FRAXIPARINE For Subcutaneous injection (apart from the kidney dialysis indication) PRESCRIBING INFORMATION

Transcription

1 The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in July 2010 FRAXIPARINE For Subcutaneous injection (apart from the kidney dialysis indication) PRESCRIBING INFORMATION 1. NAME OF THE MEDICINAL PRODUCT FRAXIPARINE 2850 anti-factor Xa IU/0.3 ml, solution for injection in pre-filled syringes FRAXIPARINE 3800 anti-factor Xa IU/0.4 ml, solution for injection in pre-filled syringes FRAXIPARINE 5700 anti-factor Xa IU/0.6 ml, solution for injection in pre-filled syringes FRAXIPARINE 7600 anti-factor Xa IU/0.8 ml, solution for injection in pre-filled syringes 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Nadroparin Calcium I.U AXa/0.3ml 3800 I.U AXa/0.4ml 5700 I.U AXa/0.6ml 7600 I.U AXa/0.8ml List of Excipients Calcium Hydroxide solution or dilute Hydrochloric acid, water for injection 3. PHARMACEUTICAL FORM Solution for Injection 4. CLINICAL PARTICULARS 4.1 Therapeutic indications This heparin is a low molecular weight heparin (LMWH). Its indications are as follows: Prophylactic treatment of venous thromboembolic disease during surgery for patients presenting with moderate or high risk. Treatment of constituted deep vein thrombosis. Prevention of coagulation in the extra corporeal circuit during haemodialysis. The prophylaxis of thromboembolic disorders in high risk medical patients (respiratory failure and/or respiratory infection and/or cardiac failure) hospitalised in intensive care unit. 4.2 Posology and method of administration SUBCUTANEOUS ROUTE (apart from the kidney dialysis indication) This dosage form is suitable for adults. Do not inject by the intramuscular route. 1 ml of FRAXIPARINE is equivalent to approximately 9500 anti-factor Xa IU nadroparin. - Subcutaneous injection technique Page 1 of 14

2 Do not purge the air bubble. Subcutaneous injection of nadroparin should preferably be given with the patient in the decubitus position, in the subcutaneous cellular tissue of the anterolateral and posterolateral abdominal girdle, on the right and left side alternately. The needle must be fully inserted perpendicularly and not tangentially into the thickness of a skin fold made between the thumb and the index finger of the person administering it. This skin fold must be maintained throughout the injection. - General recommendation Regular monitoring of platelet count is essential throughout treatment due to the risk of heparininduced thrombopenia (HIT) (cf. chapter 4.4 Warnings and precautions for use). Prevention of venous thrombo-embolic disease in surgery These recommendations generally apply to surgical procedures performed under general anaesthetic. For spinal and epidural anaesthesia techniques, the value of injection before surgery must be assessed due to the increased theoretical risk of intraspinal haematoma (cf. Chapter 4.4. Precautions for use). * Frequency of administration 1 injection per day. * Dose administered This depends on the individual level of risk, related to the patient and the type of surgery. - Situation of moderate thrombogenic risk: In the event of surgery with a moderate thrombogenic risk and when the patients do not present a high thrombo-embolic risk, effective prevention of thrombo-embolic disease is obtained by daily injection of a dose of 2850 anti-factor Xa IU (0.3 ml). The treatment regimen studied includes an initial injection conducted 2 hours before surgery. - Situation of high thrombogenic risk:. Hip and knee surgery: The nadroparin dosage depends on the weight of the patient, at a dosage of 1 daily injection of: 38 anti-factor Xa IU/kg before surgery, i.e. 12 hours before the procedure, after surgery, i.e. from the 12 th hour after the end of the procedure, then daily up to the 3 rd day after surgery inclusive. 57 anti-factor Xa IU/kg from the 4 th day after surgery. By way of indication, the dosages to be administered as a function of patients weights are as follows: Bodyweight (kg). Other situations: FRAXIPARINE volume Per injection and per day Before surgery and up to the 3 rd day FRAXIPARINE volume Per injection and per day From the 4 th day < ml 0.3 ml ml 0.4 ml > ml 0.6 ml Page 2 of 14

