PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 22 DOSAGE AND ADMINISTRATION 23 OVERDOSAGE 26 ACTION AND CLINICAL PHARMACOLOGY 26 STORAGE AND STABILITY 29 SPECIAL HANDLING INSTRUCTIONS 29 DOSAGE FORMS, COMPOSITION AND PACKAGING 29

PART II: SCIENTIFIC INFORMATION 30

PHARMACEUTICAL INFORMATION 30 CLINICAL TRIALS 31 DETAILED PHARMACOLOGY 48 TOXICOLOGY 48 REFERENCES 50

PART III: CONSUMER INFORMATION. 51

ARIXTRA(r)

fondaparinux sodium injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation (see PHARMACEUTICAL INFORMATION, Composition). Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium. Active clinically significant bleeding. Acute bacterial endocarditis.

WARNINGS AND PRECAUTIONS

General

ARIXTRA(r) (fondaparinux sodium) must be administered only by the subcutaneous (SC) or intravenous (IV) route. ARIXTRA(r) must not be administered intramuscularly.

Carcinogenesis and Mutagenesis

See TOXICOLOGY, Carcinogenicity and Mutagenicity.

Cardiovascular

Risk of catheter thrombosis during PCI

In patients undergoing any percutaneous coronary intervention (PCI), the use of ARIXTRA(r) as the sole anticoagulant during PCI is not recommended because of an increased risk of guiding catheter thrombosis. An effective anti-thrombin regimen such as unfractionated heparin (UFH) should be used as an adjunct to PCI, according to standard practice (see DOSAGE AND ADMINISTRATION, and DETAILED PHARMACOLOGY).

In STEMI patients undergoing primary PCI for reperfusion, the use of ARIXTRA(r) prior to and during PCI is not recommended (see ADVERSE REACTIONS, Risk of catheter thrombosis during PCI, and DOSING AND ADMINISTRATION).

Clinical trials have shown a low but increased risk of guiding catheter thrombosis in patients treated solely with ARIXTRA(r) for anticoagulation during PCI compared to control. Incidences during PCI in UA/NSTEMI were 1.00% with ARIXTRA(r), 0.32% with enoxaparin alone, and 0.16% with enoxaparin with adjunctive UFH (see ADVERSE REACTIONS, Risk of catheter thrombosis during PCI). In patients with STEMI undergoing primary PCI, incidences were 1.18% with ARIXTRA(r) and 0% with UFH. Use of ARIXTRA(r) during primary PCI is not recommended. It is to be expected that the risk of peri-procedural myocardial infarction (MI) may be increased in patients who develop guiding catheter thrombosis, irrespective of anticoagulant used (see ADVERSE REACTIONS, Risk of catheter thrombosis during PCI).

Hematologic

Hemorrhage

ARIXTRA(r), like other antithrombotic drugs, should be used with caution in patients who have an increased risk of hemorrhage, such as those with congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease and recent intracranial hemorrhage or shortly after brain, spinal, or ophthalmological surgery. Risk of hemorrhage is expected to increase with decreasing renal function (see ADVERSE REACTIONS). Appropriate caution should be exercised in patients with moderate to severe renal impairment (see WARNINGS AND PRECAUTIONS, Renal).

Prophylaxis and Treatment of VTE

Agents that may enhance the risk of hemorrhage, with the exception of vitamin K antagonists used concomitantly for treatment of VTE, should be discontinued prior to initiation of ARIXTRA(r) therapy. If co-administration is necessary, close monitoring may be appropriate (see DRUG INTERACTIONS).

Prophylaxis of VTE following orthopedic surgery

The timing of the first dose of ARIXTRA(r) following surgery requires strict adherence. The first dose should be given no earlier than 6 hours following surgical closure, and only after hemostasis has been established. Administration before 6 hours has been associated with an increased risk of major bleeding (see DOSAGE and ADMINISTRATION). Patient groups at particular risk are those older than 75 years of age, body weight of less than 50 kg or renal impairment with creatinine clearance less than 50 mL/min.

Management of UA/NSTEMI, STEMI

ARIXTRA(r) should be used with caution in patients who are being treated concomitantly with other therapies that increase the risk of hemorrhage (such as GPIIb/IIIa inhibitors or thrombolytics).

Thrombocytopenia

ARIXTRA(r) should be used with caution in patients with a history of heparin-induced thrombocytopenia (see DETAILED PHARMACOLOGY). Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 50,000/mm3, ARIXTRA(r) should be discontinued.

