PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 11 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 23 SPECIAL HANDLING INSTRUCTIONS 23 DOSAGE FORMS, COMPOSITION AND PACKAGING 24

PART II: SCIENTIFIC INFORMATION 25

PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 26 DETAILED PHARMACOLOGY 36 TOXICOLOGY 38 REFERENCES 39

PART III: CONSUMER INFORMATION. 40

PrFRAXIPARINE(r) nadroparin calcium injection (9,500 anti-Xa IU/mL)

PrFRAXIPARINE(r) FORTE nadroparin calcium injection (19,000 anti-Xa IU/mL)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Hypersensitivity to FRAXIPARINE(r) (nadroparin calcium) injection, or any of its constituents; or to other low molecular weight heparins and/or heparin. History of confirmed or suspected immunologically-mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), or in patients in whom an in vitro platelet-aggregation test in the presence of nadroparin is positive. Acute infective endocarditis. Active bleeding or increased risk of hemorrhage, in relation to hemostasis disorders. Major blood clotting disorders. Generalised hemorrhagic tendency or other conditions involving increased risk of bleeding. Organic lesions likely to bleed (such as active gastric or duodenal ulcers). Hemorrhagic cerebrovascular event (except if there are systemic emboli). Severe uncontrolled hypertension. Diabetic or hemorrhagic retinopathy. Injuries to and operations on the central nervous system, eyes and ears. Spinal/epidural anaesthesia is contraindicated where repeated high doses of FRAXIPARINE(r) (171 IU/kg once daily or 86 IU/kg twice daily) are required, due to an increased risk of bleeding. Severe renal insufficiency (creatinine clearance less than 30 mL/min in patients receiving treatment for thromboembolic disorders, unstable angina and non-Q wave myocardial infarction).

WARNINGS AND PRECAUTIONS

General

FRAXIPARINE(r) (nadroparin calcium) must NEVER be administered by the intramuscular route.

FRAXIPARINE(r) CANNOT BE USED INTERCHANGEABLY (UNIT FOR UNIT) WITH UNFRACTIONATED HEPARIN OR OTHER LOW MOLECULAR WEIGHT HEPARINS (LMWHs) AS THEY DIFFER IN THEIR MANUFACTURING PROCESS, MOLECULAR WEIGHT DISTRIBUTION, ANTI-XA AND ANTI-IIA ACTIVITIES, UNITS AND DOSAGES. SPECIAL ATTENTION AND COMPLIANCE WITH INSTRUCTIONS FOR USE OF EACH SPECIFIC PRODUCT IS REQUIRED DURING ANY CHANGE IN TREATMENT. Determination of anti-factor Xa levels in plasma is the only method available for monitoring nadroparin activity. Routine clotting assays are unsuitable for monitoring the anticoagulant activity, because APTT prolongation is generally observed only at very high plasma anti-Xa levels. Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered in patients at higher risk of bleeding and receiving FRAXIPARINE(r), such as the elderly, patients with renal insufficiency or the extremes of body weight, during pregnancy, or for children. At treatment doses, peak anti-Xa levels should generally be maintained at no more than 1.5 IU/mL in these patients (see ACTION AND CLINICAL PHARMACOLOGY, and WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

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.

Carcinogenesis and Mutagenesis

See TOXICOLOGY.

Cardiovascular

Use in Unstable Coronary Artery Disease

When thrombolytic treatment is considered appropriate in patients with unstable angina and non-Q wave myocardial infarction, concomitant use of an anticoagulant such as FRAXIPARINE(r) may increase the risk of bleeding.

Use in Patients with Prosthetic Heart Valves

Cases of prosthetic valve thrombosis have been reported in patients who have received low molecular weight heparins for thromboprophylaxis. Some of these patients were pregnant women in whom thrombosis led to maternal and/or fetal deaths. Pregnant women are at higher risk of thromboembolism (see WARNINGS AND PRECAUTIONS, Pregnant Women).

Endocrine and Metabolism

Dosing in Patients with Extreme Body Weight

Safety and efficacy of low molecular weight heparins in high weight (e.g. > 120 kg) and low weight (e.g. < 45 kg) patients has not been fully determined. Individualised clinical and laboratory monitoring is recommended in these patients.

Hyperkalemia

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, 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 hyperkalemia (e.g. ACE inhibitors, NSAIDs). The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be monitored in patients at risk.

Gastrointestinal

FRAXIPARINE(r) should be used with caution in patients with/or a history of gastrointestinal ulceration.

Hematologic

Hemorrhage

Bleeding may occur in conjunction with unfractionated heparin or low molecular weight heparin use. As with other anticoagulants, FRAXIPARINE(r) should be used with extreme caution in patients at increased risk of hemorrhage. Bleeding can occur at any site during therapy with FRAXIPARINE(r). An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site (see ADVERSE REACTIONS, Bleeding). In the prophylaxis or treatment of venous thromboembolic disorders and in the prevention of clotting during hemodialysis, the concomitant use of aspirin, other salicylates, non-steroidal anti-inflammatory drugs, and anti-platelet agents is not recommended, as they may increase the risk of bleeding. Where such combinations cannot be avoided, careful clinical and biological monitoring should be undertaken. In clinical studies for the treatment of unstable angina and non-Q wave myocardial infarction, FRAXIPARINE(r) was administered in combination with up to 325 mg aspirin per day (see DOSAGE AND ADMINISTRATION).

Thrombocytopenia

Rare cases of thrombocytopenia, occasionally severe, have been reported, which may be associated with arterial or venous thrombosis. Such diagnosis should be considered in the following situations:

• thrombocytopenia

• any significant reduction in platelet level compared with baseline value

• worsening of the initial thrombosis while on therapy

• thrombosis occurring on treatment

• disseminated intra-vascular coagulation.

In this event, FRAXIPARINE(r) treatment must be discontinued. These effects are probably of an immuno-allergic nature and in the case of a first treatment are reported mainly between the 5th and the 21st day of therapy, but may occur much earlier if there is a history of heparin-related thrombocytopenia. Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAXIPARINE(r). Its incidence is unknown at present. When thrombocytopenia occurs with heparin (either standard or low molecular weight heparin), substitution with a different antithrombotic class should be considered. Cases of initial thrombocytopenia continuing after substitution of nadroparin with a different anti-thrombotic class have been reported. In vitro platelet aggregation tests are only of limited value in the diagnosis of heparin- induced thrombocytopenia.

Platelets

platelet counts should be determined prior to the commencement of therapy with FRAXIPARINE(r) and subsequently, twice weekly for the duration of therapy.

Because of the possibility of heparin-induced thrombocytopenia,

Caution is recommended when administering FRAXIPARINE(r) to patients with congenital or drug-induced thrombocytopenia, or platelet defects. During FRAXIPARINE(r) administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/mL). A positive or indeterminate result obtained from in vitro tests for antiplatelet antibody in the presence of FRAXIPARINE(r) or other low molecular weight heparins and/or heparin would contraindicate FRAXIPARINE(r).

Hepatic/Biliary/Pancreatic

FRAXIPARINE(r) should be used with caution in patients with hepatic insufficiency. There have been no studies conducted in patients with hepatic insufficiency.

