to identify these signs and symptoms. Patients should be instructed to notify medical or nursing staff immediately if any of the above symptoms occur. if signs or symptoms of epidural or spinal hematoma are suspected, an immediate diagnosis should be made and treatment that includes spinal cord decompression initiated.
Heparin-induced thrombocytopenia
Thrombocytopenia is a well-known complication of heparin therapy and can appear 4 to 10 days after starting treatment, but even earlier in the case of previous heparin-induced thrombocytopenia. Mild thrombocytopenia may appear early in 10 to 20% of patients (platelet count greater than 100,000 / mm3), which may remain stable or regress, even if heparin administration is continued.
In some cases, a more severe form (type II heparin thrombocytopenia), immune-mediated, can be determined, characterized by the formation of antibodies against the heparin-platelet factor 4 complex. In these patients, new thrombus associated with thrombocytopenia can develop, resulting from " irreversible aggregation of platelets induced by "heparin, the so-called" white thrombus syndrome ". This process can lead to severe thromboembolic complications such as skin necrosis, arterial embolism of the extremities, myocardial infarction, pulmonary embolism, stroke, and sometimes death. Therefore, the administration of low molecular weight heparin should be discontinued in addition to the onset of thrombocytopenia, even if the patient develops a new thrombosis or a worsening of a previous thrombosis. The continuation of anticoagulant therapy, for thrombosis that is the cause of the treatment in progress or for a new onset or worsening of the same, should be undertaken, after heparin suspension, with an alternative anticoagulant. In these cases, the immediate introduction of anticoagulant therapy is risky. oral (cases of worsening of thrombosis have been reported).
Therefore thrombocytopenia of any nature should be carefully monitored. If the platelet count falls below 100,000 / mm3, or if recurrent thrombosis occurs, low molecular weight heparin should be discontinued. A platelet count should be assessed before treatment and twice weekly thereafter for the first month. in case of prolonged administration.
Percutaneous coronary revascularization procedures
To minimize the risk of bleeding following the use of vascular equipment during the treatment of unstable angina and non-Q myocardial infarction, the introducer should remain in place for 6-8 hours after subcutaneous administration of the enoxaparin dose. sodium. The next scheduled dose should not be administered earlier than 6-8 hours after removal of the introducer. The access site should be examined for any signs of bleeding or bruising.
Pregnant women with mechanical heart valve prostheses
The use of Clexane for thromboprophylaxis in pregnant women with mechanical heart valve prostheses has not been adequately investigated. In a clinical study in pregnant women with mechanical heart valve prostheses treated with enoxaparin (1 mg / kg / bid) to reduce the risk of thromboembolic events, only two of eight patients experienced thrombotic events leading to valve block and subsequent maternal and fetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women with mechanical valve prostheses heart prostheses while on enoxaparin therapy for thromboprophylaxis. Pregnant women with mechanical heart valve prostheses may be at increased risk for thromboembolic events (see section "Precautions for use: Cardiac mechanical valve prostheses").
Laboratory tests:
At doses used for venous thromboembolism prophylaxis, enoxaparin sodium does not significantly affect bleeding time and total blood clotting time tests, nor does it interfere with platelet aggregation or the binding of fibrinogen to platelets.
At higher doses, increases in aPTT (partially activated thromboplastin time) and ACT (activated clot time) may occur.
The increases in aPTT and ACT are not linearly correlated with the increased antithrombotic activity of enoxaparin sodium and are therefore unsuitable and unreliable tests for monitoring the activity of enoxaparin sodium.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
Animal studies have not shown embryotoxic or teratogenic properties. In women there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available on the first and third trimesters. For these reasons this drug it should only be used during pregnancy if your doctor has verified that it is necessary. (see also section "Warnings: Pregnant women with mechanical heart valve prostheses" and "Precautions: Mechanical heart valve prostheses"). If epidural anesthesia is to be used, it is advisable to discontinue treatment with heparin.
Feeding time
It is unknown whether enoxaparin sodium is excreted unchanged in human milk. Oral absorption of enoxaparin sodium is unlikely. However, as a precaution, nursing mothers receiving enoxaparin sodium should be advised not to breastfeed.
Effects on ability to drive and use machines
Clexane does not affect the ability to drive or use machines.
Dosage and method of use How to use Clexane: Dosage
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Subcutaneous administration
Treatment of unstable angina and non-Q myocardial infarction
The recommended dose of enoxaparin sodium is 100 I.U. anti-Xa (1 mg) / kg every 12 hours by subcutaneous injection, administered concomitantly with oral acetylsalicylic acid (100 to 325 mg per day). Treatment of these patients with enoxaparin sodium should be prescribed for at least 2 days and continued until the clinical situation stabilizes. Generally the duration of treatment is from 2 to 8 days.
Prophylaxis and treatment of deep vein thrombosis (DVT)
In patients with moderate thromboembolic risk, effective prevention of thromboembolic disease is achieved by injection of 2,000 I.U. aXa (0.2 ml) / day. In general surgery, the first injection should be given approximately 2 hours before surgery.