Prophylaxis of VTE following orthopedic surgery

Thrombocytopenia can occur with the administration of ARIXTRA(r) as well as any major surgical procedure. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 2.9% in patients given ARIXTRA(r) 2.5 mg in the peri-operative orthopedic surgery clinical trials. Severe thrombocytopenia (platelet counts less than 50,000/ mm3) occurred at a rate of 0.2% in patients given 2.5 mg in peri- operative clinical trials. During extended prophylaxis no cases of moderate or severe thrombocytopenia were reported (0/327).

Treatment of DVT and PE

Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the ARIXTRA(r) treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the ARIXTRA(r) treatment regimen.

Hepatic/Biliary/Pancreatic

The pharmacokinetic properties of fondaparinux have not been studied in patients with hepatic insufficiency. There is no evidence that fondaparinux is metabolized or eliminated hepatically. However, the use of ARIXTRA(r) should be considered with caution because of an increased risk of bleeding due to a deficiency of coagulation factors in patients with severe hepatic insufficiency. Thus, in patients with severe hepatic insufficiency, ARIXTRA(r), like any anticoagulant, should be used only with care.

Peri-Operative Considerations

There have been cases of intra-spinal hematomas with the concurrent use of

ARIXTRA(r) should only be used

antithrombotics (i.e. 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.

Careful vigilance for neurological signs is recommended with rapid diagnosis and treatment, if signs occur.

Renal

The plasma clearance of fondaparinux decreases with the severity of renal impairment, and is associated with an increased risk of hemorrhage (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). This has also been observed with all low molecular weight heparins (LMWH).

Prophylaxis of VTE following orthopedic surgery

Occurrences of major bleeding in patients receiving prophylactic therapy following orthopedic surgery with normal renal function, mild renal insufficiency, moderate renal insufficiency and severe renal insufficiency have been found to be 1.6% (25/1565), 2.4% (31/1288), 3.8% (19/504) and 4.8% (4/83) respectively. Therefore, ARIXTRA(r) prophylactic therapy following orthopedic surgery is not recommended in patients with severe renal insufficiency (creatinine clearance < 30 mL/min) and should be used with caution in patients with moderate renal insufficiency (creatinine clearance 30-50 mL/min) (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). Renal function should be assessed periodically in orthopedic surgery patients receiving prophylactic therapy. Consideration of immediate discontinuation of ARIXTRA(r) should be undertaken for patients who develop severe renal insufficiency or labile renal function while on prophylactic therapy. After discontinuation of ARIXTRA(r) prophylactic therapy, its anticoagulant effects may persist for 2-4 days in patients with normal renal function (ie. at least 3-5 half-lives). The anticoagulant effects of ARIXTRA(r) prophylactic therapy may persist even longer in patients with renal insufficiency.

Treatment of DVT and PE

No dosing adjustment is generally necessary in patients with mild to moderate renal insufficiency, however, close monitoring of these patients is recommended. In patients with severe renal impairment (creatinine clearance <= 30 mL/min) use is not recommended due to risk of hemorrhage.

Management of UA/NSTEMI, STEMI

There are limited clinical data available on the use of fondaparinux 2.5 mg once daily in patients with creatinine clearance <= 30 mL/min (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency).

Special Populations

Low body Weight:

Prophylaxis of VTE following orthopedic surgery

Patients with body weight < 50 kg are at increased risk of bleeding. ARIXTRA(r) prophylactic therapy should be used only with caution in patients with body weight < 50 kg undergoing orthopedic surgery.

Treatment of DVT and PE

For DVT and PE treatment, patients with body weight < 50 kg a daily dose of 5 mg is recommended. In patients with body weight > 100 kg a daily dose of 10 mg is recommended (see DOSAGE AND ADMINISTRATION).

Management of UA/NSTEMI, STEMI

Patients with body weight less than 50 kg may be at increased risk of bleeding due to reduced clearance of ARIXTRA(r). ARIXTRA(r) should be used with caution in patients weighing < 50 kg. Pregnant Women: There are very limited clinical data available on the use of ARIXTRA(r) in pregnant women. Caution should be exercised when prescribing ARIXTRA(r) to pregnant women. ARIXTRA(r) should not be prescribed to pregnant women unless the potential benefit outweighs the risk. Animal studies do not indicate either direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or post-natal development. Nursing Women: It is not known whether fondaparinux is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARIXTRA(r) is administered to breast-feeding women. Pediatrics: The safety and effectiveness of ARIXTRA(r) in children under the age of 17 years has not been established.