Peri-Operative Considerations

Spinal/Epidural Hematomas

FRAXIPARINE(r) should only be used

There have been cases of intra-spinal hematomas with the concurrent use of low molecular weight heparins and spinal/epidural anaesthesia resulting in long-term or permanent paralysis. The risk of these events may be higher with the use of post- operative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis: nonsteroidal anti-inflammatory drugs (NSAIDS), platelet inhibitors, or other drugs affecting coagulation. The risk also appears to be increased by traumatic or repeated epidural or spinal procedure.

concurrently with spinal/epidural anaesthesia when the therapeutic benefits to the patients outweigh the possible risks (also see CONTRAINDICATIONS).

When used concurrently, no spinal invasion should be performed for 12 hours following the last dose of FRAXIPARINE(r), and the next dose should be held until at least 2 hours after the anaesthesia procedure. The same rules apply to the withdrawal or manipulation of the catheter. Careful vigilance for signs and symptoms of neurologic impairment is recommended with urgent diagnosis and treatment, if signs occur (see ADVERSE REACTIONS).

Use in Knee Surgery

The risk of bleeding in knee surgery patients receiving low molecular weight heparins may be greater than in other orthopaedic surgical procedures. It should be noted that hemarthrosis is a serious complication of knee surgery. The frequency of bleeding events observed with FRAXIPARINE(r) in orthopaedic surgery patients is derived from clinical trials primarily in hip replacement surgery patients. The physician should weigh the potential risks with the potential benefits to the patient in determining whether to administer a low molecular weight heparin in this patient population.

Selection of General Surgery Patients

Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, age 60 years or above.

Renal

FRAXIPARINE(r) should be used with caution in patients with renal insufficiency. Reduced doses should be considered in patients with moderate to severe renal insufficiency receiving FRAXIPARINE(r) for thromboprophylaxis, and in patients with moderate renal insufficiency receiving FRAXIPARINE(r) for the treatment of thromboembolic disorders, angina and non-Q wave myocardial infarction (see CONTRAINDICATIONS, ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal Insufficiency). Nadroparin is known to be mainly excreted by the kidney, which results in increased nadroparin exposure in patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics - Renal Insufficiency). 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 (see DOSAGE AND ADMINISTRATION). Patients with impaired renal function should be carefully monitored because half-life for anti-Xa activity after administration of low molecular weight heparin may be prolonged in this patient population (see DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women:

Teratogenic Effects: Studies in animals have not shown any teratogenic or fetotoxic effects. However, there is only limited clinical data concerning transplacental passage of nadroparin in pregnant women. As with other low molecular weight heparins, FRAXIPARINE(r) should not be used in pregnant women unless the therapeutic benefits to the patients outweigh the possible risks. There have been reports of congenital anomalies in infants born to women who received LMWHs during pregnancy, including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia and cardiac defects. A causal relationship has not been established nor has the incidence been shown to be higher than in the general population. Non-teratogenic Effects: There have been post-marketing reports of fetal death when pregnant women received LMWHs. Causality for these cases has not been established. Pregnant women receiving anticoagulants, including FRAXIPARINE(r), are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving FRAXIPARINE(r) should be carefully monitored. Pregnant women and women of child-bearing potential should be informed of the potential hazard to the fetus and the mother if FRAXIPARINE(r) is administered during pregnancy. There are also post-marketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving low molecular weight heparins for thromboprophylaxis. These events led to maternal death or surgical interventions. Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of thromboembolism. An incidence of thromboembolism approaching 30% has been reported in these patients, in some cases even with apparent adequate anticoagulation at treatment doses of low molecular weight heparins or unfractionated heparin. Any attempt to anticoagulate such patients should normally only be undertaken by medical practitioners with documented expertise and experience in this clinical area. Nursing Women: It is not known whether nadroparin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FRAXIPARINE(r) is administered to nursing women.

Pediatrics (<18 years of age): (r)

The safety and effectiveness of FRAXIPARINE

in children has not been established

Geriatrics (> 65 years of age):

Geriatric patients receiving low molecular weight heparins are at increased risk of bleeding. Careful attention to dosing, and concomitant medications, especially anti-platelet preparations, is advised. Close monitoring of elderly patients with low body weight (e.g. < 45 kg) and those predisposed to decreased renal function is recommended.

Caution should be exercised when FRAXIPARINE(r) is administered in the following situations as they may be associated with an increased risk of bleeding:

• hepatic failure

• renal insufficiency

• severe arterial hypertension

• history of peptic ulcer 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

Monitoring and Laboratory Tests

Since FRAXIPARINE(r) use may be associated with a rise in hepatic transaminases, this observation should be considered when liver function tests are assessed (see ADVERSE REACTIONS, Hepatic/Biliary). Nadroparin has only a moderate prolonging effect on clotting time assays such as APTT or thrombin time. For lab monitoring of effect, anti-Xa methods are recommended. Clinically meaningful prolongation of APTT during hemodialysis or treatment of acute deep vein thrombophlebitis with FRAXIPARINE(r) should only be used as an indication of overdosage. Dose increases aimed at prolonging APTT to the same extent as with unfractionated heparin could cause overdose and bleeding. FRAXIPARINE(r) is administered subcutaneously, and therefore, the individual patient's anti-factor Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous intravenous infusion throughout the entire dosing interval. The peak plasma anti-factor Xa level occurs approximately 4 hours after subcutaneous administration. The peak level following a dose of 171 anti-Xa IU/kg is to 1.8 IU/mL and following a dose of 86 anti-Xa IU/kg is 0.5 to 1.1 IU/mL. The steady state level is attained by Day 6. FRAXIPARINE(r) should be administered as directed (see DOSAGE AND ADMINISTRATION). As with all antithrombotic agents, there is a risk of systemic bleeding with FRAXIPARINE(r) administration. Care should be taken with FRAXIPARINE(r) use in high dose treatment of newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and anti- factor Xa determinations. With normal prophylactic doses, FRAXIPARINE(r) does not modify global clotting tests of activated partial thromboplastin (APTT), prothrombin time (PT) and thrombin clotting time (TT). Therefore, treatment can not be monitored with these tests. At higher doses, increases in APTT and ACT may occur. Increases in APTT and ACT are not linearly correlated with increasing nadroparin antithrombotic activity and therefore are unsuitable and unreliable for monitoring FRAXIPARINE(r) activity.

DRUG INTERACTIONS

Drug-Drug Interactions

FRAXIPARINE(r) (nadroparin calcium) and FRAXIPARINE(r) FORTE should be used with caution in patients receiving oral anticoagulants, dextrans, platelet inhibitors and thrombolytic agents because of increased risk of bleeding. Aspirin, unless contraindicated, is recommended in patients treated for unstable angina and/or non-Q wave myocardial infarction as concomitant therapy (see DOSAGE AND ADMINISTRATION).

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

See WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Testing.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Thromboprophylaxis in general surgery

(FRAXIPARINE(r) (nadroparin calcium) 9,500 anti-Xa IU/mL)

Single daily s.c. injections of 2,850 anti-Xa IU (0.3 mL): The first dose should be given 2 to 4 hours before surgery. Treatment should continue for at least 7 days. In all cases, prophylaxis should continue throughout the risk period and at least until the patient is actively ambulant or is no longer at risk of deep vein thrombosis.