In patients at high thromboembolic risk and in particular in preparation for orthopedic surgery, it is recommended to administer a dose of enoxaparin equal to 4,000 I.U. aXa (0.4 ml) / day in a single daily administration. In orthopedic surgery the first injection will be given 12 hours before the operation.
The duration of the treatment will coincide with that of the persistence of the thromboembolic risk, and in general up to the patient's ambulation (on average from 7 to 10 days after the operation). In normal conditions of use, enoxaparin does not modify the coagulation parameters Treatment surveillance based on these tests is therefore unnecessary.
In the treatment of deep vein thrombosis, enoxaparin follows traditional heparin therapy established following a positive diagnosis. Enoxaparin will be administered at the rate of one injection every 12 hours for 10 days.
The dose of each injection will be 100 I.U. aXa / kg body weight. In bedridden non-surgical patients at risk of DVT, the recommended dose of enoxaparin sodium is 40 mg once daily by subcutaneous injection. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until return to full walking, for a maximum of 14 days.
Longer duration treatment may be appropriate: enoxaparin administration should continue as long as there is a thromboembolic risk and until the patient is walking.
Biological surveillance: see "Special warnings".
Injection technique
The subcutaneous injection should be conducted, preferably with the patient in decubitus, in the subcutaneous cellular tissue of the anterolateral or posterolateral abdominal belt, alternately on the right and left.
The pre-filled syringes are ready to use, so you do not have to expel the air in the syringe before injection.
The injection itself must be performed by completely introducing the needle, perpendicularly and not tangentially, into the thickness of a skin fold made between the thumb and the index finger of the operator.
The skin fold must be maintained for the duration of the injection.
For syringes with automatic safety system
The pre-filled syringes are equipped with an automatic safety system to prevent accidental needle sticks after injection. At the end of the injection, keeping the plunger at the end of its stroke, remove the needle from the injection site.
By orienting the needle away from yourself and other people, activate the safety system by pressing the plunger firmly. The protective sleeve will automatically cover the needle and simultaneously an audible "click" will confirm the activation of the safety system. syringe in the appropriate container.
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Intravascular administration
Prevention of coagulation during hemodialysis In patients to undergo repeated sessions of hemodialysis, the prevention of coagulation within the hemodialysis circuit can be achieved by administering a dose equal to 100 IU / kg into the arterial line of the circuit, at the beginning of the session. This dose is usually sufficient to conduct a session lasting 4 hours. If fibrin filaments appear within the circuit, an additional dose of 50-100 IU / kg may be used, depending on the time missing at the end of the session. In patients at risk of bleeding (in particular in the case of pre- or post-operative hemodialysis sessions) or who have evolving hemorrhagic syndromes, dialysis sessions can be performed using a dose of 50 IU / kg (access double vascular) or 75 IU / kg (simple vascular access).
Overdose What to do if you have taken too much Clexane
In case of accidental ingestion / intake of an excessive dose of Clexane, notify your doctor immediately or go to the nearest hospital.
As a general rule, serious consequences are not to be feared for a massive oral intake of enoxaparin (no reported cases), taking into account the minimum gastric and intestinal absorption of the product.
However, a plasma assay of the anti-Xa and anti-IIa activities may be carried out for verification.
An accidental overdose of enoxaparin by the extracorporeal (intravascular) or subcutaneous route may cause bleeding complications due to the appearance of anticoagulant activity, largely neutralizable by slow intravenous injection of protamine (sulphate or hydrochloride).
The protamine dose should be equal to that of enoxaparin injected ie: 1 mg or 100 anti-heparin units of protamine to neutralize the anti-IIa activity, determined by 1 mg (100 IU aXa) of enoxaparin, if enoxaparin is was given within the previous 8 hours. However, if enoxaparin has been administered more than 8 hours prior to protamine administration or if it has been determined that a second dose of protamine is required, an infusion of 0.5 mg of protamine per 1 mg of enoxaparin can be used. After 12 hours of enoxaparin administration, protamine administration may not be necessary.
However, even in the case of high dosages of protamine, the anti-Xa activity is never totally neutralized (maximum: about 60%), and thus allows the persistence of an antithrombotic activity. If you have any questions about the use of Clexane, ask your doctor or pharmacist.
Side Effects What are the side effects of Clexane
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The frequency of adverse reactions described below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to
Hemorrhages
In clinical trials, haemorrhages were the most commonly reported adverse reactions. They included major bleeding, reported with a maximum incidence of 4.2% (surgical patients). Some of these cases have been fatal.
As with other anticoagulants, bleeding can occur in the presence of associated risk factors such as: organic lesions with bleeding diathesis, invasive procedures or following the concomitant use of drugs that interfere with haemostasis.
* such as hematomas, bruises in addition to those appeared at the injection site, wounds with hematoma, hematuria, epistaxis and gastrointestinal bleeding.
Thrombocytopenia and thrombocytosis
* increase in platelet count> 400 G / L ** mild, transient and asymptomatic during the first days of therapy.
Other clinically relevant adverse reactions
These reactions are listed below, regardless of indications, by system organ class, grouped by frequency and order of decreasing severity.