3 When the thrombo-embolic risk related to the type of surgery (in particular, oncological) and/or the patient (in particular, history of thrombo-embolic disease) appears to be increased, a nadroparin dosage of 2850 IU (0.3 ml) appears to be sufficient. * Treatment duration: Treatment with a LMWH, accompanied by the usual elastic lower limb compression techniques, must be maintained until complete active deambulation of the patient. In general surgery, the duration of LMWH treatment must be less than 10 days, in the absence of any specific venous thrombo-embolic risk related to the patient (Cf. Chapter 4.4 Precautions for use, platelet monitoring). If the venous thrombo-embolic risk persists beyond the recommended treatment duration, it is necessary to consider continuing preventive treatment, notably using oral anticoagulants. However, the clinical benefit of long-term treatment with low molecular weight heparin or anti-vitamin K has not been evaluated at the current time.. Prevention of coagulation of the extra-corporal circulation loop/kidney dialysis INJECTION BY THE INTRAVASCULAR ROUTE (into the arterial line of the dialysis loop). In patients given repeated kidney dialysis sessions, prevention of coagulation in the extra-renal purification loop is obtained by injecting an initial dose of 65 IU/kg into the arterial line of the dialysis loop at the start of the session. This dose, administered as a single intravascular bolus, is only suitable for dialysis sessions lasting 4 hours or less. It may subsequently be adjusted due to the high level of intra- and inter-individual variability. By way of indication, the dosages to be administered as a function of patients weights are as follows: Bodyweight < 51 kg kg > 70 kg FRAXIPARINE volume per session 0.3 ml 0.4 ml 0.6 ml If necessary, the dose is adjusted to the specific case of each patient and the technical dialysis conditions. In subjects with a haemorrhagic risk, the dialysis sessions may be conducted using a halved dose.. Curative treatment of deep-vein thrombosis (DVT) Any suspicion of deep-vein thrombosis must be rapidly confirmed by means of appropriate tests. * Frequency of administration 2 injections per day, given 12 hours apart. * Dose administered: The dose per injection is 85 anti-factor Xa IU/kg. The dosage of LMWH has not been evaluated as a function of bodyweight in patients with a bodyweight of more than 100 kg or less than 40 kg. The efficacy of LMWH may be reduced for patients weighing more than 100 kg, or there may be an increased haemorrhagic risk for patients weighing less than 40 kg. Specific clinical monitoring is required. By way of indication, the dosages to be administered as a function of patients weights are 0.1 ml/10 kg every 12 hours, as indicated in the table below: Page 3 of 14

4 Bodyweight kg kg kg kg kg kg 100 kg FRAXIPARINE volume per injection 0.4 ml 0.5 ml 0.6 ml 0.7 ml 0.8 ml 0.9 ml 1.0 ml Adjust the volume to be administered by moving the piston to the desired graduation, holding the syringe upright. * Treatment duration for DVT: Treatment with LMWH must be quickly switched to oral anticoagulants, unless contraindicated. The LMWH treatment duration must not exceed 10 days, including the stabilising period with AVKs, unless there are stabilising difficulties (Cf. Chapter 4.4. Precautions for use: platelet monitoring). Oral anticoagulant treatment should therefore be instigated as soon as possible. The prophylaxis of thromboembolic disorders in high risk medical patients (respiratory failure and/or respiratory infection and/or cardiac failure) hospitalised in intensive care unit Nadroparin is administered subcutaneously once daily. The dose should be adjusted for body weight according to the table below. Treatment should be continued throughout the risk period of thromboembolism. Body weight Once daily (kg) Volume injected (ml) Anti-Xa IU ,800 > ,700 Renal Impairment Prophylaxis of thromboembolic disorders Dose reduction is not required in patients with mild renal impairment (creatinine clearance greater than or equal to 50 ml/min). Moderate and severe renal impairment is associated with increased exposure to nadroparin. These patients are at increased risk of thromboembolism and haemorrhage. If a dose reduction is considered appropriate by the prescribing physician, taking into account the individual risk factors for haemorrhage and thromboembolism in patients with moderate renal impairment (creatinine clearance greater than or equal to 30 ml/min and less than 50 ml/min) the dose should be reduced by 25 to 33% (see Warnings and Precautions and Pharmacokinetics). The dose should be reduced by 25% to 33% in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see Warnings and Precautions and Pharmacokinetics). Treatment of thromboembolic disorders Dose reduction is not required in patients with mild renal impairment (creatinine clearance greater than or equal to 50 ml/min). Moderate and severe renal impairment is associated with increased exposure to nadroparin. These patients are at increased risk of thromboembolism and haemorrhage. Page 4 of 14