Thromboprophylaxis in hip replacement surgery (FRAXIPARINE(r) (nadroparin calcium) 9,500 anti-Xa IU/mL)

Single daily s.c. doses should be adjusted according to the patient's body weight, as follows:

• 38 anti-Xa IU/kg administered 12 hours before surgery (if in the opinion of the physician the potential benefits outweigh the potential risks),

• 38 anti-Xa IU/kg administered 12 hours after the end of surgery,

• 38 anti-Xa IU/kg re-administered on a daily basis, up to and including post-operative Day 3,

• 57 anti-Xa IU/kg administered as of post-operative Day 4.

Treatment should continue for at least 10 days and should continue in all cases throughout the risk period and at least until the patient is actively ambulant. As an example, the following dosages as a function of patient body weight are recommended:

Table 5

Treatment of deep vein thrombosis

The following dosage is recommended: 171 anti-Xa IU/kg s.c. once daily. The expected plasma anti-Xa levels during s.c. treatment would be <0.2 anti-Xa IU/mL before injection and 1.2 to 1.8 anti-Xa IU/mL 3- 4 hours post-injection. Monitoring of the activity of nadroparin is performed by a functional assay for anti-Xa 3-4 hours post-injection. The maximum daily dose should not exceed 17,100 IU. As an example, the following dosages as a function of patient body weight are recommended:

Table 6

For patients at increased risk of bleeding, a dose of 86 anti-Xa IU/kg s.c. twice daily is recommended. The expected plasma anti-Xa levels during s.c. treatment would be 0.2- 0.4 anti-Xa IU/mL before injection and 0.5 to 1.1 anti-Xa IU/mL 3-4 hours post- injection. Monitoring of the activity of nadroparin is performed by a functional assay for anti-Xa 3-4 hours post-injection. As an example, the following dosages as a function of patient body weight are recommended:

Table 7

Monitoring of the activity of nadroparin is performed by a functional assay for anti-Xa 3- 4 hours post-injection. Concomitant therapy with vitamin K antagonists is usually started immediately. FRAXIPARINE(r) therapy should continue until the INR ratio is within the therapeutic range, usually at least 5 days.

Treatment of unstable angina and non-Q wave myocardial infarction (FRAXIPARINE(r) 9,500 anti-Xa IU/mL)

FRAXIPARINE(r) should be given subcutaneously twice daily (every 12 hours) in combination with ASA up to 325 mg per day. The initial dose should be given as an IV bolus of 86 anti-Xa IU/kg followed by subcutaneous injections of 86 anti- Xa IU/kg. The expected plasma anti-Xa levels during subcutaneous treatment would be < 0.4 anti-Xa IU/mL before injection and < 1.2 anti-Xa IU/mL 3-4 hours after injection. The usual treatment duration is 6 days with a dose adjusted to body weight as shown below:

Table 8 Treatment of unstable angina and non-Q wave myocardial infarction

Prevention of clotting during hemodialysis (FRAXIPARINE(r) 9,500 anti-Xa/mL)

Only patients with chronic renal failure, without other risk factors for hemorrhage participated in the clinical trial, and the following dosage recommendations are for that patient population:

• Optimisation of dosage is required for each individual patient (different clotting stimuli are produced by different dialysis circuits and membranes, and there is inter-patient variability).

• In patients with no risk of hemorrhage: single dose of approximately 65 anti-Xa IU/kg into the arterial line at the start of each session, for a session lasting 4 hours or less. This dose normally produces plasma anti-Xa levels in the range 0.5 -1.0 anti-Xa IU /mL.

• An additional dose may be given during sessions lasting longer than 4 hours.

• Doses in subsequent dialysis sessions should be adjusted as required.

As an example, the following dosages as a function of patient body weight are recommended:

Table 9

In patients at higher risk of hemorrhage: dialysis sessions may be carried out using halved doses. An additional smaller dose may be given during dialysis for sessions lasting longer than 4 hours. The dose in subsequent dialysis sessions should be adjusted as necessary to achieve plasma levels within the range of 0.2 - 0.4 anti-Xa IU/mL.

Dosing Considerations

Use in Renal Insufficiency

The risk of hemorrhage increases with renal failure. The benefit and risk should be carefully assessed before the administration of FRAXIPARINE(r) to patients with renal insufficiency. The administration of LMWHs to patients with renal insufficiency has been shown to result in prolongation of anti-Xa activity, especially in those with severe renal insufficiency (creatinine clearance < 30 mL/min), leading to increased risk of bleeding (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). All patients with renal insufficiency treated with LMWHs must be continuously monitored. The dose must be individualized and adjusted (see Tables 5, 6, 7 and 8 for recommended doses as a function of body weight). Circulating anti-factor Xa activity must be closely monitored to adjust the dose administered.

Prophylaxis of thromboembolic disorders

Dose reduction is not required in patients with mild renal insufficiency (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 hemorrhage. If a dose reduction is considered appropriate by the prescribing physician, taking into account the individual risk factors for hemorrhage 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 ACTION AND CLINICAL PHARMACOLOGY, 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 ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Treatment of thromboembolic disorders, unstable angina and non-Q wave myocardial infarction 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 hemorrhage. If a dose reduction is considered appropriate by the prescribing physician, taking into account the individual risk factors for hemorrhage 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 ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics). FRAXIPARINE(r) is contraindicated in patients with severe renal insufficiency (see WARNINGS AND PRECAUTIONS, and ACTIONS AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Hepatic Insufficiency

There have been no studies conducted in patients with hepatic insufficiency.

Administration

FRAXIPARINE(r) (nadroparin calcium) and FRAXIPARINE(r) FORTE are sterile solutions for subcutaneous injection into the anterolateral abdominal wall, with subsequent doses to be administered alternately, on the right and left sides of the abdominal wall. The thigh may be used as an alternative site. The needle should be fully inserted; perpendicularly into a pinched-up fold of skin. FRAXIPARINE(r) and FRAXIPARINE(r) FORTE injection should be visually inspected for any particulate matter and discoloration before use. If any visual change is noted, the solution must be discarded.

Care should be taken to ensure use of the correct formulation, either FRAXIPARINE(r) (9,500 anti-Xa IU/mL) or FRAXIPARINE(r) FORTE (19,000 anti-

Xa IU/mL), when using these products.

Given the high degree of bioavailability of nadroparin calcium by the subcutaneous route (approximately 98%), the use of the intravascular route is not necessary except for

FRAXIPARINE(r) and FRAXIPARINE(r) FORTE must not be administered intramuscularly (see WARNINGS AND PRECAUTIONS).

hemodialysis.