Geriatrics (> 65 years of age)

:

ARIXTRA(r) should be used with caution in elderly patients because of increased risk of hemorrhage (see ADVERSE REACTIONS). Since fondaparinux sodium is substantially excreted by the kidney, risks associated with its use may be expected to be greater in patients with impaired renal function (see ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function (see WARNINGS AND PRECAUTIONS, Renal).

Monitoring, Laboratory and Coagulation Tests

Since the international standards of heparin or low molecular weight heparins (LMWH) are not appropriate calibrators, the activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or LMWH. Routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalized Ratio (INR) tests in plasma are not affected by the activity of 2.5 mg ARIXTRA(r) (fondaparinux sodium). When administered at the recommended prophylactic dose, routine coagulation tests such as PT and aPTT are relatively insensitive measures of ARIXTRA(r) activity, and therefore unsuitable for monitoring. Although monitoring of ARIXTRA(r) is generally not required, the anti-factor Xa assay is the preferred test to measure the anti-coagulant activity of ARIXTRA(r). Only fondaparinux can be used to calibrate the anti-Xa assay (see ACTION AND CLINICAL PHARMACOLOGY, Mechanism of Action). If during ARIXTRA(r) therapy, unexpected changes in coagulation parameters or major bleeding occurs, ARIXTRA(r) should be discontinued and a search for other causes such as concomitant medications that could interfere with coagulation, should be undertaken.

DRUG INTERACTIONS

Drug-Drug Interactions

In clinical studies performed with ARIXTRA(r) (fondaparinux sodium), the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with the pharmacokinetics/pharmacodynamics of ARIXTRA(r). In addition, ARIXTRA(r) neither influenced the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam and digoxin, nor the pharmacokinetics of digoxin at steady state. Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of ARIXTRA(r) therapy unless indicated for the management of the underlying condition, such as vitamin K antagonists for the treatment of venous thromboembolism (VTE). If co-administration is necessary, close monitoring may be appropriate. Since fondaparinux does not inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4) in vitro, ARIXTRA(r) is not expected to interact with other drugs metabolized in vivo via these isoenzymes. ARIXTRA(r) does not bind significantly to plasma proteins other than ATIII, therefore, drug interactions by protein binding displacement are not expected.

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, Laboratory and Coagulation Tests.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Prophylaxis of VTE following orthopedic surgery:

The recommended dose of ARIXTRA(r) (fondaparinux sodium) is 2.5 mg once daily administered post-operatively by subcutaneous injection. After hemostasis has been established, the initial dose should be given no earlier than 6 hours after surgical closure. In clinical studies, 99% of the patients had received the initial dose of ARIXTRA(r) by 18 hours after surgical closure. Administration before 6 hours after orthopedic surgery has been associated with an increased risk of major bleeding. The timing of the first dose of ARIXTRA(r) following surgery requires strict adherence (see WARNING AND PRECAUTIONS, Hemorrhage, and Peri- Operative Considerations; ACTION AND CLINICAL PHARMACOLOGY). The usual duration of prophylactic therapy with ARIXTRA(r) is 7 +- 2 days. Treatment should be continued for as long as the risk of VTE persists. In patients for whom extended prophylaxis is indicated, administration of ARIXTRA(r) in or out of the hospital up to an additional 24 days is recommended. In clinical trials of extended prophylaxis, a total of 32 days (peri-operative and extended prophylaxis) has been tolerated.

Treatment of DVT and PE:

The recommended dose of ARIXTRA(r) is 5 mg (body weight < 50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight > 100 kg) by subcutaneous injection once daily. Concomitant oral anticoagulation treatment should be initiated as soon as possible, usually within 72 hours. ARIXTRA(r) injection treatment should be continued for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2.0 to 3.0). The average duration of administration is 7 days. In controlled clinical trials administration of ARIXTRA(r) injection for up to 26 days to a small number of patients has been well tolerated.