5 If a dose reduction is considered appropriate by the prescribing physician, taking into account the individual risk factors for haemorrhage and thromboembolism in patients with moderate renal impairment (creatinine clearance greater than or equal to 30 ml/min and less than 50 ml/min) the dose should be reduced by 25 to 33% (see Warnings and Precautions and Pharmacokinetics). Nadroparin is contraindicated in patients with severe renal impairment (see Warnings and Precautions and Pharmacokinetics). 4.3 Contraindications Irrespective of the doses (curative or preventive), this drug MUST NOT BE USED in the following situations: - hypersensitivity to nadroparin or any of the excipients of nadroparin injections; - history of severe type-ii heparin-induced thrombopenia (or HIT) induced under unfractionated heparin or under low molecular weight heparin (Cf. Chapter 4.4 Precautions for use); - haemorrhagic signs or tendencies linked to haemostasis disorders (disseminated intravascular coagulations may be an exception to this rule if these are not related to heparin treatment Cf. Chapter 4.4 Precautions for use); - organic lesion liable to bleed. At curative doses, this drug MUST NOT BE USED in the following situations: - intracerebral haemorrhage; - in the absence of data, severe kidney failure (defined by creatinine clearance of approximately 30 ml/min according to calculation using the Cockroft formula), apart from the specific situation of dialysis. In severe kidney failure, use unfractionated heparin. For calculation of the Cockroft formula, it is necessary to have a recent weight of the patient (Cf. Chapter 4.4 Precautions for use). - In addition, an epidural or spinal anaesthetic must never be given in the event of curative treatment with LMWH. At curative doses, this drug is NOT GENERALLY RECOMMENDED in the following situations: - extensive ischemic cerebrovascular accident in the acute phase, with or without impaired consciousness. When the stroke is of embolic origin, the period to be complied with is 72 hours. Evidence of the efficacy of LMWH at curative doses has not, however, been established to date, irrespective of the cause, extent and clinical severity of the cerebral infarction; - acute infectious endocarditis (apart from certain emboligenic cardiopathies); mild to moderate kidney failure (creatinine clearance > 30 and < 50ml/min) (Cf. Chapter 4.2 Posology and method of administration). In addition, this drug at curative doses is NOT GENERALLY RECOMMENDED in subjects of any age in combination with (Cf. Chapter 4.5 Interactions with other medicinal products and other forms of interactions) + acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses, + NSAIDs (systemic route), + dextran 40 (parenteral route). At preventive doses, this drug is NOT GENERALLY RECOMMENDED in the following situations: severe kidney failure (creatinine clearance of approximately 30 ml/min according to calculation using the Cockroft formula, Cf. Chapter 4.4 Precautions for use and Chapter 4.2 Posology and method of administration). - within the first 24 hours following an intracerebral haemorrhage. In addition, at preventive doses, this drug is NOT GENERALLY RECOMMENDED in elderly subjects over the age of 65, in combination with (Cf. Chapter 4.5 Interactions with other medicinal products and other forms of interactions): + acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses, Page 5 of 14