* such as injection site edema, haemorrhage, hypersensitivity, inflammation, mild swelling, pain or local reactions (NOS) ** transaminase levels> 3 times the upper limit of normal
Post-marketing experience
The following adverse reactions have been identified during the use of Clexane after its authorization and marketing. These reactions arise from spontaneous reports, therefore their frequency is "not known" (frequency cannot be estimated from the available data)
- Immune system disorders - Anaphylactic / anaphylactoid reactions including shock
- Nervous system disorders - Headache
- Vascular disorders - Cases of spinal or epidural hematomas have been reported in association with the prophylactic use of heparin during spinal or epidural anesthesia or lumbar puncture. These reactions have resulted in neurological changes of varying degrees including prolonged or permanent paralysis (see section Special warnings).
- Blood and lymphatic system disorders - Anemia (predominantly in the context of bleeding) - Cases of immune-allergic thrombocytopenia with thrombosis; in some of these cases the thrombosis was complicated by organ infarction or limb ischaemia (see section Special warnings) - Eosinophilia isolated or associated with skin manifestations
- Skin and subcutaneous tissue disorders - Hypersensitivity cutaneous vasculitis, usually localized skin necrosis at the injection site (these reactions are usually preceded by the appearance of purpura or erythematous, infiltrated and painful plaques). In these cases it is necessary to discontinue treatment with enoxaparin sodium. Nodules at the injection site (inflammatory nodules, which are not cystic inclusions of enoxaparin sodium). These events resolved within a few days and did not require treatment discontinuation. Alopecia
- Musculoskeletal and connective tissue disorders Osteoporosis following long-term therapy
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist. You can also report side effects directly via the national reporting system of the Italian Medicines Agency. Website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse By reporting side effects you can help to provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date indicated on the package. The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date indicated on the package.
Store at a temperature not exceeding 25 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
Composition and pharmaceutical form
COMPOSITION
Clexane 2,000 I.U. aXa / 0.2 ml solution for injection
One 0.2 ml pre-filled syringe contains:
Active ingredient: enoxaparin sodium 2,000 I.U. aXa
Excipients: water for injections
Clexane 4,000 I.U. aXa / 0.4 ml solution for injection
One 0.4 ml pre-filled syringe contains:
Active ingredient: enoxaparin sodium 4,000 I.U. aXa
Excipients: water for injections
PHARMACEUTICAL FORM AND CONTENT
Solution for injection for subcutaneous and intravascular use.
2000 U.I. aXa / 0.2 ml - 6 pre-filled syringes of 0.2 ml with or without automatic safety system
4000 I.U. aXa / 0.4 ml - 6 pre-filled syringes of 0.4 ml with or without automatic safety system
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
Clexane 2,000 I.U.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Clexane 2,000 I.U. aXa / 0.2 ml solution for injection
One 0.2 ml pre-filled syringe contains:
Active ingredient: enoxaparin sodium 2,000 I.U. aXa.
Clexane 4,000 I.U. aXa / 0.4 ml solution for injection
One 0.4 ml pre-filled syringe contains:
Active ingredient: enoxaparin sodium 4,000 I.U. aXa.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection for subcutaneous and intravascular use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
- Prophylaxis of deep vein thrombosis (DVT) in general surgery, in orthopedic surgery and in bedridden non-surgical patients at risk of DVT.
- Treatment of deep vein thrombosis with or without pulmonary embolism.
- Treatment of unstable angina and non-Q myocardial infarction in combination with acetylsalicylic acid.
- Prevention of coagulation during hemodialysis.
04.2 Posology and method of administration
Treatment of unstable angina and non-Q myocardial infarction
The recommended dose of enoxaparin sodium is 100 I.U. anti-Xa (1 mg) / kg every 12 hours by subcutaneous injection, administered concomitantly with oral acetylsalicylic acid (100 to 325 mg per day). Treatment of these patients with enoxaparin sodium should be prescribed for at least 2 days and continued until the clinical situation stabilizes. Generally the duration of treatment is from 2 to 8 days.
Prophylaxis and treatment of deep vein thrombosis (DVT)
In patients with moderate thromboembolic risk, effective prevention of thromboembolic disease is achieved by injection of 2,000 I.U. aXa (0.2 ml) / day.
In general surgery the first injection should be given about 2 hours before the surgery.
In patients at high thromboembolic risk and in particular in preparation for orthopedic surgery, it is recommended to administer a dose of enoxaparin equal to 4,000 I.U. aXa (0.4 ml) / day in a single daily administration.
In orthopedic surgery the first injection will be given 12 hours before the surgery.
The duration of treatment will coincide with that of the persistence of the thromboembolic risk, and in general up to the patient's ambulation (on average from 7 to 10 days after surgery).
Under normal conditions of use, enoxaparin does not modify the coagulation parameters. Treatment surveillance based on these tests is therefore unnecessary.
In treatment of deep vein thrombosis, enoxaparin follows traditional heparin therapy established following a positive diagnosis.
The enoxaparin will be administered at the rate of one injection every 12 hours for 10 days. The dose of each injection will be 100 I.U.xa / kg body weight.
In bedridden non-surgical patients at risk of DVT, the recommended dose of enoxaparin sodium is 40 mg once daily by subcutaneous injection. Treatment with enoxaparin sodium is prescribed for a minimum of 6 days and continued until return to full walking, for a maximum of 14 days.