Management of Unstable Angina/Non-ST Segment Elevation Myocardial Infarction (UA/NSTEMI):

The recommended dose of ARIXTRA(r) is 2.5 mg once daily, administered by subcutaneous injection. Treatment should be initiated as soon as possible following diagnosis and may be continued for up to 8 days or until hospital discharge. If a patient is to undergo percutaneous coronary intervention (PCI) while being treated with ARIXTRA(r), an effective anti-thrombin regimen such as unfractionated heparin (UFH) should be administered as an adjunct to PCI, as per standard practice, taking into account the patient's potential risk of bleeding, including the time since the last dose of ARIXTRA(r) (see WARNINGS AND PRECAUTIONS, Risk of catheter thrombosis during PCI, and Hemorrhage). The timing of restarting subcutaneous ARIXTRA(r) after sheath removal should be based on clinical judgment. In the UA/NSTEMI clinical trials treatment with ARIXTRA(r) was restarted no earlier than 2 hours after sheath removal. In patients who are to undergo coronary artery bypass graft (CABG) surgery, ARIXTRA(r) where possible, should not be given during the 24 hours before surgery and may be restarted 48 hours post-operatively.

Management of ST Segment Elevation Myocardial Infarction (STEMI):

The recommended dose of ARIXTRA(r) is 2.5 mg once daily. The first dose of ARIXTRA(r) is administered intravenously and subsequent doses are administered by subcutaneous injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge. ARIXTRA(r) should not be used if primary PCI is the planned reperfusion therapy (see INDICATIONS, WARNINGS AND PRECAUTIONS, Risk of catheter thrombosis during PCI). ARIXTRA(r) is indicated for use in patients who are managed with thrombolytics or who initially are to receive no form of reperfusion therapy. If a patient is to undergo subsequent PCI while being treated with ARIXTRA(r), an effective anti-thrombin regimen such as unfractionated heparin (UFH) should be administered as an adjunct to PCI as per standard practice, taking into account the patient's potential risk of bleeding, including the time since the last dose of ARIXTRA(r) (see WARNINGS AND PRECAUTIONS, Risk of catheter thrombosis during PCI, and Hemorrhage). The timing of restarting subcutaneous fondaparinux after sheath removal should be based on clinical judgment. In the STEMI clinical trials treatment with fondaparinux was restarted no earlier than 3 hours after sheath removal. In patients who are to undergo coronary artery bypass graft (CABG) surgery, fondaparinux where possible, should not be given during the 24 hours before surgery and may be restarted 48 hours post-operatively.

General Dosing Considerations

Use in Patients with Renal Insufficiency

The risk of hemorrhage increases with increasing renal insufficiency. ARIXTRA(r) should be used with caution in patients with moderate renal insufficiency (creatinine clearance 30-50 mL/min) (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency). In severe renal impairment, the use of ARIXTRA(r) should be avoided or, if the physician determines that the benefit outweighs the risk, ARIXTRA(r) should only be used with caution. Renal function should be assessed periodically in patients receiving the drug. For prophylactic use following orthopedic surgery, ARIXTRA(r) should be discontinued immediately in patients who develop severe renal insufficiency or labile renal function while on therapy. After discontinuation of ARIXTRA(r), its anticoagulant effects may persist for 2-4 days in patients with normal renal function (i.e., at least 3-5 half-lives). The anticoagulant effects of ARIXTRA(r) may persist even longer in patients with renal insufficiency.

Use in Patients with Hepatic Insufficiency

Use with caution in patients with hepatic insufficiency (see also WARNINGS AND PRECAUTIONS).

Use in Geriatric Patients

Use with caution in elderly patients (see WARNINGS AND PRECAUTIONS, Geriatrics, and ADVERSE REACTIONS, Geriatrics).

Use in Patients with Low Body Weight

For patients of body weight < 50 kg, ARIXTRA(r) should be used with caution (see WARNINGS AND PRECAUTIONS, Low Body Weight).

Administration

Subcutaneous administration:

Do not inject ARIXTRA(r) intramuscularly.

Administration is by subcutaneous injection only.

To avoid the loss of medicinal product when using the pre-filled syringe do not expel the air bubble from the syringe before the injection. For step-by-step instructions for use, please see CONSUMER INFORMATION.