6 + NSAIDs (systemic route), + dextran 40 (parenteral route). 4.4 Special warnings and special precautions for use Although the various proprietary low molecular weight heparin products all have their concentrations expressed in anti-factor Xa international units, their efficacy is not limited to this anti-factor Xa activity. It would be dangerous to substitute the dosage regimen of one LMWH for another, since each regimen has been validated by specific clinical trials. Particular caution is therefore required and the specific instructions for use for each proprietary medicinal product must be complied with. Warnings. Haemorrhagic risk It is essential to follow the recommended treatment regimens (dosages and treatment durations). Otherwise, haemorrhagic accidents could occur, particularly in patients at risk (elderly subjects, patients with kidney failure, etc.). Serious haemorrhagic accidents have notably been observed: - in the elderly, in particular due to the deterioration in kidney function related to age, - in the event of kidney failure, - in the event of a bodyweight under 40 kg - in the event of treatment prolonged beyond the recommended mean duration of 10 days, - in the event of non-compliance with the recommended treatment conditions (in particular treatment duration and dosage adjustment on the basis of weight for curative treatments), - in the event of combination with drugs increasing the haemorrhagic risk (Cf. Chapter 4.5 Interactions with other medicinal products and other forms of interactions). Caution should be exercised when nadroparin is administered in the following situations as they may be associated with an increased risk of bleeding: hepatic failure severe arterial hypertension history of peptic ulceration or other organic lesion likely to bleed vascular disorder of the chorio-retina during the post-operative period following surgery of the brain, spinal cord or eye. Renal Impairment Nadroparin is known to be mainly excreted by the kidney, which results in increased nadroparin exposure in patients with renal impairment (see Pharmacokinetics Renal Impairment). Patients with impaired renal function are at increased risk of bleeding and should be treated with caution. The decision on whether a dose reduction is appropriate for patients with creatinine clearance 30 to 50 ml/min should be based on the physician s assessment of an individual patient's risk of bleeding versus the risk of thromboembolism. In all cases, specific monitoring is essential in the elderly and/or subjects with kidney failure, and also in the event of long-term treatment for more than 10 days. In order to detect any accumulation, measurement of anti-factor Xa activity can be useful in certain cases (Cf. Chapter 4.4 Precautions for use/laboratory monitoring).. Risk of heparin-induced thrombopenia (HIT) In the event of a patient treated with LMWH (at curative or preventive doses) presenting a thrombotic event, such as: - an exacerbation of the thrombosis for which he/she is being treated, Page 6 of 14

7 - phlebitis, - pulmonary embolism, - acute ischemia of the lower limbs, - or even myocardial infarction or ischemic cerebrovascular accident, one must systematically consider heparin-induced thrombopenia (HIT) and urgently perform a platelet count (Cf. Chapter 4.4 Precautions for use).. Use in children In the absence of data, the use of LMWHs in children is not recommended. Precautions for use. Kidney function Before starting treatment with LMWH, it is essential to assess kidney function, particularly in the elderly over the age of 75 years, calculating creatinine clearance (Clcr) using the Cockroft formula and on the basis of a recent weight for the patient: In men, Clcr = (140 age) x weight / (0.814 x serum creatinine) with age expressed in years, weight in kg and serum creatinine in µmol/l. This formula must be corrected for women by multiplying the result by When creatinine is expressed in mg/ml, multiply by a factor of 8.8. Detection of severe kidney failure (Clcr of approximately 30 ml/min) contraindicates the prescription of LMWH in curative indications (Cf. Chapter 4.3 Contraindications).. Laboratory monitoring * Platelet monitoring Heparin-induced thrombopenia (or HIT) There is a risk of severe thrombopenia, sometimes causing thrombosis, induced by heparin (unfractionated heparin and, less commonly, low molecular weight heparins), of immunological origin, called type II thrombopenia (see also Chapter 4.8 Undesirable effects). Due to the risk of HIT, monitoring of platelet count is necessary, irrespective of the indication for treatment and the dosage administered. Perform a platelet count before treatment or, at the latest, within 24 hours after treatment instigation, then twice weekly throughout the usual duration of the treatment. HIT must be suspected if the platelet count is < 100,000/mm 3 and/or there is a relative fall in platelets of 30 to 50% in 2 successive counts. It mainly develops between the 5 th and 21 st day following the start of heparin treatment (with a peak in frequency at around the 10 th day). But it can occur much earlier when there is a history of thrombopenia under heparin treatment and isolated cases have been reported beyond 21 days. This type of history must be systematically investigated during an in-depth interview prior to treatment. In addition, the risk of recurrence in the event of the reintroduction of heparin could persist for several years or even indefinitely (Cf. Chapter 4.3 Contraindications). In all cases, the onset of HIT is an emergency situation and requires specialist advice. Any significant fall (30 to 50% of the initial value) in platelet count must be seen as an alert, before the value reaches a critical level. Observation of a fall in the number of platelets always demands: 1) - an immediate platelet count; 2) the suspension of heparin treatment if the fall is confirmed or even accentuated at this count, in the absence of any other obvious cause. Page 7 of 14