OVERDOSAGE

Accidental overdosage following administration of FRAXIPARINE(r) (nadroparin calcium) may lead to hemorrhagic complications. FRAXIPARINE(r) should be immediately discontinued, at least temporarily, in cases of significant excess dosage. In more serious cases, protamine should be administered. The anticoagulant effect of FRAXIPARINE(r) is inhibited by protamine. This effect may be largely neutralised by slow intravenous injection of protamine sulfate. The dose of protamine should be equal to the dose of FRAXIPARINE(r) used, on a mg to mg basis. A second infusion of 0.5 mg protamine per 1 mg FRAXIPARINE(r) may be administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged. However, even with higher doses of protamine, the APTT may remain prolonged to a greater extent than usually seen with unfractionated heparin. Anti-factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation equipment and treatment of anaphylactic shock are readily available.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

FRAXIPARINE(r) (nadroparin calcium) is a low molecular weight heparin (LMWH). It is a heterogeneous mixture of sulphated polysaccharide glycosaminoglycan chains. Nadroparin calcium is obtained by the depolymerisation of porcine mucosal sodium heparin, followed by extraction/purification and conversion to the calcium salt. The mean molecular weight of nadroparin is approximately 4,300 daltons; 75-95% of the glycosaminoglycan chains have molecular weights in the 2,000 to 8,000 dalton range. Nadroparin is composed of molecules with and without a specifically characterized pentasaccharide, which is the specific site for high affinity binding to the plasma protein antithrombin III (ATIII). This binding leads to an accelerated inhibition of factor Xa, which accounts for the majority of the antithrombotic effect of nadroparin. Other properties that are not dependent upon ATIII may contribute to the antithrombotic activity as well, but the relative contribution of these actions has not been determined. These include stimulation of tissue factor pathway inhibitor TFPI, activation of fibrinolysis via direct release of tissue plasminogen activator from endothelial cells, and modification of hemorreological parameters (decreased blood viscosity and increased platelet and granulocyte membrane fluidity.)

Pharmacodynamics

The pharmacodynamic effect of nadroparin appears thus to be primarily related to its anti-Xa activity at approximately 90 IU/mg (range 85 to 110 IU/mg), with anti-IIa activity at approximately 27 IU/mg. The ratio of anti-Xa to anti-IIa activity for nadroparin is about 3.5:1, whereas it is 1:1 for heparin. The presence of nadroparin is not measured directly in the blood stream, but rather its effect on clotting mechanisms, e.g. level of anti-Xa activity.

Pharmacokinetics

The pharmacokinetics of nadroparin have been assessed by measuring anti-Xa activity.

Table 10 Summary of Mean (SD) Pharmacokinetics in Healthy Volunteers

Absorption:

A linear relationship between nadroparin dose and plasma anti-Xa activity was observed in the pharmacokinetic studies. Peak concentrations of nadroparin are reached 3-6 hours after subcutaneous injection. Steady state is attained by Day 6. Following subcutaneous injection, the bioavailability of nadroparin is about 89%.

Maximal prolongation of APTT and thrombin time occurs at approximately 4 hours. After subcutaneous administration of prophylactic doses (2850 IU) of nadroparin in healthy volunteers, maximum APTT and thrombin time were increased by a negligible 2 seconds at 4 hours, and APTT returned to baseline by 8 hours. After administration of treatment doses, APTT was only slightly prolonged (1.2 times the control value; with unfractionated heparin, APTT values at curative dosage are aimed at obtaining 1.5- 2.5 times the control value).

Distribution:

The mean volume of distribution in humans is estimated to be 3.59 L.

Metabolism:

The pharmacokinetics of nadroparin are linear over a wide range of doses. The mean half-life in healthy volunteers ranges between approximately 3.5 hours and

11.2 hours after subcutaneous administration.

Elimination:

Although anti-Xa activity persists for at least 18 hours after injection, the elimination half-life is approximately 3.5 hours. Elimination of nadroparin is primarily by nonsaturable renal mechanisms, although recent data suggest that hepatic metabolism may occur prior to renal elimination.

Special Populations and Conditions

Pediatrics: The safety and effectiveness of FRAXIPARINE(r) in children has not been established.

Geriatrics:

In a small study in geriatric male and female subjects with normal renal function (n=6 per sex, age range 59-69), the mean anti-Xa peak and total exposure was 22 and 45% higher, respectively, than that observed in a similar study in healthy volunteers. The mean half-life values for anti-Xa activity were similar between the two studies. Renal function generally decreases with age so elimination of nadroparin anti-Xa activity may be slower in geriatric subjects (see Pharmacokinetics, Renal Insufficiency below). The possibility of renal insufficiency in this age group must be considered and the dosage adjusted accordingly (see WARNINGS AND PRECAUTIONS).

Geriatric patients receiving low molecular weight heparins are at increased risk of bleeding. Careful attention to dosing and concomitant medications, especially anti- platelet preparations, is advised. Close monitoring of elderly patients with low body weight (e.g. < 45 kg) and those predisposed to decreased renal function is recommended (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency:

In a clinical study investigating the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal insufficiency (creatinine clearance values < 10 mL/min, 10-20 mL/min, 30-50 mL/min and 75-

200 mL/min), a correlation was found between nadroparin clearance and the creatinine clearance. In patients with moderate renal impairment (creatinine clearance 36-43 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 insufficiency (creatinine clearance 10-20 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 hemodialysis, both mean AUC and half-life were increased by 62 and 65% respectively compared with healthy volunteers. Plasma clearance in hemodialysis patients with severe renal impairment was decreased to 67% of that observed in patients with normal renal function (see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS).

Hepatic Insufficiency

: The effects of hepatic insufficiency on the pharmacokinetics of nadroparin have not been studied. Because hepatic insufficiency is associated with an increased risk of bleeding, caution should be observed when administering nadroparin to such patients (see WARNINGS AND PRECAUTIONS).

Gender

: In two studies of 12 healthy young or geriatric male and female volunteers, there was no clinically significant sex difference in the pharmacokinetics of nadroparin.

Race

: The effect of race on the pharmacokinetics of nadroparin has not been studied.

Genetic polymorphism

: The effect of genetic polymorphisms on the pharmacokinetics of nadroparin has not been studied.

STORAGE AND STABILITY

Store between 15o to 30o C; do not freeze. Do not refrigerate, as cold injections may be painful. Syringes are intended for single use only - discard unused portion of each syringe. Do not mix with other preparations or re-dispense.

SPECIAL HANDLING INSTRUCTIONS

Keep out of reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

FRAXIPARINE(r) (nadroparin calcium, 9,500 anti-Xa IU/mL) is available in single dose, disposable prefilled glass syringes of:

FRAXIPARINE(r) FORTE (nadroparin calcium, 19,000 anti-Xa IU/mL) is available in single dose, disposable prefilled glass syringes of:

FRAXIPARINE(r) 0.2 mL *, 0.3 mL and 0.4 mL syringes are intended for administration of fixed dosages; FRAXIPARINE(r) and FRAXIPARINE(r) FORTE 0.6 mL, 0.8 mL and mL syringes are graduated so that adjusted dosages can be given.

Cartons contain 10 prefilled glass syringes.