Intravenous administration:

For STEMI patients treated with ARIXTRA(r), the initial dose is to be administered intravenously. Administration should be through an existing intravenous line either directly or using a small volume (25 mL or 50mL) 0.9% saline minibag as the first dose in the treatment of STEMI. To avoid the loss of medicinal product when using the pre-filled syringe, do not expel the air bubble from the syringe before the injection. The intravenous tubing should be well flushed with saline after the administration of ARIXTRA(r) injection to ensure that all of the medicinal product is administered. If administered via a minibag, the infusion should be given over 1 to 2 minutes. If ARIXTRA(r) is added to a 0.9% saline minibag it should be infused immediately, but can be stored between 15-30degC for up to 24 hours. Minibags are typically composed of a variety of polymers including PVC, polyethylene, polypropylene, or styrene-ethylene- butadiene, individually or in combination. In the absence of compatibility studies, ARIXTRA(r) must not be mixed with other medicinal products.

OVERDOSAGE

Hemorrhage is the major clinical sign of overdosage. Minor bleeding rarely requires specific therapy, and reducing or delaying subsequent doses of ARIXTRA(r) (fondaparinux sodium) is usually sufficient. Overdosage associated with bleeding complications should lead to treatment discontinuation, search for the primary cause of bleeding and initiation of appropriate therapy.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ARIXTRA(r) (fondaparinux sodium) Injection is a synthetic and specific inhibitor of activated Factor X (Xa). As ARIXTRA(r) has no animal-sourced components, there is no risk of animal contamination such as transmissable spongiform encephalitis (TSE). The mechanism of action of ARIXTRA(r) is the potentiation of antithrombin III (ATIII) which selectively inhibits Factor Xa. By selectively binding to ATIII, ARIXTRA(r) potentiates approximately 300 times the neutralization of Factor Xa. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. ARIXTRA(r) does not inactivate thrombin (activated Factor II) and has no effect on platelets. At the recommended dose, ARIXTRA(r) does not affect fibrinolytic activity or bleeding time. At equivalent antithrombotic concentrations, experimental bleeding models demonstrate that ARIXTRA(r) induces less bleeding than unfractionated heparin. ARIXTRA(r) does not bind to Human Platelet Factor 4 (unlike heparin) and does not cross-react with sera from patients with heparin-induced thrombocytopenia. No thrombocytopenia with suspected immuno-allergic pathophysiology was documented in the overall clinical development program. On this basis, no antibody-induced thrombocytopenia is anticipated with ARIXTRA(r) treatment. Anti-Xa Activity: The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin or Low Molecular Weight Heparin [LMWH] are not appropriate for this use). As a result, the activity of fondaparinux sodium is expressed as milligram (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately 3 hours.

Pharmacokinetics

Absorption:

Following a single 4 mg i.v. bolus administration to normal healthy subjects, mean peak fondaparinux plasma concentration is approximately 0.81 mg/L at the first sampling time point of 5 minutes. After subcutaneous dosing, fondaparinux is completely and rapidly absorbed, with an absolute bioavailability of 100%. Following a single subcutaneous injection of 2.5 mg, peak plasma concentration (Cmax = 0.34 mg/L) is obtained 2 hours post-dosing. Plasma concentrations of half the mean Cmax values are reached 25 minutes post-dosing.

Pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by the subcutaneous route. At steady state, mean plasma concentrations 2 hours post dosing ranged between 0.32 and 0.47 mg/L in patients undergoing orthopedic surgeries receiving ARIXTRA(r) 2.5 mg. In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight < 50 kg), 7.5 mg (body weight 50-100 kg) and 10 mg (body weight > 100 kg) once daily, the body-weight- adjusted doses provide similar exposure across all body weight categories. The peak steady-state plasma concentration is, on average, 1.20-1.26 mg/L. In these patients, the minimum steady-state plasma concentration is 0.46-0.62 mg/L.

Distribution:

In healthy adults, intravenously or subcutaneously administered fondaparinux distributes mainly in blood as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L.

In vitro

fondaparinux is highly (at least 94% in the concentration range from

0.5 to 2 mg/L) and specifically bound to ATIII and does not bind significantly to other plasma proteins, including Platelet Factor 4 (PF4).

Metabolism:

There is no evidence that fondaparinux is metabolized since most of the administered dose is eliminated unchanged in urine.

Excretion:

The elimination half life (T1/2) is 17 to 21 hours in healthy subjects. Up to 77% of a single subcutaneous dose of fondaparinux is excreted in urine as

unchanged compound in 72 hours in healthy individuals up to 75 years of age.

Special Populations and Conditions

Geriatrics:

Fondaparinux elimination is prolonged in patients over 75 years old. In studies evaluating fondaparinux sodium 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients over 75 years old as compared to patients less than 65 years old. A similar pattern is observed in DVT and PE treatment patients.