Longer duration treatment may be appropriate: enoxaparin administration should continue as long as there is a thromboembolic risk and until the patient is walking.
Biological surveillance: see section 4.4.
Injection technique
The subcutaneous injection should be conducted, preferably with the patient in decubitus, in the subcutaneous cellular tissue of the anterolateral or posterolateral abdominal belt, alternately on the right and left.
The pre-filled syringes are ready to use, so you do not have to expel the air in the syringe before injection.
The injection itself must be performed by completely introducing the needle, perpendicularly and not tangentially, into the thickness of a skin fold, made between the thumb and the index finger of the operator.
The skin fold must be maintained for the duration of the injection.
For syringes with automatic safety system
The pre-filled syringes are equipped with an automatic safety system to prevent accidental needle sticks after injection. At the end of the injection, keeping the plunger at the end of its stroke, extract the needle from the injection site and, orienting it away from any other people and yourself, press firmly on the piston again to activate the safety system: the protective sleeve will automatically cover the needle and simultaneously you will hear a "click" to confirm the activation of the safety system.
Intravascular administration
Prevention of coagulation during hemodialysis
In patients to undergo repeated sessions of hemodialysis, the prevention of coagulation within the hemodialysis circuit can be achieved by administering a dose of 100 IU / kg into the arterial line of the circuit at the beginning of the session. This dose is usually sufficient. for conducting a 4-hour session. Should fibrin filaments appear within the circuit, an additional dose of 50-100 IU / kg may be used, depending on the time remaining until the end of the session. patients at high risk of bleeding (in particular in the case of pre- or post-operative hemodialysis sessions) or who have evolving haemorrhagic syndromes, dialysis sessions can be performed using a dose of 50 IU / kg (double vascular access) or 75 IU / kg (simple vascular access).
04.3 Contraindications
- Hypersensitivity to the active substance, to heparin or its derivatives including other low molecular weight heparins or to any of the excipients listed in section 6.1.
- History of thrombocytopenia with enoxaparin (see section 4.4).
- Hemorrhagic manifestations or tendencies related to haemostasis disorders, with the exception of consumption coagulopathies not related to heparin.
- Organic lesions at risk of bleeding.
- Acute infective endocarditis (except those related to mechanical prostheses).
- Hemorrhagic cerebrovascular accidents.
- Locoregional anesthesia for elective surgery procedures is contraindicated in those patients who receive heparin for reasons other than prophylaxis.
- Relative contraindications: association with ticlopidine, with salicylates or NSAIDs, with antiplatelet agents (dipyridamole, sulfinpyrazone, etc.).
04.4 Special warnings and appropriate precautions for use
Warnings
The low molecular weight heparins differ in the method used in the production, in the molecular weight and in the specific anti-Xa activity, unit and dosage; therefore it is not necessary to switch from one active ingredient to another. This determines differences in pharmacokinetics and biological activities associated (eg: antithrombin activity and platelet interactions). Special attention is therefore required and compliance with the instructions for use of each individual medicinal product is required.
Spinal / epidural anesthesia
In patients undergoing spinal or epidural anesthesia, epidural analgesia or lumbar puncture, low-dose low-molecular-weight heparin prophylaxis may rarely be associated with spinal or epidural hematomas that can lead to prolonged or permanent paralysis. The risk is increased by the use of indwelling peridural catheters for continuous infusion, by the concomitant intake of drugs that affect haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors or anticoagulants, from trauma or from repeated spinal puncture, from the presence of an underlying haemostatic disorder and from old age, or in patients with a history of spinal surgery or spinal deformity. The presence of one or more of these risk factors must be carefully evaluated before proceeding with this type of anesthesia / analgesia, during prophylaxis with low molecular weight heparins.
As a rule, the insertion of the spinal catheter must be carried out at least 8-12 hours after the last administration of low molecular weight heparin at prophylactic doses. Subsequent doses should not be administered until at least 2-4 hours have elapsed after catheter insertion or removal, or further delayed or not administered in the case of hemorrhagic aspirate during initial spinal or epidural needle placement. Removal of an "indwelling" epidural catheter should be done as far away as possible from the last prophylactic heparin dose (approximately 8-12 hours) performed under anesthesia.
If it is decided to administer low molecular weight heparin before or after a "epidural or spinal anesthesia, extreme caution and frequent monitoring should be performed to identify signs and symptoms of neurological alterations such as: lumbar pain, sensory and motor deficit (numbness and weakness of the lower limbs), changes in bladder or bowel function Nursing staff should be instructed to identify these signs and symptoms Patients should be instructed to notify medical or nursing staff immediately if any of the above symptoms occur.
If signs or symptoms of epidural or spinal hematoma are suspected, an immediate diagnosis should be made and treatment that includes spinal cord decompression initiated.
Heparin-induced thrombocytopenia
Thrombocytopenia is a well-known complication of heparin therapy and can appear 4 to 10 days after starting treatment, but even earlier in the case of previous heparin-induced thrombocytopenia. Mild thrombocytopenia may appear early in 10 to 20% of patients (platelet count greater than 100,000 / mm3), which may remain stable or regress, even if heparin administration is continued.