8 A sample must be taken in a citrate tube to perform platelet aggregation tests in vitro and immunological tests. But, under these conditions, the immediate measures to be taken do not depend on the results of these in vitro or immunological platelet aggregation tests because only a few specialised laboratories conduct them routinely and the results are obtained, at best, only after several hours. These tests must nonetheless be performed to assist the diagnosis of this complication since if heparin treatment is continued, there is a major risk of thrombosis. 3) prevention or treatment of thrombotic complications of HIT. If it appears to be essential to continue anticoagulation, heparin must be replaced with another class of antithrombotic: danaparoid sodium or hirudin, prescribed at preventive or curative doses depending on the case. Substitution with AVKs should only take place once the platelet count has normalised, due to the risk of exacerbation of the thrombotic phenomenon by AVKs. * Substitution of heparin with AVKs In this case, reinforce clinical and laboratory monitoring (Quick time expressed in INR) to monitor the effect of AVKs. Due to the latency time prior to the full effect of the antivitamin K used, heparin must be maintained at an equivalent dose for as long as necessary to ensure that the INR is within the desired therapeutic zone of the indication at two successive controls. * Control of anti-factor Xa activity Since the majority of clinical trials demonstrating the efficacy of LMWH have been conducted at a dose tailored to bodyweight and without any specific laboratory monitoring, the value of this type of laboratory monitoring has not been established to assess the efficacy of LMWH. However, laboratory monitoring by determination of anti-factor Xa activity may be useful to manage the haemorrhagic risk in some clinical situations frequently associated with a risk of overdose. These situations mainly concern the curative indications of LMWH, due to the doses administered, when there is: - mild to moderate kidney failure (clearance calculated using the Cockroft formula of around 30 to 50ml/min): in fact, in contrast with unfractionated standard heparin, LMWHs are largely eliminated by the kidneys and any impaired kidney function can lead to relative overdose. As for severe kidney failure, this is a contraindication to the use of LMWHs at curative doses (Cf. Chapter 4.3 Contraindications); - an extreme weight (underweight or even cachexia, obesity); - unexplained haemorrhage. Conversely, laboratory monitoring is not recommended at preventive doses if treatment with LMWH complies with the recommended treatment conditions (particularly for treatment duration) and during kidney dialysis. In order to detect a possible accumulation after several administrations, it is recommended that a blood sample be taken from the patient if necessary at the peak activity (according to the data available), i.e.: - approximately 4 hours after the 3 rd administration, when the drug is given as 2 SC injections per day, - approximately 4 hours after the 2 nd administration, when the drug is given as 1 SC injection per day. Repetition of assay of anti-factor Xa activity to measure serum heparin levels every 2 to 3 days, for example should be discussed on a case-by-case basis, depending on the results of the previous assay and adjustment of the LMWH dose should be considered if necessary. For each LMWH and each treatment regimen, the anti-factor Xa activity generated is different. By way of indication and according to the data available, the mean observed ( standard deviation) at the 4 th hour for nadroparin, administered: - at a dose of 83 IU/kg by injection, as 2 injections per 24 hours, was IU. Page 8 of 14