Following a single intravenous dose of fondaparinux 4 mg in healthy elderly subjects, a mean Cmax of 0.86 mg/L was observed at the first sampling timepoint of 5 minutes. Other pharmacokinetic parameters following intravenous administration were similar to those observed for subcutaneous administration.

Renal Insufficiency:

Fondaparinux elimination is prolonged in patients with renal insufficiency since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal insufficiency (creatinine clearance 50 to 80 mL/min), approximately 40% lower in patients with moderate renal insufficiency (creatinine clearance 30 to 50 mL/min) and approximately 55% lower in patients with severe renal insufficiency (< 30 mL/min) compared to patients with normal renal function. The associated terminal half-life values were 29 hours in moderate and 72 hours in patients with severe renal insufficiency. A similar pattern is observed in DVT and PE treatment patients (see WARNINGS AND PRECAUTIONS, Renal).

Patients Weighing Less Than 50 kg:

Total clearance of fondaparinux sodium is decreased by approximately 30% in patients weighing less than 50 kg (see DOSAGE and ADMINISTRATION).

Pediatrics:

The pharmacokinetics of fondaparinux have not been investigated in pediatric patients.

STORAGE AND STABILITY

ARIXTRA(r) (fondaparinux sodium) injection should be stored between 15-30degC. Do not freeze. If ARIXTRA(r) is added to a 0.9% saline minibag it should be infused immediately, but can be stored between 15-30degC for up to 24 hours. Minibags are typically composed of a variety of polymers including PVC, polyethylene, polypropylene, or styrene-ethylene- butadiene, individually or in combination.

SPECIAL HANDLING INSTRUCTIONS

Keep out of reach of children. Single dose syringes. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ARIXTRA(r) (fondaparinux sodium) injection, supplied as a sterile injectable solution for subcutaneous and intravenous use, is available in the following strengths and package sizes: Package of 10: 2.5 mg ARIXTRA(r) in pre-filled 0.5 mL single use syringes, affixed with a 27-gauge x 1/2 inch needle with blue built-in automatic needle protection. Packages of 2, 7 and 10: 5 mg ARIXTRA(r) in 0.4 mL single use pre-filled syringe, affixed with a 27-gauge x 1/2 inch needle with orange built-in automatic needle protection. 7.5 mg ARIXTRA(r) in 0.6 mL single use pre-filled syringe, affixed with a 27-gauge x 1/2 inch needle with magenta built-in automatic needle protection. 10 mg ARIXTRA(r) in 0.8 mL single use pre-filled syringe, affixed with a 27-gauge x 1/2 inch needle with violet built-in automatic needle protection. As with all parenteral drug products, syringes should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: fondaparinux sodium Chemical name: methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-a- D-glucopyranosyl-(1- 4)-O-b-D-glucopyranuronosyl- (1-4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino) -a- D-glucopyranosyl-(1 -4)-O-2-O-sulfo-a- L-idopyranuronosyl-(1-4)-2-deoxy-6-O-sulfo-2- (sulfoamino)- a-D-glucopyranoside, decasodium salt Molecular formula and molecular mass: C31H43N3 Na10O49S8 Structural formula: Molecular weight: 1728 Physicochemical properties: pH is 7.1 at a concentration of 2.5% (m/V) Solubility: Freely soluble at any pH (>2 g in 1 mL water), sodium chloride solution, and sodium hydroxide solution. Practically insoluble (less than 1 g in 10,000 mL) in ethanol. Composition: Each pre-filled syringe of ARIXTRA(r), affixed with an automatic needle protection system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5.0 mg of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux sodium in 0.6 mL or 10.0 mg of fondaparinux sodium in 0.8 mL of an isotonic solution of sodium chloride, water for injection and if necessary, sodium hydroxide or hydrochloric acid for pH adjustment (pH 5-8).

CLINICAL TRIALS

Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

Table 12 Summary of patient demographics for clinical trials in the prophylaxis of thromboembolic events following hip fracture surgery

In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, ARIXTRA(r) (fondaparinux sodium) 2.5 mg subcutaneous (SC) once daily was compared to enoxaparin 40 mg SC once daily (the dose of enoxaparin sodium approved for use in prophylaxis in conjunction with orthopedic surgery in Canada is 30 mg SC twice daily). A total of 1711 patients were randomized and 1673 were treated. Patients ranged in age from 17-101 years (mean age 77 years) with 25% men and 75% women. Patients were 99% Caucasian, 1% other races. Patients with multiple trauma affecting more than one organ system, serum creatinine level more than 180 umol/L (2 mg/dL), or platelet count less than 100,000/mm3 were excluded from the trial. ARIXTRA(r) was initiated 6 hours after surgery in 88% of patients and the comparator was initiated an average of 18 hours after surgery in 74% of patients. For both drugs, treatment was continued for 7 +- 2 days. Efficacy results are provided in Table 13 below. Major bleeding episodes for both drugs are provided in Tables 1 and 2 (see ADVERSE REACTIONS).