In some cases, a more severe form (type II heparin thrombocytopenia), immune-mediated, can be determined, characterized by the formation of antibodies against the heparin-platelet factor 4 complex. In these patients, new thrombus associated with thrombocytopenia may develop, resulting from " irreversible aggregation of platelets induced by "heparin, the so-called" white thrombus syndrome ". This process can lead to severe thromboembolic complications such as skin necrosis, arterial embolism of the extremities, myocardial infarction, pulmonary embolism, stroke, and sometimes death. Therefore, the administration of low molecular weight heparin should be discontinued in addition to the onset of thrombocytopenia, even if the patient develops a new thrombosis or a worsening of a previous thrombosis. The continuation of anticoagulant therapy, for thrombosis that is the cause of the treatment in progress or for a new onset or worsening of the same, should be undertaken, after heparin suspension, with an alternative anticoagulant. In these cases, the immediate introduction of anticoagulant therapy is risky. oral (cases of worsening of thrombosis have been reported).
Therefore thrombocytopenia of any nature should be carefully monitored.
If the platelet count falls below 100,000 / mm3, or if recurrent thrombosis occurs, the low molecular weight heparin should be discontinued.
A platelet count should be evaluated before treatment and twice weekly thereafter for the first month in case of prolonged administration.
Percutaneous coronary revascularization procedures
To minimize the risk of bleeding following the use of vascular equipment during the treatment of unstable angina and non-Q myocardial infarction, the introducer should remain in place for 6-8 hours after subcutaneous administration of the enoxaparin dose. sodium. The next scheduled dose should not be administered earlier than 6-8 hours after removal of the introducer. The access site should be examined for any signs of bleeding or bruising.
Pregnant women with mechanical heart valve prostheses
The use of Clexane for thromboprophylaxis in pregnant women with mechanical heart valve prostheses has not been adequately investigated. In a clinical study in pregnant women with mechanical heart valve prostheses treated with enoxaparin (1 mg / kg / bid) to reduce the risk of thromboembolic events, only two of eight patients experienced thrombotic events leading to valve block and subsequent maternal and fetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women with mechanical valve prostheses while on enoxaparin therapy for thromboprophylaxis. Pregnant women with mechanical heart valve prostheses may be at increased risk for thromboembolic events (see section 4.4 "Precautions for use: Mechanical Cardiac Valve Prostheses').
Laboratory tests:
At doses used for venous thromboembolism prophylaxis, enoxaparin sodium does not significantly affect bleeding time and total blood clotting time tests, nor does it interfere with platelet aggregation or the binding of fibrinogen to platelets.
At higher doses, increases in aPTT (partially activated thromboplastin time) and ACT (activated clot time) may occur.
The increases in aPTT and ACT are not linearly correlated with the increased antithrombotic activity of enoxaparin sodium and are therefore unsuitable and unreliable tests for monitoring the activity of enoxaparin sodium.
Precautions for use
• Do not administer intramuscularly
• Bleeding
As with other anticoagulants, bleeding can occur at any site (see "Side effects"). In the event of bleeding, the source of the bleeding should be sought and appropriate treatment instituted.
• As with other anticoagulant therapies, enoxaparin sodium should be used with caution in conditions of potentially increased bleeding, such as:
- haemostasis disorders;
- history of peptic ulcer;
- recent ischemic stroke;
- severe uncontrolled arterial hypertension;
- diabetic retinopathy;
- recent neurological surgery or ophthalmology;
- concomitant use of drugs that affect haemostasis (see section 4.5)
Mechanical heart valve prostheses
The use of Clexane for thromboprophylaxis in patients with mechanical heart valve prostheses has not been adequately investigated. There have been isolated reports of valve thrombosis in patients with mechanical heart valve prostheses while on enoxaparin therapy for thromboprophylaxis. Confounding factors including underlying disease, as well as insufficient clinical data limit the assessment of these cases. Some of these cases were pregnant women in whom thrombosis has led to maternal and fetal death. Pregnant women with mechanical heart valve prostheses may have increased risk of thromboembolic events (see section 4.4 "Warnings: Pregnant women with mechanical heart valve prostheses').
Hemorrhage in elderly patients
With the doses used in the prophylaxis of venous thromboembolism in elderly patients, no increased tendency for bleeding has been observed. Elderly patients (especially 80 years of age or older) may have an increased risk of bleeding complications with therapeutic doses. Close clinical monitoring is recommended. (see section 5.2).
Kidney failure
In patients with renal insufficiency there is a risk of increased levels of enoxaparin sodium which could lead to an increased risk of bleeding. Since enoxaparin sodium levels are significantly increased in patients with severe renal insufficiency (creatinine clearance dose adjustment in both prophylaxis and treatment of venous thromboembolism. creatinine 30-50 ml / min) and mild (creatinine clearance 50-80 ml / min), careful clinical monitoring is advisable (see section 5.2).
Hemodialysis: the doses will have to be adjusted if the anti-Xa activity is lower than 0.4 IU / ml or higher than 1.2 IU / ml.