*0.2 mL syringe not available in Canada

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Nadroparin calcium Chemical name: Fragments of the glycosaminoglycan, heparin. WHO Definition of nadroparin calcium: Calcium salt depolymerised heparin obtained by fragmentation using nitrous acid of heparin obtained from porcine intestinal mucus. Most of the compounds have a 2- O-sulpho-a-L-idopyranosuronic acid at the non-reducing end and a 6-O-sulpho-2-5-anhydro-D-mannitol structure at the reducing end of their chains. There are approximately 2.1 sulphate groups per disaccharide unit. Molecular formula and molecular mass: Comprises glycosaminoglycan heparin fragments of varying molecular mass. Mean molecular weight of approximately 4300 daltons; 75-95% of the glycosaminoglycan chains have molecular weights in the 2,000 to 8,000 daltons range. Structural formula:

C OO ( 1 / 2 C a )

CH 2 OR 1

COO ( 1 / 2 C a )

CH 2 OR

O O O

O

O O O

HO

HO OR

R1 O

NHR 2 HO OR 1 HO

CH 2 OH

R = S O 3 (1 /2 Ca)

R 1 = H o r S O 3 ( 1 / 2 C a )

R2 = H o r S O 3 ( 1 / 2 C a ) o r CO - CH 3

n = 2 t o 1 6 ( f o r a b o u t 9 0 % o f t h e c o mp o n e n t s )

Physicochemical properties

Description: White or almost white hygroscopic powder Solubilities: Very soluble in water, 0.1N hydrochloric acid. Practically insoluble in methanol, methylene chloride, ethanol, dimethylformamide, acetone, ethyl acetate. pH: Nadroparin calcium: From 5.5 to 8.0 (1.0 percent aqueous solution) Composition FRAXIPARINE(r): Nadroparin calcium 9500 anti-Xa IU/mL, WFI qs.ad 1 L, hydrochloric acid and/or calcium hydroxide for pH adjustment (pH 5.5 to 7.5). FRAXIPARINE(r) FORTE: Nadroparin calcium 19,000 anti-Xa IU/mL, WFI qs.ad 1 mL, hydrochloric acid and/or calcium hydroxide for pH adjustment (pH 4.5 to 7.5).

CLINICAL TRIALS PROPHYLAXIS

Prophylaxis of Thromboembolic Disorders in General Surgery (Deep Vein Thrombosis and Pulmonary Embolism)

Prophylaxis of thromboembolic disorders in general surgery was the subject of a single pivotal study (IVB1) which included 1909 patients. Patients ranged in age from 23 to 88 years (mean age 61 years) with 52% men and 48% women.

Table 11 Summary of patient demographics for clinical trials in the prophylaxis of thromboembolic disorders in general surgery

This pivotal study showed FRAXIPARINE(r) prophylaxis to be associated with a statistically significant lower frequency of deep vein thrombosis (DVT) (27/960, 2.8%) than UH (42/936, 4.5%) prophylaxis (p < 0.05). The difference was particularly marked with regard to proximal thrombosis, generally considered the most important likely precursor of pulmonary embolism (PE), 4 (0.4%) of FRAXIPARINE(r) patients compared with 13 (1.4%) of unfractionated heparin (UH) patients, (p < 0.05). In the pivotal study, there were 2 PEs in the FRAXIPARINE(r) group compared with 5 in the UH group. No differences were observed between treatment groups with respect to hemorrhagic complications. Intra- and post-operative blood loss, the number of hematomas, and the frequency of volume transfusions were similar in both groups. This trial demonstrated that a single daily subcutaneous injection of FRAXIPARINE(r) demonstrated a significant reduction in DVT events in patients receiving FRAXIPARINE(r) (0.3 mL daily) compared to UH, with comparable tolerability (see ADVERSE EVENTS).

Table 12 Efficacy Results of study in the prophylaxis of thromboembolic events following general surgery

1. FRAXIPARINE

was initiated 2 hours pre-surgery and 8 hours post-surgery; administered once daily for 7

days thereafter. Unfractionated calcium heparin was initiated 2 hours pre-surgery and every 8 hours post- surgery up to 7 days.

p value = 0.034

p value < 0.05

p value not available

Prophylaxis of Thromboembolic Disorders in Orthopedic Surgery (Deep Vein Thrombosis and Pulmonary Embolism)

Study IVB8 included patients over 40 years of age (range 33-88) with 45% men & 55% women undergoing surgery for total hip replacement (THR). THR is a very common and high-risk procedure. Patients who underwent spinal anesthesia were excluded from this study. A total of 409 patients were treated for 10 +- 1 days.

Table 13 Summary of patient demographics for clinical trials in the prophylaxis of thromboembolic disorders in orthopedic surgery

The overall incidence of DVT was similar in the FRAXIPARINE(r) (13%) and UH (16%) efficacy evaluable treatment groups. However, the incidence of proximal DVT (the most likely precursor of PE) was significantly lower in the FRAXIPARINE(r) efficacy evaluable group (3%) than in the UH group (13%) (p < 0.001). In addition, the incidence of PE was lower in the FRAXIPARINE(r) group (0.5%, 1/198) than in the UH group (2%, 4/199 including 1 fatal). This study provides good evidence that FRAXIPARINE(r) administered once daily is more effective than unfractionated heparin given three times daily, in the prevention of proximal DVT after total hip replacement surgery and does not require the dose to be adjusted according to any coagulation test. There was a lower incidence overall of DVT and PE in the FRAXIPARINE(r) group, although the difference was not statistically significant. There were more PEs in the UH group including one fatality. In the populations studied, FRAXIPARINE(r) appears to be as well tolerated as unfractionated heparin. The number of major events did not differ significantly between the two groups although the incidence of hemorrhages and thrombocytopenias were lower in the FRAXIPARINE(r) group (see ADVERSE EVENTS).

Table 14 Efficacy Results of study in the prophylaxis of thromboembolic events following orthopedic surgery

1. FRAXIPARINE(r) was initiated at 100 ICU/kg 12 hrs pre -surgery then once daily to Day 3; 150 ICU/kg daily from Day 4 to Day 10 +-1. Unfractionated heparin was initiated 10-24 hours pre-surgery, 2nd injection 2 hours pre-surgery APTT adjusted, then APTT adjusted days 1 to 10 +- 1 t.i.d.

2. p value < 0.001

3. p value = 0.45

4. One case of fatal PE occurred in the unfractionated heparin group

5. p value < 0.37

TREATMENT

Treatment of Thromboembolic Disorders (Deep Vein Thrombosis and Pulmonary Embolism)

The objective of the pivotal studies was to treat moderate/severe PE or lower limb proximal DVT of medical or surgical origin. In study IVB13 the mean ages of patients in the 4 treatment groups ranged from 55 to 65 years, and in pivotal studies IVB11 and IVB12 the mean age of patients was greater than 60 years.

