CLEXANE (Enoxaparin)

 

Clexane

(Enoxaparin)

 

DESCRIPTION

ACTIVE INGREDIENTS: Enoxaparin sodium

THERAPEUTIC CLASS: Antithrombotic Agents, Heparin group

PHARMACEUTICAL FORM(s): Sterile pyrogen-free solution for injectionsSANOFI

 

COMPOSITION

Clexane Injection 20mg/0.2ml: Each 0.2ml contains enoxaparin sodiun 20mg.

Clexane Injection 40mg/0.4ml: Each 0.4ml contains enoxaparin sodium 40mg.

Clexane Injection 60mg/0.6ml: Each 0.bml contains enoxaparin sodium 60mg.

Clexane Injection 80mg/0.8ml: Each 0.8ml contains enoxaparin sodium 80mg.

 

INDICATIONS

·         Prophylaxis of venous thrombo-embolic disease in patients undergoing an orthopedic or generalsurgery  rocedure, including cancer surgery, with a moderate or high risk of thromboembolism.

·         Prophylaxis of venous thrombo-embolism in medical patients bedridden due to acute illnessesincluding cardiac insufficiency, respiratory failure, severe infections, rheumatic diseases.

·         Treatment of deep vein thrombosis with or without pulmonary embolism.

·         Prevention of thrombus formation in extra corporeal circulation during hemodialysis.

·         Treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently withaspirin.

·         Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) including patients to bemanaged medically or with subsequent Percutaneous Coronary Intervention (PCI).

DOSAGE AND ADMINISTRATION

GENERAL

·         Prophylaxis of venous thrombosis in surgical patients:

Duration and dose of Clexane therapy are based upon patient risk. The thromboembolic risk for individualpatient can be estimated using validated risk stratification models

In patients with a moderate risk of thrombo-embolism, the recommended dose of enoxaparin sodium is 20mg/0.2ml or 40mg/0.4ml once daily by subcutaneous injection. In general

Surgery, the first injection should be given 2 hours before the surgical procedure.

Enoxaparin sodium treatment is usually prescribed for an average period of 7 to 10 days. A longer treatment duration may be appropriate in some patients and enoxaparin sodium should be continued for as long as there is a risk of venous thromboembolism and until the patient is ambulatory.

In patients with a high risk of thrombo-embolism, the recommended dose of enoxaparin sodium given by subcutaneous injection, is 40mg/0.4ml once daily, initiated 12 hours prior to surgery. –For patients who undergo major orthopedic surgery with a high venous thromboembolism risk, athromboprophylaxis up to 5 weeks is recommended.-For patients who undergo cancer surgery with a high venous thromboembolism risk, a-thromboprophylaxis up to 4 weeks is  recommended.

For special recommendations concerning dosing intervals for Spinal/Epidural

Anesthesia and coronary revascularisation procedures: See Warnings

·         Prophylaxis of venous thrombo-embolism in medical patients:

The recommended dose of enoxaparin sodium is 40mg once dailyby subcutaneous injection. Treatment  with enoxaparin sodium isprescribed for a minimum of 6 days and continued until the return to full   ambulation, for a maximum of 14 days.

·         Treatment of deep vein thrombosis with or without pulmonary embolism:

Enoxaparin sodium can be administered subcutaneously either as a single injection of 1.5mg/kg or as twice daily injections of 1mg/kg.In patients with complicated thrombo-embolic disorders, a dose of  1mg/kg administered twice daily is recommended.

Enoxaparin sodium treatment is usually prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate and enoxaparin sodium treatment should be continued until a therapeutic anticoagulant effect has been achieved (International Normalisation Ratio 2 to 3).

·         Prevention of extra corporeal thrombus during hemodialysis:

The recommended dose is 1mg/kg of enoxaparin sodium. For patients with a high risk of hemorrhage, the dose should be reduced to 0.5mg/kg for double vascular access or 0.75 mg/kg for single vascular access.

During hemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session;  however, if fibrin rings are found, for example after a louger tnan normal session, a further dose of 0.5 to 1mg/kg may be given.

·         Treatment of unstable ansid and non-0-wave myocardial infarction:

The recommende se o enoxaparin sodium is 1mg/kg every 12 hours by subcutaneous inec ministered concurrently with oral aspirin (100 to 325 mg once da Catment with enoxaparin sodium in these patients should be presciDcd, Tor a minimum of 2 days and continued until clinical stabilizalion. Ine u duralion of treatment is 2 to 8 days.