9 - at a dose of 166 IU/kg as 1 injection per 24 hours, was IU. This mean value was observed during clinical trials for assays of anti-factor Xa activity conducted using the chromogenic method (amidolytic). * Activated partial thromboplastin time (APTT) Certain LMWHs moderately prolong APTT. In the absence of any established clinical relevance, any treatment monitoring based on this test is pointless. Hyperkalaemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with raised plasma potassium, or at risk of increased plasma potassium levels, such as patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis or those taking drugs that may cause hyperkalaemia (e.g. ACE inhibitors, NSAIDs). The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be monitored in patients at risk.. Administration of spinal/epidural anaesthetic in the event of preventive treatment with LMWH - As with other anticoagulants, rare cases of intraspinal haematoma leading to long-term or permanent paralysis have been reported during the administration of LMWH during spinal or epidural anaesthetic. The risk of intraspinal haematoma appears to be higher with an epidural using a catheter than with a spinal anaesthetic. The risk of these rare events may be increased by the prolonged use of epidural catheters after surgery. - If pre-surgical treatment with LMWH is necessary (prolonged bed rest, injury) and the benefit of a loco-regional spinal anaesthetic has been carefully evaluated, this technique may be used in a patient having received an injection of LMWH before surgery, as long as a period of at least 12 hours is left between the heparin injection and administration of the spinal anaesthetic. Careful neurological monitoring is recommended due to the risk of intraspinal haematoma. In almost all cases, preventive treatment with LMWH can be started within 6 to 8 hours following the technique or removal of the catheter, under neurological monitoring. Particular caution is required in the event of combination with other drugs interfering with haemostasis (notably nonsteroidal anti-inflammatories, aspirin).. Situations at risk Monitoring of treatment should be reinforced in the following cases:. liver failure,. history of gastrointestinal ulcers or any other organic lesions liable to bleed,. vascular diseases of the chorioretina,. in the post-operative period following brain and spinal bone marrow surgery, the performance of a lumbar puncture must be discussed, taking into account the risk of intraspinal bleeding. It must be deferred wherever possible.. Latex Allergy The needle guard of the pre-filled syringe contains dry natural latex rubber that has the potential to cause allergic reactions in latex sensitive individuals. 4.5 Interactions with other medicinal products and other forms of interaction Certain drugs or therapeutic classes are liable to promote the onset of hyperkalaemia: potassium salts, hyperkalaemic diuretics, conversion enzyme inhibitors, angiotensin II inhibitors, nonsteroidal antiinflammatories, heparins (low molecular weight or unfractionated), ciclosporin and tacrolimus, trimethoprim. The onset of hyperkalaemia may depend on the existence of concomitant risk factors. Page 9 of 14

10 This risk is increased in the event of combination with the above mentioned drugs. 1. In subjects under the age of 65 at curative LMWH doses, and in the elderly (> 65 years) irrespective of the LMWH dose Inadvisable combinations + Acetylsalicylic acid at analgesic, antipyretic and anti-inflammatory doses (and, by extrapolation, other salicylates) Increase in haemorrhagic risk (inhibition of platelet function and aggression of the gastroduodenal mucosa by salicylates), Use a non-salicylate antipyretic analgesic (such as paracetamol). + NSAIDs (systemic route) Increase in haemorrhagic risk (inhibition of platelet function and aggression of the gastroduodenal mucosa by nonsteroidal anti-inflammatories), If the combination cannot be avoided, close clinical monitoring. + Dextran 40 (parenteral route) Increase in haemorrhagic risk (inhibition of platelet function by Dextran 40). Combinations requiring precautions for use + Oral anticoagulants Potentiation of anticoagulant action When switching from heparin to an oral anticoagulant, reinforce clinical monitoring. Combinations to be taken into account + Platelet anti-aggregants (other than acetylsalicylic acid at analgesic, antipyretic and antiinflammatory doses; NSAIDs): abciximab, acetylsalicylic acid at anti-aggregant doses in cardiological and neurological indications, beraprost, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban Increase in haemorrhagic risk. 2. In subjects under the age of 65 at preventive LMWH doses Combinations to be taken into account The concomitant use of drugs acting at various levels on haemostasis increases the risk of bleeding. Thus, irrespective of age, combination of LMWHs at preventive doses with oral anticoagulants, platelet anti-aggregants (abciximab, NSAIDs, acetylsalicylic acid irrespective of dose, clopidogrel, eptifibatide, iloprost, ticlopidine, tirofiban) and thrombolytics must be taken into account, maintaining clinical and, if necessary, laboratory monitoring. 4.6 Pregnancy and lactation Pregnancy Studies conducted in animals have not revealed any teratogenic effect of nadroparin. Page 10 of 14