Table 15 Summary of patient demographics for clinical trials in the treatment of pulmonary embolism and deep vein thrombosis

In the dose finding study, IVB13, both lower FRAXIPARINE(r) doses (200 ICU/kg b.i.d. and 200 ICU/kg t.i.d.) and UH produced significant change in percent pulmonary obstruction and in Miller's Index during 8 days of treatment (p < 0.0001 for each parameter). The evolution of clinical signs associated with PE was similar in these three treatment groups. This study demonstrated that FRAXIPARINE(r) is as effective as unfractionated heparin in the treatment of PE, and that doses of 300 ICU t.i.d. are too high in these patients. Patients in the 300 ICU t.i.d. treatment group were discontinued due to hemorrhagic complications. In the two Phase III pivotal studies (IVB11 and IVB12) efficacy of treatment was assessed by comparison of venographic Arnesen and Marder scores obtained on D10 and D0. In both studies, scores in FRAXIPARINE(r) and UH treatment groups were improved and patients in the FRAXIPARINE(r) group had a significantly greater improvement in score than patients in the UH group (p<0.05) In study IVB11, results were analyzed separately for medical and surgical patients; the reduction in score was significant in the medical sub-group, but did not reach significance in the surgical sub-group, probably due to the small number of patients (n = 38). When proximal locations alone were considered the improvement in scores was significant for FRAXIPARINE(r) (p = 0.0001) but not for UH. In study IVB12, more patients in the UH group (12/85, 14%) suffered thromboembolic complications than in the FRAXIPARINE(r) group (6/85, 7%), but this did not reach statistical significance. There was a significant improvement in Marder scores in the FRAXIPARINE(r) group, superior to that in the UH group (p = < 0.05), and fewer patients on FRAXIPARINE(r) had defects on isotope lung scan (p = < 0.05). Data from these three pivotal studies (IVB11, IVB12, IVB13) suggest that mortality is similar among patients treated with FRAXIPARINE(r) and patients treated with unfractionated heparin. There was a trend towards a reduction in PE with FRAXIPARINE(r) in all 3 studies, but the studies were too small to detect any statistically significant changes. The incidence of major hemorrhage is lower among patients treated with FRAXIPARINE(r) (200 ICU/kg b.i.d.) than among patients treated with unfractionated heparin (see ADVERSE EVENTS).

Treatment of Unstable Angina and Non-Q Wave Myocardial Infarction

In study P2628, 3468 patients participated in the multi-centre, parallel-group, double- blind, comparative study of subcutaneous FRAXIPARINE(r) therapy for 6 +- 2 days or 14 days versus intravenous unfractionated heparin. Patients ranged in age from 26-97 years and presented with unstable angina or non-Q wave myocardial infarction. The main efficacy endpoint was a combined endpoint of cardiac death, myocardial infarction and recurrent or refractory angina at Day 14.

Table 16 Summary of patient demographics for clinical trials in the treatment of unstable angina and non-Q wave myocardial infarction

No statistically significant difference could be found in the incidence of the main combined endpoint of cardiac death, myocardial infarction, and refractory or recurrent angina at Day 14 between UH group (18.1%), FRAXIPARINE(r) 6-day group (17.8%), and FRAXIPARINE(r) 14-day group (20.0%) (p = 0.33). No additional benefit was observed when prolonging the FRAXIPARINE(r) treatment up to 14 days. There was no statistically significant difference among the three groups in any of the other secondary endpoints (cardiac death, fatal and non-fatal myocardial infraction, combined outcome of death from any cause and non-fatal MI, refractory angina, recurrent angina, revascularization procedures or emergency revascularization). The comparison of safety data at Day 14 between the FRAXIPARINE(r) 6-day group and UH showed a similar incidence of major hemorrhages and a slightly lower incidence of SAEs for which a relationship with the study drug was not excluded (see ADVERSE EVENTS). There were statistically significantly more major hemorrhages in the nadroparin 6-Day group at both Day 14 and Month 3. There were statistically significantly more adverse events in the Body System "Platelet, Bleeding, and Clotting disorders" in the FRAXIPARINE(r) 14-day group than in either of the short-term treatments (p < 0.001) in both cases.

Efficacy of FRAXIPARINE(r) Injection in Unstable Angina and Non-Q Wave Myocardial Infarction

Table 17 Summary of Combined Cardiac Events2

1. FRAXIPARINE(r) 86 IU/kg iv bolus, then 86 IU/kg sc every 12 hours, for either 6 +- 2 days or 14 days; UH 5000 IU iv bolus, then initial iv infusion of 1250 IU/hr, then adjusted to APTT for 6 +- 2 days

2. The primary endpoint of combined cardiac events included cardiac death, myocardial infarction, refractory angina or recurrence of unstable angina

3. Absolute difference (between FRAXIPARINE(r) 6 days and UH) and 95% CI in combined cardiac events

4. Absolute difference (between FRAXIPARINE(r) 14 days and UH) and 95% CI in combined cardiac events

PREVENTION

Prevention of Clotting During Hemodialysis

Blood clotting in the extracorporeal circulation (ECC) can be prevented by the administration of standard heparin with the initial bolus dose usually has to be supplemented by additional bolus doses or continuous infusion. The longer half-life of nadroparin means that this disadvantage may be overcome. Prevention of clotting during hemodialysis was the subject of two pivotal studies including a total of 109 patients. The nature of the patient populations in the studies IVB15 and IVB16 were similar and included patients with stable, chronic renal failure who were undergoing chronic, intermittent hemodialysis. The mean ages of the populations were similar, 55 years and 54 years in IVB15 and IVB16 respectively. In these studies the primary efficacy criteria were the absence of clots in the extracorporeal circulation and the quality of blood restitution.

Table 18 Summary of patient demographics for clinical trials in the prevention of clotting during hemodialysis

Dose-ranging study IVB15 assessed the appearance of clots in the extracorporeal circulation (filter, bubble trap and line) expressing the qualitative degree of blood restitution. The lowest dose of nadroparin (5000 ICU) resulted in poor outcome and blood restitution while the 10 000 and 15 000 anti-Xa ICU doses, like unfractionated heparin, were associated with satisfactory outcomes. The 15 000 ICU dose appeared to reduce fibrin formation. This study supports the dosage of at least 10 000 ICU given as a single bolus at the start of a 4 hour dialysis session, irrespective of the patient's weight. In study IVB16, similar numbers of patients in the FRAXIPARINE(r) and UH treatment groups completed the 26-week study without experiencing clinically relevant clotting or bleeding events. The quality of blood restitution at the session of weeks 4, 13 and 26 was similar in both treatment groups. Comparison of the treatment groups at weeks 4, 13 and 26 for visible clots in the extracorporeal circuit showed no differences for the individual centres. However, for the compiled data at week 13, more patients on FRAXIPARINE(r) than on unfractionated heparin had clots (p =0.04). There were no significant differences in quality of restitution between the hematocrit strata. This suggests that FRAXIPARINE(r), at the doses used, is as effective as unfractionated heparin at maintaining the quality of restitution in the extracorporeal circulation. Data from these two studies suggest that a single bolus dose of FRAXIPARINE(r) administered before a hemodialysis session is an effective and well tolerated antithrombotic treatment. For the major safety events of death, hemorrhage and thrombocytopenia, FRAXIPARINE(r) did not differ significantly from unfractionated heparin (see ADVERSE EVENTS). Doses must be adjusted to individual patient needs considering weight, hematocrit levels, type of dialysis membrane, the use of heparin to 'prime' the ECC, the session length, the hemorrhagic risk and former experience with UH.

DETAILED PHARMACOLOGY

Table 19

Table 19 (continued)

TOXICOLOGY

Acute toxicity

Median lethal dose (LD50) values of nadroparin after i.v. administration in the rat and rabbit are >1000 mg/kg in both males and females. The LD50 values of nadroparin after s.c. administration in the rat and rabbit are >1000 mg/kg and >200 mg/kg respectively. (Clinical dosages are less than 3 mg/kg/day.)