Low body weight patients
In women with low body weight (
Obese patients
Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI> 30 kg / m2) have not been fully established and there is no consensus for dose adjustment. These patients should be carefully observed for signs and symptoms of thromboembolism
04.5 Interactions with other medicinal products and other forms of interaction
Associations not recommended:
- Acetylsalicylic acid and other salicylates (generally):
Increased risk of bleeding (inhibition of platelet function and aggression of the gastroduodenal mucosa by salicylates).
Use other substances for an analgesic or antipyretic effect.
- NSAIDs (generally)
Increased risk of bleeding (inhibition of platelet function and aggression of the gastroduodenal mucosa by non-steroidal anti-inflammatory drugs).
If the association cannot be avoided, institute careful clinical and biological surveillance.
- Ticlopidine
Increased risk of bleeding (inhibition of platelet function by ticlopidine).
The association with high doses of heparin is not recommended.
The association with low doses of heparin (preventive heparinotherapy) requires a careful clinical and biological surveillance.
- Other antiplatelet agents (clopidogrel, dipyridamole, sulfinpyrazone, etc.)
Increased risk of bleeding (inhibition of platelet function).
Associations requiring precautions for use:
- Oral anticoagulants
Enhancement of anticoagulant action. Heparin distorts the prothrombin rate.
When replacing heparin with oral anticoagulants:
to. reinforce clinical surveillance
b. to check the effect of oral anticoagulants, take the sample before heparin administration, if this is discontinuous or, preferably, use a reagent that is not sensitive to heparin.
- Glucocorticoids (via general)
Worsening of the haemorrhagic risk typical of glucocorticoid therapy (gastric mucosa, vascular fragility) at high doses or in prolonged treatment for more than ten days.
The association must be justified; enhance clinical surveillance.
- They dexter (Injecting)
Increased risk of bleeding (inhibition of platelet function).
Adjust the dosage of heparin so as not to exceed a hypocoagulability greater than 1.5 times the reference value, during the combination and after the suspension of dextran.
04.6 Pregnancy and lactation
Pregnancy
Animal studies have not shown embryotoxic or teratogenic properties.
In the pregnant rat female, the transfer of 35S-labeled enoxaparin sodium to the fetus through the placenta is minimal.
In women, there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available on the first and third trimesters. For these reasons and since animal studies are not always predictive of human response, this drug should only be used in pregnancy if the physician has verified that it is necessary.
(see also section 4.4 "Warnings: Pregnant women with mechanical heart valve prostheses " And "Precautions: Mechanical cardiac valve prostheses')
Pregnancy
In lactating rats, the concentration of 35S-labeled enoxaparin sodium or its labeled metabolites in milk is very low.
It is not known whether enoxaparin sodium is excreted unchanged in human milk.
Oral absorption of enoxaparin sodium is unlikely. However, as a precaution, nursing mothers receiving enoxaparin sodium should be advised not to breastfeed.
04.7 Effects on ability to drive and use machines
Clexane does not affect the ability to drive or use machines.
04.8 Undesirable effects
The frequency of adverse reactions described below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to
Hemorrhages:
In clinical trials, haemorrhages were the most commonly reported adverse reactions. They included major bleeding, reported with a maximum incidence of 4.2% (surgical patients). Some of these cases have been fatal.
As with other anticoagulants, bleeding may occur in the presence of associated risk factors such as: organic lesions with bleeding diathesis, invasive procedures or following concomitant use of drugs that interfere with haemostasis (see sections 4.4 and 4.5).
* such as hematomas, ecchymoses in addition to those appeared at the injection site, hematoma at the wound site, hematuria, epistaxis and gastrointestinal haemorrhages.
Thrombocytopenia and thrombocytosis:
* increased platelet count> 400 G / L
** mild, transient and asymptomatic during the first days of therapy
Other clinically relevant adverse reactions:
These reactions are listed below, regardless of indications, by system organ class, grouped by frequency and order of decreasing severity.
* such as injection site edema, haemorrhage, hypersensitivity, inflammation, mild swelling, pain or local reactions (NOS)
** transaminase levels> 3 times the upper limit of normal
Post-marketing experience
The following adverse reactions have been identified during the use of Clexane after its authorization and marketing. These reactions arise from spontaneous reports, therefore their frequency is "not known" (frequency cannot be estimated from the available data)
• Disorders of the immune system
- Anaphylactic / anaphylactoid reactions including shock
• Nervous system disorders
- Headache
• Vascular pathologies
- Cases of spinal or epidural hematomas have been reported in association with the prophylactic use of heparin during spinal or epidural anesthesia or lumbar puncture. These reactions have resulted in neurological changes of varying degrees including prolonged or permanent paralysis (see section 4.4).
• Disorders of the blood and lymphatic system
- Anemia (mainly in the context of bleeding)
- Cases of immune-allergic thrombocytopenia with thrombosis; in some of these cases the thrombosis was complicated by organ infarction or limb ischemia (see section 4.4)
- Eosinophilia isolated or associated with skin manifestations
• Skin and subcutaneous tissue disorders
- Hypersensitivity cutaneous vasculitis, skin necrosis usually localized at the injection site (these reactions are usually preceded by the appearance of purpura or erythematous, infiltrated and painful plaques). In these cases it is necessary to discontinue treatment with enoxaparin sodium.