11 In the absence of any teratogenic effect in animals, no malformative effect is expected in humans. In fact, to date, substances responsible for malformations in humans have been shown to be teratogenic in animals during properly conducted studies in two species. Preventive treatment in the 1 st trimester and curative treatment In a clinical context, there are not yet enough relevant data in order to evaluate a possible teratogenic or foetotoxic effect of nadroparin when administered at a preventive dose during the first trimester of pregnancy or at a curative dose throughout pregnancy. Consequently, as a precautionary measure, it is preferable to avoid use of nadroparin at a preventive dose during the first trimester of pregnancy or at a curative dose throughout pregnancy. Preventive treatment in the 2 nd and 3 rd trimesters In a clinical context, the use of nadroparin during the 2 nd and 3 rd trimesters of a limited number of pregnancies does not appear to have evidenced any teratogenic or foetotoxic effects to date. However, further studies are necessary in order to evaluate the consequences of exposure under these conditions. Consequently, the use of nadroparin at a preventive dose during the 2 nd and 3 rd trimesters of pregnancy must only be envisaged during pregnancy if necessary. If epidural anaesthesia is envisaged, it is advisable to suspend heparin treatment at the latest within 12 hours prior to anaesthesia, insofar as possible, for preventive treatment. Lactation There is limited information on the excretion of nadroparin in breast milk. Therefore, the use of nadroparin during breast feeding is not advised. 4.7 Effects on ability to drive and use machines Not applicable. 4.8 Adverse Reactions Adverse reactions are listed below by system organ class and frequency. The following convention has been used for the classification of adverse reactions in terms of frequency: Very common 1/10, common 1/100 and <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000. Blood & lymphatic system disorders Very common: Haemorrhagic manifestations at various sites, more frequent in patients with other risk factors (see Contraindications and Interactions). Rare: Very rare: Thrombocytopenia, sometimes thrombogenic (see Warnings and Precautions), thrombocytosis. Eosinophilia, reversible following treatment discontinuation. Immune system disorders Very rare: Hypersensitivity reactions (including angioedema and cutaneous reactions), anaphylactoid reaction. Metabolism & nutrition disorders Very rare: Reversible hyperkalaemia related to heparin-induced aldosterone suppression, particularly in patients at risk (see Warnings and Precautions). Hepato-biliary disorders Page 11 of 14

12 Common: Raised transaminases, usually transient. Reproductive system & breast disorders Very rare: Priapism. General disorders and administration site conditions Very common: Small haematoma at the injection site. In some cases, the emergence of firm nodules, which do not indicate an encystment of the heparin may be noted. These nodules usually disappear after a few days. Common: Injection site reaction. Rare: Calcinosis at the injection site. Calcinosis is more frequent in patients with abnormal calcium phosphate product, such as in some cases of chronic renal failure. Very rare: Cutaneous necrosis, usually occurring at the injection site. Cutaneous necrosis is preceded by purpura or infiltrated or painful erythematous blotches, with or without general signs. In such cases, treatment should be immediately discontinued. 4.9 Overdose - Accidental overdose following the subcutaneous administration of massive doses of low molecular weight heparin could cause haemorrhagic complications. In the event of haemorrhage, treatment with protamine sulphate may be indicated in certain cases, taking into account the following facts:. its efficacy is significantly less than that reported in the event of overdose with unfractionated heparin;. due to its adverse events (in particular, anaphylactic shock), the benefit/risk ratio of protamine sulphate must be carefully assessed before it is prescribed. In this event, neutralisation is conducted by slow intravenous injection of protamine (sulphate or hydrochloride). The effective protamine dose depends on:. the heparin dose injected (100 anti-heparin units of protamine can be used to neutralise the activity of 100 anti-factor Xa IU of low molecular weight heparin),. the time elapsed since injection of the heparin, with possible reduction of the antidote doses. Nevertheless, it is not possible to totally neutralise the anti-factor Xa activity. Moreover, the absorption kinetics of low molecular weight heparin may make this neutralisation transient and require fragmentation of the total calculated protamine dose into several injections (2 to 4) divided over 24 hours. - In the event of ingestion even massive of low molecular weight heparin (no cases reported), no serious consequences are, in principle, expected, given the very low gastrointestinal absorption of the product. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties B01 AB 06: ANTI-THROMBOTICS - Nadroparin is a low molecular weight heparin in which the antithrombotic and anticoagulant properties of standard heparin have been split. Page 12 of 14