·         Treatment of acute ST-segment Elevation Myocardial infarction

The recommended dose of CONdpdrin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose  followed by T mg/kg administered SC every 12 hours (max 100 mg for each of the hrst two Sc doses only, followed by 1 mg/kg SC dosing for the remaining doses). For dosage in patients 275 years of age, see Special Populations- Elderly.

When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enOxaparin sodium should be given between 15 minutes before and 30 minutes atter the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained under (75 to 325 mg once daily) unless contraindicated.

The recommended duration of enoxaparin sodium treatment is 8 days or until hospital discharge,  whichever comes first. For patients managed With Percutaneous Coronary Intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon infation, no additional dosing is needed. If the last SC administration was given more than 8 hours before balloon inflation, an V bolus of 0.3 mg/kg of enoxaparin sodium should be administered.

Special Populations:

Children:

The safety and efficacy of enoxaparin sodium in children has not been established.

Elderly:

For treatment of acute ST-segment Elevation Myocardial lInfarction in elderly patients275 years of age, do not use an initialV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for each of the first two SC doses only, followed by 0.75 mg/kg SC dosing for the remaining doses). For other indications: no dosage adjustment is necessary, unless kidnėy function is impaired (See Precautions and Dosage &t Administration)

Hepatic impairment:

Caution shoukd be used in hepatically impaired patients

Renal impairment:

See Precautions

·         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 patientfeiisttai toalst so9 2ii,5?population.

The following dosage adjustments are recommended for therapeutic dosage Ranges

 

 

The recommended dosage adjustments do not apply to the hemodialysisindication.

·         Moderate and mild renal impairment  Although no dose adjustment is recommended in patients witn moderate (creatinine clearance 30-50ml/min) and mild (reatinine clearance s0-80mi/min) renal impairment, careful clinical monitoring is advised.

Spinal/epidural anesthesia

For patients receiving Spinai/epiaural anesthesia see section Warnings, Spinal/epidural anesthesia.

Administration:

Subcutaneous Injection:

Enoxaparin sodium is administered by subcutaneous injection for the prevention of venous   thromboembolic disease, trealment of deep vein thrombosis, 1realment of unstable angina and non-Q-wave myocardial infarction and Ircatment of acute ST-segment tlevalion Myocardial Inlarction.

IV bolus injection:

 For acule SI-segment Clevation Myocardial Infarction, treatment is to be initialed with a single IV blous injeclion immediately followed by a subcutaneous injection.

Arterial line Injection:

It is adminislered through the arterial line of a dialysis circuit for the prevention ol thrombus formation in the extra-corporeal circulation during haemodialysis. It must nol be administered by lhe intramuscular route.

The pre-filed disposable syringe is ready for immediate use

Subcutaneous Injection Technique:

Injection should be made preferably when the patient is lying down,Enoxaparin sodium is administered by deep subcutaneous injection. Do not expel the air buhble from the syringe before the injection to avoid the loss of drug when using the 20mgl and 40mg pre-filled syringes, The administration should be alternated between the ieft and right anterolateral or posterolateral abdominal wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the thumb and index finger. The skin fold should not be released until the injection is complete. Do not rub the injection site after administration.

·         Intravenous (Bolus) Injection Technique (for acute STEMI indication only):

Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or coadministered with other medications. To avoid the possible mixture of enoxaparin sodium with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of drug. Enoxaparin sodium may be safely administered with normal saline solution (0.96) or 5%dextrose in water.

·         Initial 30-mg bolus

For the initial 30-mg bolus, using an enoxaparin sodium graduated pre-filled syringe, expel the excessive volume to retain only 30 mg (0.3 ml) in the syringe. The 30-mg dose can then be directly injected into the intravenous line.

·         Additional bolus for PCI when last SC administration was given more than 8 hours hefore balloon  inflation

For patients being managed with Percutaneous Coronary Intervention (PCI), an additional IV bolus of 0.3 mg/kg is to be administered if last SC administration was given more than 8 hours before balloon inflation (see Dosage and Administration: Treatment of acute STEM.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the drug to 3 mg/ml.