- Nodules at the injection site (inflammatory nodules, which are not cystic inclusions of enoxaparin sodium). These events resolved within a few days and did not require treatment discontinuation
- Alopecia
• Musculoskeletal and connective tissue disorders
- Osteoporosis following long-term therapy
Reporting of adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "Italian Medicines Agency. Website: www.agenziafarmaco.gov.it/it/responsabili
04.9 Overdose
As a general rule, serious consequences are not to be feared for a massive oral intake of enoxaparin (no reported cases), taking into account the minimum gastric and intestinal absorption of the product.
However, a plasma assay of the anti-Xa and anti-IIa activities may be carried out for verification.
An accidental overdose of enoxaparin by the extracorporeal (intravascular) or subcutaneous route may cause bleeding complications due to the appearance of anticoagulant activity, largely neutralizable by slow intravenous injection of protamine (sulphate or hydrochloride).
The protamine dose should be equal to that of enoxaparin injected ie: 1 mg or 100 anti-heparin units of protamine to neutralize the anti-IIa activity, determined by 1 mg (100 IU aXa) of enoxaparin, if enoxaparin is was given within the previous 8 hours. However, if enoxaparin has been administered more than 8 hours prior to protamine administration or if it has been determined that a second dose of protamine is required, an infusion of 0.5 mg of protamine per 1 mg of enoxaparin can be used. After 12 hours of enoxaparin administration, protamine administration may not be necessary.
However, even in the case of high dosages of protamine, the anti-Xa activity is never totally neutralized (maximum: about 60%), and thus allows the persistence of an antithrombotic activity.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotics - heparin.
ATC code: B01AB05.
Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of approximately 4500 daltons.
The molecular weight distribution is as follows:
2000 to 8000 daltons ≥ 68%
> 8000 daltons ≤ 18%.
Enoxaparin sodium is obtained by alkaline depolymerization of the benzyl ester of heparin derived from the intestinal mucosa of the pig. Its structure is characterized by a group of 2-O-sulfo-4-enepiranosuronic acid on the non-reducing end, and from a 2-N, 6-O-disulfo-D-glucosamine on the reducing end of the chain. About 20% of the enoxaparin structure (15% to 25%) contains an anhydrous 1,6 derivative on the reducing end of the chain. polysaccharide chain.
In an in vitro purified system, enoxaparin sodium possesses high anti-Xa activity (approximately 100 IU / mg) and low anti-IIa or antithrombin activity (approximately 28 IU / mg). Pharmacodynamic parameters studied in healthy volunteers concentrations of enoxaparin above 100-200 mg / ml were comparable.
Clinical data in the treatment of unstable angina and non-Q myocardial infarction
In a large multicenter study, 3,171 patients with acute unstable angina or non-Q myocardial infarction were enrolled and randomized to receive subcutaneous enoxaparin sodium 1 mg / day in combination with aspirin (100 to 325 mg once daily). kg every 12 hours or intravenous unfractionated heparin at doses adjusted according to activated partial thromboplastin time (aPTT). Patients were treated in hospital for a minimum of 2 days up to a maximum of 8 days, until clinical conditions stabilized, revascularization procedures or hospital discharge. Patients were followed up for 30 days. Enoxaparin sodium compared to classical heparin it significantly decreased the incidence of recurrent angina, myocardial infarction or death with a relative risk reduction of 16.2% at day 14, with maintenance throughout the 30 day period. In addition, fewer patients in the enoxaparin sodium group underwent revascularization with percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) (relative risk reduction at day 30: 15.8% ).
05.2 Pharmacokinetic properties
The pharmacokinetic parameters of enoxaparin were studied, at the recommended doses for single and repeated subcutaneous administration and after single intravenous administration, mainly in terms of evolution of anti-Xa and also anti-IIa activity.
The quantitative determination of the anti-Xa and anti-IIa pharmacokinetic activity was carried out by an amidolytic method validated on a specific substrate and a calibrated standard of enoxaparin with respect to the international standard for low molecular weight heparins (NIBSC).
• Bioavailability and absorption
The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is close to 100%. In healthy volunteers, the injection volume and concentration in the range of 100-200 mg / ml do not influence the pharmacokinetic parameters.
Maximum plasma anti-Xa activity is observed on average 3-5 hours after subcutaneous administration and reaches levels of approximately 0.2, 0.4, 1.0 and 1.3 IU / ml anti-Xa after subcutaneous doses 20 mg, 40 mg, 1.0 mg / kg and 1.5 mg / kg respectively.
The pharmacokinetics of enoxaparin over the recommended dose ranges are linear. Within-patient and between-patient variability is low.
In healthy volunteers, after repeated subcutaneous administration of doses of 40 mg / day and 1.5 mg / kg / day, steady-state is reached on day 2 with a mean exposure ratio approximately 15% higher than that evidenced after the administration of a single dose. Steady-state activity levels of enoxaparin can be predicted after single dose administration. After repeated subcutaneous administration of doses of 1 mg / kg bid, steady-state is reached after 3 or 4 days with a mean exposure 65% higher than for single dose administration and with a mean and minimum peak of approximately 1.2 and 0.52 IU / ml respectively. This difference in steady-state is expected due to the pharmacokinetics of enoxaparin sodium and is within the therapeutic range.