Chronic toxicity

Daily administration of s.c. nadroparin (2.5, 10 or 40 mg/kg/day) to rats over a 26 week period caused local hemorrhagic reaction in animals receiving >10 mg/kg/day. Changes in hematological and biochemical profiles were consistent with the pharmacological activity of nadroparin; there were no unexpected findings. There was no reduced calcium content of bones. The no effect dose was 2.5 mg/kg/day. In dogs given repeated s.c. doses of nadroparin (2.5, 10 or 40 mg/kg/day), large hematoma occurred in those receiving 40 mg/kg/day. In dogs given IV nadroparin for 26 weeks (5, 15 or 50 mg/kg/day), no significant toxicological events occurred; findings were similar to those for unfractionated heparin administration. An increase in liver weight was observed but it was without morphological change.

Reproduction studies

Daily s.c. doses of 0, 2.5, 10 and 40 mg/kg/day nadroparin were administered to rats. No effects on fertility or mating performance were observed. No treatment-related effects on development, fertility and reproductive performance of the F1 generation, or effects in F2 offspring were observed, other than reduced weight gain and delay in some development tests in offspring of dams treated with 40 mg/kg/day (equivalent to about 4500 IU/kg). At dose levels of nadroparin calcium producing signs of maternal toxicity (40 mg/kg/day), no teratogenic effects were found in rat or rabbit.

REFERENCES

1. Barradell LB, Buckley MM. Nadroparin calcium. A review of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disorders. Drugs 1992; 44(5):858-888.

2. Beguin S, Wielders S, Lormeau JC, Hemker HC. The mode of action of CY216 and CY222 in plasma. Thromb Haemost 1992; 67(1):33-41.

3. Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d'Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group. Thromb Haemost 1998; 79(5):897-901.

4. Clagett GP, Anderson FA, Jr., Heit J, Levine MN, Wheeler HB. Prevention of venous thromboembolism. Chest 1995; 108(4 Suppl):312S-334S.

5. Davis R, Faulds D. Nadroparin calcium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders. Drugs Aging 1997; 10(4):299-322.

6. German Hip Arthroplasty Trial (GHAT) Group. Prevention of deep vein thrombosis with low molecular-weight heparin in patients undergoing total hip replacement. A randomized trial. Arch Orthop Trauma Surg 1992; 111(2):110- 120.

7. Hirsh J, Siragusa S, Cosmi B, Ginsberg JS. Low molecular weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism. Thromb Haemost 1995; 74(1):360-363.

8. Steinbach G, Bosc C, Caraman PL, Azoulay E, Olry L, d'Azemar P et al. [Use in hemodialysis and hemofiltration of CY 216 (Fraxiparine) administered via intravenous bolus in patients with acute and chronic renal insufficiency with and without hemorrhagic risk]. Nephrologie 1990; 11(1):17-21.

9. Van Heereveld H, Laan R, Van Den HF, De Waal MM, Novakova I, Van De PL. Prevention of thrombosis with (low molecular weight) heparin in patients with rheumatoid arthritis after hip or knee replacement. British Journal of Rheumatology 1997; 36(suppl 1):188.

PART III: CONSUMER INFORMATION

PrFRAXIPARINE(r)

nadroparin calcium injection (9, 500 anti-Xa IU/mL)

FRAXIPARINE(r) FORTE

nadroparin calcium injection (19, 000 anti-Xa IU/mL)

This leaflet is part III of a three-part "Product Monograph" published when FRAXIPARINE(r) and FRAXIPARINE(r) FORTE was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about FRAXIPARINE(r) and FRAXIPARINE(r) FORTE. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

FRAXIPARINE(r) is used to prevent the blood from clotting in the wrong places after having surgery, during hemodialysis

and also to treat existing blood clots that are blocking blood vessels.

What it does:

FRAXIPARINE(r) is a type of medicine called low molecular weight heparin (LMWH). FRAXIPARINE(r) works by

delaying the action by which blood clots. This results in the blood remaining thin and prevents formation of clots which may become lodged in blood vessels. FRAXIPARINE(r) works by inhibiting the formation of thrombin in the body. Thrombin is a naturally occurring component of your blood that contributes to blood clotting.

What the medicinal ingredient is:

Nadroparin Calcium

What dosage forms it comes in:

FRAXIPARINE(r) (nadroparin calcium, 9,500 anti-Xa IU/mL) is available in single dose, disposable prefilled glass syringes of:

mL (ungraduated syringe) * 1,900 anti-Xa IU YellowmL (ungraduated syringe) 2,850 anti-Xa IU GreenmL (ungraduated syringe) 3,800 anti-Xa IU Orange

0.6 mL (graduated syringe) 5,700 anti-Xa IU Brown

0.8 mL (graduated syringe) 7,600 anti-Xa IU Green (Teal)

1.0 mL (graduated syringe) 9,500 anti-Xa IU Violet

FRAXIPARINE(r) FORTE (nadroparin calcium, 19,000 anti- Xa IU/mL) is available in single dose, disposable prefilled glass syringes of:

0.6 mL (graduated syringe) 11,400 anti-Xa lU Process Blue

0.8 mL (graduated syringe) 15,200 anti-Xa IU Magenta

1.0 mL (graduated syringe) 19,000 anti-Xa IU Reflex Blue

*0.2 mL syringe not available in Canada

When it should not be used:

It is necessary that you advise your doctor of any serious medical problems you have had or currently have, as these conditions could affect the action of FRAXIPARINE(r).

If you have had or currently suffer from any of the conditions listed below, it is necessary that you inform your doctor before starting treatment:

• Allergy to FRAXIPARINE(r) or any of its ingredients or to other low molecular weight heparins and/or heparin

• A history of thrombocytopenia (decrease in the number of platelets)

• Bacterial infection of the heart (bacterial endocarditis)

• Active bleeding or any other diseases that could involve an increased risk of bleeding

• A severe blood clotting disorder (hemorrhagic diathesis, hemophilia)

• Bleeding due to acute gastroduodenal ulcer (stomach or intestinal bleed/ulcer)

• A history of cerebral hemorrhage (bleeding in or against the brain)

• High blood pressure

• Disorders of the retina of the eye due to diabetes or bleeding

• Injuries and/or operations on the central nervous system (brain or spine), eyes or ears

• Severe kidney problems, unless you are receiving FRAXIPARINE(r) to prevent clots forming

WARNINGS AND PRECAUTIONS

Certain medications may increase the effect of FRAXIPARINE(r) on bleeding. Therefore, it is important for you to advise your doctor of all drugs that you are presently taking.

It is necessary that you follow the instructions of your doctor or nurse carefully when using FRAXIPARINE(r). Only give yourself the injections prescribed and do so for the entire time period specified by your doctor.

Do not take any drugs other than those prescribed by your doctor while you are taking FRAXIPARINE(r).

If you need to consult with another doctor or see your dentist, be absolutely sure to tell them that you are being treated with FRAXIPARINE(r).

FRAXIPARINE(r) should not be administered intramuscularly.

BEFORE you use FRAXIPARINE(r) talk to your doctor or pharmacist if you have had or currently have any of the conditions listed below:

Artificial heart valves

Heart disease, including angina and recent heart attack.