To obtain a 3-mg/ml solution, usinga 60-mg enoxaparin sodium pre-filled syringe, it is recommended to use a 50-ml infusion bag (i.e. using either normal saline solution (0.9%) or 5% dextrose in water) as follows:

Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject the complete contents of the 60-mg enOxaparin sodium pre-filled syringe into the 20 ml remaining in the bag. Gently mix the contents of the bag. Withdraw the required volume of diluted solution with a syringe foradministration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula

Volume of diluted solution (m) = Patient weight (kg) x 0.1] or using the table below. It is recommended to prepare the dilution immediately beforeUse.

Volume to be injected through intravenous line after dilution is completed

 

CONTRAINDICATIONS

Hypersensitivity to enoxaparin soium, heparin or its derivatives including other Low Molecular Weight Heparins,

History of immune mediated heparin-induced thrombocytopenia (HIT within the past 100 days or in the presence of Circulating antibodies (see Precautions)

Active major bleeding and conditions with a high risk of uncontrolled T hemorrhage. including recent hemorrhagic stroke,

WARNINGS

General

Low Molecular Weight Heparins should not be used interchangeably since they differ in their manufacturing process, molecular weights specihe anti-Na activities, units and dosage. This results in differences in pharmacokinetics and associated biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.

·         Spinal/Epidural Anesthesia

There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia resulting in long term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens 40 mg once daily or lower. The risk is greater with higher enoxaparin sodium dosage regimens, use of post-operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDSs (see Interactions with other medicinal products or other forms of interaction). The risk also appears to be increased by traumatic or repeated neuraxial purncture or in patients with a history of  spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered. Placement and removal of the catheter is best performed when the anticoagulant effect of enoxaparin is low; however, the exact timing to reach a sufficiently low 2 anticoagulant effect in each patient is not known.

Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (20 mg once diaily, 30 mg once or twice daily or 40 mg once daily) of enoxaparin, and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial haematoma will be avoided. Patients receiving the 0.75 mg/kg twice-daily dose or the 1 mg/kg twice-daily dose should not receive the second enoxaparin dose in the twice-daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin dose after catheter removal cannot be made, consider delaying this next dose for at least four' hours, based on a benent-risk assessment considering both the risk fori thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30ml/minute,additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of  removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day).

Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or

weakness in lower limbs), bowel and/or bladder dystunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

·         Heparin-induced thrombocytopenian

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in the presernce of circulating antibodies is contraindicated (see Contraindications). Circulating antibodies may persistin several years.

Enoxaparin sodium is to be used with extreme caution in patients with a history (more than 100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a une case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments are considered.

·         Percutaneous coronary revascularisation procedures:

To minimize the risk of bleeding following the vascular instrumentation during the treatment ot nstable angina, non-0-wave myocardial infarction and acute ST-segment elevation myocardial intarction, adhere precisely to the intervals recommended between Clexane Injection doses. it is important to achieve hemostasis at the puncture site after PCI. In case a closure davice is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removth enoxaparin last IV/SC enoxaparin sodium inject sodium is to be continued, the next scheduled dose t the procedure sooner than 6 to 8 hours after sheath  removal. The site of procedure should be observed for signs of bleeding or hematoma formation.

·         Pregnant women with mechanical prosthetic heart valves

the use of Clexane Injection for thromboprophylaxis in pregnant wone WIh mechanical prosthetic heart valves has not becen adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves gIven enoxaparin (1 mg/kg bid) to reduce 1he risk of thrombo-embolism,2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death.

·         Laboratory tests

At doses used for prophylaxis of venous thrombo-embolism, enoxaparin SOdium does not intluence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets.

At higher doses, increases in aPTT (activated partial thromboplastin time), and ACT (activated clotting time) may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity

PRECAUTIONS

Do not administer by the intramuscular route.

·         Hemorrhage

AS With other anticoagulants, bleeding may occur at any site (see Section Adverse Reactions).

If bleeding occurs, the origin of the hemorrhage should be investigated and appropriate treatment instituted.

·         Enoxaparin sodium, as with any other anticoagulant therapy,should be used with caution in conditions with increased potential for bleeding, such as:

                     i.            impaired hemostasis,

                   ii.            history of peptic ulcer,

                  iii.            recent ischemic stroke,

                 iv.            uncontrolled severe arterial hypertension

                   v.            diabetic retinopathy,

                 vi.            recent neuro- or ophthalmologic surgery,

                vii.            Concomitant use of medications affecting hemostasis (see Sectiont Interaction).