The plasma anti-IIa activity after subcutaneous administration is approximately 10 times lower than the anti-Xa activity. After repeated administration of doses of 1 mg / kg bid and 1.5 mg / kg / day, respectively, maximal anti-IIa plasma activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU / ml and 0.19 IU / ml.
• Distribution
The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 5 liters and is similar to the blood volume.
• Metabolism and elimination
Enoxaparin sodium is a drug with low clearance, the mean anti-Xa plasma clearance is 0.74 L / h after an intravenous infusion of 1.5 mg / kg lasting 6 hours. Elimination appears monophasic with a half-life of approximately 4 hours after single subcutaneous administration and up to approximately 7 hours after repeated administration. Enoxaparin sodium is mainly metabolized by the liver by desulfation and / or depolymerization into fragments of lower molecular weight and with very low biological potency.
Renal clearance of active fragments accounts for approximately 10% of the administered dose, while total renal excretion of active and inactive fragments accounts for 40% of the dose.
CHARACTERISTICS OF THE PRODUCT IN PARTICULAR POPULATIONS
• Senior citizens
Based on the results obtained from the analysis of the pharmacokinetic parameters in this population, the pharmacokinetic profile of enoxaparin sodium is no different in elderly subjects compared to young subjects when renal function is normal. Since renal function tends to decrease with age, elderly patients may show reduced elimination of enoxaparin sodium (see section 4.4).
• Kidney failure
A linear relationship at steady-state was observed between plasma anti-Xa clearance and creatinine clearance demonstrating a decrease in the clearance of enoxaparin sodium in patients with impaired renal function.
Steady-state anti-Xa exposure, represented by AUC, increased marginally after repeated subcutaneous dosing of 40 mg / day in patients with mild renal impairment (creatinine clearance 50-80 ml / min) or moderate (creatinine clearance 30-50 ml / min). In patients with severe renal insufficiency (creatinine clearance
• Weight
In obese healthy volunteers (BMI 30-48 kg / m2), after repeated subcutaneous administration of 1.5 mg / kg / day, the mean AUC of anti-Xa activity at steady-state is marginally higher than in control subjects. not obese while A max did not increase. Lower clearance related to body weight is observed in obese subjects treated subcutaneously.
It has been shown that after an unadjusted administration for weight, such as a single subcutaneous dose of 40 mg, the anti-Xa exposure is 52% higher in low body weight women (
• Hemodialysis
In a study conducted in patients undergoing dialysis, after administration of a single dose of 0.25 or 0.50 mg / kg intravenously, the elimination rate was comparable, while the AUC was doubled compared to the population of check.
05.3 Preclinical safety data
Long-term studies have not been conducted to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in studies in vitro, including the Ames test, mutation test in mouse lymphoma cells, chromosomal aberration test in human lymphocytes and the in vivo study of chromosomal aberration in the rat bone marrow.
Enoxaparin was found to have no effect on fertility or reproductive capacity in male and female rats at doses up to 20 mg / kg / day sc. Teratogenic studies were conducted in pregnant female rats and rabbits with doses of enoxaparin up to 30 mg / kg / day administered sc There were no teratogenic effects or foetotoxicity due to enoxaparin.
Apart from the anticoagulant effect of enoxaparin, there were no adverse events in a subcutaneous toxicity study in rats and dogs at a dose of 15 mg / kg / day for 13 weeks or in a subcutaneous and intravenous toxicity study at dose of 10 mg / kg / day for 26 weeks in both rat and monkey.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Water for injections.
06.2 Incompatibility
Do not mix with other drugs.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Box of 6 pre-filled syringes of 0.2 ml (2,000 IU aXa) with or without automatic safety system
Box of 6 pre-filled syringes of 0.4 ml (4,000 IU aXa) with or without automatic safety system
06.6 Instructions for use and handling
The pre-filled syringe is ready for immediate use.
Clexane solution for injection can be supplied in pre-filled syringes with an automatic safety system to prevent needle sticks after injection.
For more information on how to use the syringe see section 4.2.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi S.p.A. - Viale L. Bodio, 37 / B - 20158 Milan
08.0 MARKETING AUTHORIZATION NUMBER
Clexane 2000 U.I. aXa / 0.2 ml solution for injection - 6 pre-filled syringes of 0.2 ml AIC n. 026966034
Clexane 2000 U.I. aXa / 0.2 ml solution for injection - 6 pre-filled syringes of 0.2 ml with AIC safety system n. 026966059
Clexane 4000 I.U. aXa / 0.4 ml solution for injection - 6 pre-filled syringes of 0.4 ml AIC n. 026966046
Clexane 4000 I.U. aXa / 0.4 ml solution for injection - 6 pre-filled syringes of 0.4 ml with AIC safety system n. 026966061
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
01.02.1993 / 16.02.2008
10.0 DATE OF REVISION OF THE TEXT
October 2014