If you are taking any medications such as ASA (e.g., Aspirin(r)), or other drugs to reduce blood clotting such as warfarin or non-steroidal anti-inflammatory drugs (NSAIDS: drugs used to treat painful and/or inflammatory conditions of muscles or joints), including those that you buy without a prescription (see INTERACTIONS WITH THIS MEDICATION)

Any medical condition that increases your risk of bleeding (such as recent surgery or stomach ulcer)

Liver or kidney problems

If you have an allergy to latex

Pregnancy and Breast Feeding:

If you are pregnant or breast feeding, you should tell your doctor so that the possible risks to you and your child can be assessed.

To separate the packaged syringes, carefully fold the twin pack several times so that the syringes are back to back, then slowly, using even pressure, separate the two packaged syringes starting from the plunger end of the pack.

To remove the syringe from its plastic packaging, gently tear the top backing paper completely from the plastic tray (starting at the plunger end), then allow the syringe to roll onto the palm of your other hand (Figures 1 and 2).

Figure 1. Removal of backing strip from syringes

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with FRAXIPARINE(r) include: Other blood thinners (oral anticoagulants), platelet inhibitors, thrombolytic agents or ASA (e.g., Aspirin(r)). You should talk to your doctor or pharmacist if you are taking these medications.

Figure 2. Removal of syringe from packaging

PROPER USE OF THIS MEDICATION

Usual dose:

How FRAXIPARINE(r) is Given:

FRAXIPARINE(r) is a prescription drug and must be used as directed. It is administered as a subcutaneous (s.c.) injection, which means the injection is made just under the surface of the skin. While you are in the hospital, your doctor or nurse will give your first injection of FRAXIPARINE(r) within

24 hours of your operation.

It is possible that after you go home, you may need to continue your injections of FRAXIPARINE(r).

Instructions for self-injection of FRAXIPARINE(r):

Your doctor may want you to continue your FRAXIPARINE(r) injections at home for a few days. If so, a health professional will show you how to administer your FRAXIPARINE(r)

injections before you are released from hospital. It is essential

that you follow these instructions exactly. If you have questions, be sure you ask your doctor or nurse to provide the explanations you require.

Removal of Packaging

To avoid damaging the syringe presentation it is recommended that the following steps are followed.

FRAXIPARINE(r) and FRAXIPARINE(r) FORTE solution for injections should be visually inspected for any particles and discoloration before use. If any visual change is noted, the solution must be discarded.

Preparation of the Syringe for Subcutaneous Injection

Removal of the cap from the syringe needle (Figure 3)

Hold the syringe vertically (grey cap uppermost).

Hold the grey cap by its collar, and the syringe barrel in your other hand, then slowly rotate the syringe barrel, gently pulling downwards at the same time, until the needle is fully withdrawn from the cap.

Do not pull the cap upwards from the syringe as this could bend the needle.

Figure 3. Removal of cap from syringe needle

FRAXIPARINE(r) 0.2 mL, 0.3 mL and 0.4 mL prefilled syringes are intended for administration of unit dosages only. There may be a small air bubble in the syringe but this does not have to be removed.

FRAXIPARINE(r) and FRAXIPARINE(r) FORTE 0.6 mL,

0.8 mL and 1.0 mL prefilled graduated syringes may be used to administer adjusted dosages.

Hold the syringes vertically with the needle uppermost and ensure the air bubble is at the top of the syringe.

Advance the plunger to the volume/dosage required, expelling air and any excess.

Pay special attention to the instructions for the product you are using. Always ask your doctor's advice.

Injection Technique

Always use FRAXIPARINE(r) exactly as your doctor or nurse has instructed you. You should ask their advice if you are having any difficulties injecting FRAXIPARINE(r).

1. Wash your hands thoroughly with soap and water. Towel dry.

2. Sit or lie down in a comfortable position.

The injection is given in the side of the lower stomach area (figure 4). Alternate the left and right side of the stomach at each injection.

Figure 4

Figure 5

1. Hold the syringe firmly by the finger hold. Insert the full length of the needle straight (at an angle of 90 @) into the skin fold (figure 6) over a period of 10 to 15 seconds.

Figure 6

Inject the contents of the syringe by pressing down on the plunger as far as it goes.

Remove the syringe from the skin at the same angle it was inserted (figure 7). The injection site should not be rubbed.

Figure 7

1. Clean the injection area with an alcohol swab.

2. Pull off the cap that protects the needle. Discard the cap.

Important note:

• Do not touch the needle or allow it to come in contact with any surface before the injection

• The presence of a small air bubble in the syringe is normal. Do not try to remove this air bubble before making the injection.

Gently pinch the skin that has been cleaned to make a fold (figure 5). Hold the fold between the thumb and the forefinger during the entire injection.

9. After injection use the safety shield to protect from needle injuries. To do this, hold the syringe in one hand by gripping the safety shield, then use the other hand to pull firmly on the finger hold. This unlocks the shield. Slide the shield up the body of the syringe until it locks into position over the needle (figures 8 & 9).

How to Safely Dispose of FRAXIPARINE(r):

As with all medications, keep out of reach of children. For safe disposal after injection, a safety system of protection for the needle has been designed as outlined below:

Fig. 8. FRAXIPARINE(r) safety system

Therefore, if you suspect that you have used too much FRAXIPARINE(r), call your doctor immediately even if you do not yet observe any unusual symptoms. Your doctor can then make arrangements to admit you to hospital for observation and/or treatment.

Missed Dose:

Do not inject a double dose to make up for forgotten individual doses. If you are not sure what to do, ask your doctor or

pharmacist.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Fig. 9 Installing safety system on FRAXIPARINE(r) syringe after injection.

Administration of FRAXIPARINE(r) may result in bleeding which can have serious or life-threatening consequences. Stroke caused by bleeding into the brain and serious bleeding within the abdomen have been reported. FRAXIPARINE(r) is generally well tolerated when used according to directions of use.

You should alert your doctor immediately if you notice any of the following effects:

Bleeding from the surgical wound

Other bleeding episodes, for example, nosebleeds, blood in the urine, or if you throw up blood

Allergic reactions such as skin rash, swelling of the face including mouth, lips and/or tongue, throat, wheezing and shortness of breath

Return used needles in their safety devices to a licensed healthcare facility for safe disposal.

Overdose:

Accidental overdosage may result in hemorrhaging (internal or external bleeding) which cannot be treated at home.

HOW TO STORE IT

FRAXIPARINE(r) and FRAXIPARINE(r) FORTE should be stored between 15deg-30degC. Do not refrigerate as cold injections may be painful. Do not freeze. Keep out of reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Health Products and Food Branch

Health Canada

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

*If you think you have these side effects, it is important that you seek medical advice from your doctor immediately.

This is not a complete list of side effects. For any unexpected effects while taking FRAXIPARINE(r) or FRAXIPARlNE(r) FORTE, contact your doctor or pharmacist.

MORE INFORMATION

This document plus the full Product Monograph, prepared for health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.

7333 Mississauga Road Mississauga, Ontario

L5N 6L4

1-800-387-7374

This leaflet was prepared by GlaxoSmithKline Inc. Last revised: September 16, 2008

(c)

2008 GlaxoSmithKline Inc. All Rights Reserved

(r)

FRAXIPARINE is a registered trademark, used under license by GlaxoSmithKline Inc.

(r) ASPIRIN is a registered trademark of BAYER AKTIENGESELLSCHAFT