·         Mechanical prosthetic heart valves

The use of Clexane Injection has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Confounding factors, indluding underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal death. Pregnant women with prosthetic heart valves may be at higher risk for thrombo-embolism (see Section Warnings: Pregnant women with mechanical prosthetic heart).

·         Hemorrhage in the elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical monitoring is advised (see Section Dosage and Administration).

·         Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the risk of bleeding. Since exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min), a dosage adjustment is reconmended for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised (see Section Dosage & Administration: Renal impairment).

·         Low weight

An increase in exposure of enoxaparin sodium with prophylactic dosages tnon-weight adjusted) has been observed in low-weight women (<45 kg) and OW-weight men (<57 kg), Therefore, careful clinical monitoring is advisea in these patients.

·         Obese Patients

Obese patients are at higher ris thromboembolism. The safety and efficacy of prophylactic doses in Dese patients (BMI >30 kg/m2) has not been fully derermined and tntc o onsensus for dose adjustment.These patients should be obseic Laretully for signs and symptoms ofthromboembolism.

·         Monitoring of platelet counts

The risk of antibody-mediated ean-induced thrombocytopenia also exists with Low Molecular Weight epds. Should thrombocytopenia occur, it usually appears between the >tu" dld the 21st day following the beginning of enoxaparin sodiunm treatmenl. Ineretore, it i5 recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment. In practice, if a conhrmed signihcant decrease of the platelet count is observed (30 to 50 % of the initial value). enoxaparin sodium treatment must be immediately discontinued and the patient switched to another therapy.

INTERACTIONS

It is recommended that agents which affect hemostasis should be discontinued prior to enoxaparin sodium therapy unless strictly indicated.

These agents include medications such as:

         i.            Systemic salicylates, acetylsalicylic acid, and NSAIDs including ketorolac,

       ii.            Dextran 40, ticlopidine and clopidogrel,

      iii.            Systemic glucocorticoids,

     iv.            Thrombolytics and anticoagulants,

       v.            Other anti-platelet agents including 8lycoprotein ib/llla antagonists.

If the combination is indicated, enoxaparin sodium should be used with careful clinical and laboratorymonitoring when appropriate.

PREGNANCY

In humans. there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available concerning the first and the third trimesters.As there are no adequate and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this drug should be used during pregnancy only if the physician has established a clear need (See Warnings and Precautions).

Lactation: It is not known whether unchanged enoxaparin sodium is excreted in human breast milk. The oral absorption of enoxaparin sodium is unlikely. However, as a precaution, lactating mothers receiving enoxaparin sodium should be advised to avoid breast-feeding.

DRIVING A VEHICLE OR PERFORMING OTHER HAZARDOUS TASKS:

Enoxaparin sodium has no effect on the ability to drive and operate machines.

ADVERSE REACTIONS:

Enoxaparin has been evaluated in more than 15 000 patients who received enoxaparin in clinical trials. These included 1776 for prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1169 for prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility, 559 for treatment of deep vein thrombosis with or without pulmonary embolism, 1578 for treatment of unstable angina and non-Q-wave myocardial infarction and 10 176 for treatment of acute ST-elevation myocardial infarction.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The enoxaparin sodium dose was 40 mg SC once daily for prophylaxis of deep vein thrombosis following surgery or in acutely is medical patients with severely restricted mobility. In treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE), patients receiving enoxaparin were treated with either a 1 mg/kg SC dose every 12 hours or a 1.5 mg/kg SC dose once a day. In the clinical studies for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 1 mg/kg SC every 12 hours and in the clinical study for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium regimen was a 30 mg IV bolus followed by 1 mg/kg SC every 12 hours.

The adverse reactions observed in these clinical studies and reported in post marketing experience are detailed below. Frequencies are defined as follows: very common (2 1/10); common (z 1/100 to < 1/10); uncommon ( 1/1000 to< 1/100); rare (z 1/10,000 to <1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from available data). Post-r reactions are designated with a frequency "not known".