13 It is characterised by a higher anti-factor Xa activity than anti-factor IIa or thrombotic activity. For nadroparin, the ratio between these two activities is between 2.5 and 4. - At prophylactic doses, nadroparin does not cause any marked changes in APTT. At curative doses, at the peak activity, APTT may be prolonged to 1.4 times the reference time. This prolongation is a reflection of the residual antithrombotic effect of nadroparin. 5.2 Pharmacokinetic properties The pharmacokinetic parameters are studied on the basis of the evolution in plasma anti-factor Xa activities. - Bioavailability After subcutaneous injection, almost 100% of the product is rapidly absorbed. Peak plasma activity is reached between the 3 rd and the 4 th hour if nadroparin is administered as 2 injections per day. This peak is shifted to between the 4 th and the 6 th hour if nadroparin is administered as 1 injection per day. - Metabolism This mainly occurs in the liver (desulfatation, depolymerisation). - Distribution After subcutaneous injection, the half-life of anti-factor Xa activity is higher for low molecular weight heparins than for unfractionated heparins. This half-life is around 3 to 4 hours. As for the anti-factor IIa activity, this disappears more rapidly from the plasma than the anti-factor Xa activity with low molecular weight heparins. - Elimination Elimination is primarily by the renal route in little or non-metabolised form. - Populations at risk * The elderly: In the elderly, since kidney function is physiologically reduced, elimination is slowed down. This modification does not affect the doses and rhythm of injections for preventive treatment as long as the kidney function of these patients remains within acceptable limits, i.e. only slightly impaired. It is essential to systematically assess the kidney function of elderly subjects over the age of 75 using the Cockroft formula, before instigating LMWH treatment (Cf. 4.2 Posology and method of administration, Chapter 4.4 Precautions for use). Renal Impairment In a clinical study investigating the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal impairment, a correlation was found between nadroparin clearance and the creatinine clearance. In patients with moderate renal impairment (creatinine clearance ml/min) both mean AUC and half-life were increased by 52 and 39% respectively compared with healthy volunteers. In these patients, mean plasma clearance of nadroparin was decreased to 63% of normal. Wide inter-individual variability was observed in the study. In subjects with severe renal impairment (creatinine clearance ml/min) both mean AUC and half-life were increased by 95 and 112% respectively compared with healthy volunteers. Plasma clearance in patients with severe renal impairment was decreased to 50% of that observed in patients with normal renal function. In subjects with severe renal impairment (creatinine clearance 3-6 ml/min) on haemodialysis, both mean AUC and half-life were increased by 62 and 65% respectively compared Page 13 of 14

14 with healthy volunteers. Plasma clearance in haemodialysis patients with severe renal impairment was decreased to 67% of that observed in patients with normal renal function (see Warnings and Precautions). * Mild to moderate kidney failure (creatinine clearance > 30 ml/min): It may be useful in certain cases to monitor circulating anti-factor Xa activity to eliminate the possibility of overdose in curative indications (Cf. Chapter 4.4. Precautions for use). * Kidney dialysis: Low molecular weight heparin is injected into the arterial line of the dialysis loop at high enough doses to prevent coagulation of the loop. In principle, the pharmacokinetic parameters are not modified, except for in the event of overdose, when passage into the systemic circulation can lead to an increased anti-factor Xa activity, related to the terminal kidney failure. 5.3 Preclinical safety data Not applicable. 6. PHARMACEUTICAL PARTICULARS 6.1 Incompatibilities Not applicable. 6.2 Shelf life 3 years. 6.3 Special precautions for storage Store below 30 C. Store in original packaging until time of use. 6.4 Nature and contents of container 0.3 ml or 0.4 ml or 0.6 ml or 0.8 ml of injectable solution in a pre-filled syringe (glass) with security device; transparent plastic sleeve; box of 2 or 10 MANUFACTURED BY: Glaxo Wellcome Production, Notre Dame De Bondeville, France LICENSE HOLDER: GlaxoSmithKline (Israel) Ltd. 25 Basel St., Petach Tikva LICENSE NUMBER: FRAXIPARINE 2850 IU AXa/ 0.3 ML FRAXIPARINE 3800 IU AXa/ 0.4 ML FRAXIPARINE 5700 IU AXa/ 0.6 ML FRAXIPARINE 7600 IU AXa/ 0.8 ML Page 14 of 14