Haemorrhages:

In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2 % of the patients (Surgical patients). Some of these cases have been fatal.with As with other anticoagulants, haemorrfhage may ocCur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis (see Precautions and Interactions)

Vascular disorders:

        i.            Prophylaxis in surgical patients

Very common: Haemorrhage*

Rare: Retroperitoneal haemorrhage

      ii.            Prophylaxis in medical patients

Common: Haemorrhage

    iii.            Treatment in patients with DVT with or without PE

Very comnmon: Haemorrhage

Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage

     iv.            Treatment in patients with unstable angina and non-Q-wave Mi

Common: Haemorrhage

Rare: Retroperitoneal haemorrhage

       v.            Treatment in patients with acute STEMI

Common: Haemorrhage

Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage Such as haematoma, ecchymosis other than at injection site, wound hacmatoma, haematuria, epistaxis and gastro-intestinal  haemorrnagea

Thrombocytopenia and thrombocytosis:

·         Blood and lymphatic system disorders:

Prophylaxis in surgical patients

Very common: Thrombocytosis*

Common: Thrombocytopenia

Prophylaxis in medical patients

Uncommon: Thrombocytopenia

Treatment in patients with DVT with or without PEl

Very common: Thrombocytosis *

Common: Thrombocytopenia

Treatment in patients with unstable angina and non-Q-wave MI

Uncommon: Thrombocytopenia

Treatment in patients with acute STEMI

Common: Thrombocytosis* Thrombocytopeniaatdsi

Very rare: Immuno-allergic thrombocytopenia nbs tuu,

*: Platelet increased> 400 G/L

Other clinically relevant adverse reactions

·         Immune system disorders:

Common: Allergic reaction

Rare: Anaphylactic/ anaphylactoid reaction (see also Post marketing experience)

·         Hepatobilary disorders:

Very common; Hepatic enzymes increase (mainly transaminases )

·         Skin and subcutaneous tissue disorders:

Common: Urticaria, pruritus, erythema

Uncommon: Bullous dermatitis

·         General disorders and administration site conditions:

Common: Injection site haematoma, injection site pain, other injectionsite site reaction*

Uncommon: Local irritation; skin necrosis at injection site

·         Investigations:

Rare: Hyperkaliemia:

such as injection site oedema, haemorrhage, hypersensitivity, inflammation,mass, pain, or reaction (NOS)

**:transaminases levels > 3 times the upper limit of normality

Post marketing experience

The following adverse reactions have been identified during post-approval use of Clexane. The adverse reactions are derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).

·         Immune System Disorders

Anaphylactic/ anaphylactoid reaction including shock

·         Nervous System Disorders

Headache

·         Vascular Disorders

Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/epidural anaesthesia or spinal puncture. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see Section Warnings: Spinal/epidural anesthesia)

Skin and subcutaneous disorders

Cutaneous vasculitis, skin necrosis usually occurring at the inhematous (these phenomena havebeen usually preceded by purpura or plaques, infiltrated and painful).

Treatment with enoxaparin sodium must he disrontinued

Injection site nodules (infiammatory noauies, which were not cystic enclosure of enoxaparin)

They resolve after a few days and should not cause treatment discontinuation.

Alopecia

Hepatobilary disorders

Hepatocellular liver injury dnnni fuit 9

Cholestatic liver injury

Musculoskeletal and connective tissue disorders

Osteoporosis following long-term therapy (greater than 3 months)

OVERDOSAGE

Signs and Symptoms:

Symptoms and Severity

Accidental overdosage with enoxaparin sodium after intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin sodium will be absorbed.

Management:

Antidote and Treatment

The anticoagulant effects can be largely neutralized by the slow intravenous injection of protamine. The dose of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration,or if it has been determined that a second dose of protamine is required.

After 12 hours of the enoxaparin sodium injection, protamine administration may not be required. However, even with high doses of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralized (maximumabout 60%).

STORAGE

Do not store above 25°C. Do not freeze pre-filled syringes.

Keep medicine out of the reach of children.

Expiry Date:

Do not uses after the expiry date indicated on outer packaging

PRESENTATION

Clexane Injection 20mg/0.2ml: 2 Pre-filled syringes

Clexane Injection 40mg/0.4ml: 2 Pre-filled syringes

Clexane Injection 60mg/0.6ml: 2 Pre-filled syringes

Clexane Injection 80mg/0.8ml: 2 Pre-filled syringes

Manufactured by:

Sanofi Winthrop industrie

180 rue Jeans Jaures - BP 40 94702 Maisons-Alfort Cedex, Franeitv 1d3t mo si,ts

For:

Sanofi-aventis Pakistan limited Plot No. 23, Sector No. 22, Korangi Industrial Area, Kararhi-Palistan. (Enoxaparin-cCDS-v14)