Table 13 Efficacy Results of study in the prophylaxis of thromboembolic events following hip fracture surgery

1. (r)

ARIXTRA

was initiated 6 hours after surgery in 88% of patients and the enoxaparin was initiated an average of 18 hours

after surgery in 74% of patients.

Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip fracture surgery of the upper third of the femur), with an adequate efficacy assessment up to Day 11.

VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

p-value <0.001

Number in parentheses indicates 95% confidence interval

p-value: Not Significant (NS)

Extended Prophylaxis of Thromboembolic Events

Table 14 Summary of patient demographics for clinical trials in the extended prophylaxis of thromboembolic events following orthopedic surgery

In an unblinded manner, 737 patients undergoing hip fracture surgery were initially treated with ARIXTRA(r) 2.5 mg once daily for 7 +- 1 days. At the end of this period, 326 patients were randomized to receive ARIXTRA(r) 2.5 mg once daily and 330 to placebo in a double-blind trial for 21 +- 2 days; 81 patients were not eligible for randomization. Patients ranged in age from 23 to 96 years (mean age 75 years) and were 29% men and 71% women. Patients were 99% Caucasian and 1% other races . Patients undergoing standard surgery for fracture of the upper third of the femur or the femoral head and neck not more than 48 hours after admission were entered unless they had, mainly, active and significant bleeding, bleeding disorders, creatinine level above 180 mol/L (2.0 mg/dL), received other anticoagulants between admission and surgery and diagnosed deep vein thrombus or pulmonary emboli (PE) during screening or pre- randomization period. The primary efficacy endpoint was the composite of the following adjudicated VTE outcomes, evaluated during the randomization period up to day 24: symptomatic DVT and/or adjudicated non-fatal PE, and mandatory venogram positive for VTE. The efficacy data are provided in Table 15 below and demonstrate that extended prophylaxis with fondaparinux sodium was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI=[-99.7; -87.2], p<0.0001). Major bleeding episodes for non-randomized and randomized patients are provided in Table 3 (see ADVERSE REACTIONS, Hemorrhage)

Table 15 Efficacy of ARIXTRA(r) Injection In the Extended Prophylaxis Period (Day 7 +- 1 to Day 28 +- 2) Number and Percentage of thromboembolic events in patients who had undergone hip fracture surgery one week earlier.1

1. During the one week pre-randomization period preceding the Extended Prophylaxis Period all patients had been treated

(r)

with open-label ARIXTRA

2.5 mg SC once daily.

Evaluable patients were those who were treated in the post-randomization period, with an adequate efficacy assessment up to Day 24 following randomization.

VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 24 following

randomization.

p-value <0.001

Number in parentheses indicates 95% confidence interval

p-value = 0.021

Prophylaxis of Thromboembolic Events following Hip Replacement Surgery

Table 16 Summary of patient demographics for clinical trials in the prophylaxis of thromboembolic events following hip replacement surgery

In two randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, ARIXTRA(r) 2.5 mg SC once daily was compared to either enoxaparin sodium 30 mg SC every 12 hours (Study 1) or to enoxaparin sodium 40 mg SC once a day (Study 2). The dose of enoxaparin sodium approved for prophylaxis in conjunction with orthopedic surgery in Canada is 30 mg SC twice daily. In Study 1, a total of 2275 patients were randomized and 2257 were treated. Patients ranged in age from 18 to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% Black, <1% Asian, and 2% others. In Study 2, a total of 2309 patients were randomized and 2273 were treated. Patients ranged in age from 24 to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99% Caucasian, and 1% other races. Patients with serum creatinine level more than 180 umol/L (2 mg/dL), or platelet count less than 100,000/mm3 were excluded from both trials. In Study 1, ARIXTRA(r) was initiated 6 +- 2 hours (mean 6.5 hrs) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hrs) after surgery in 97% of patients. In Study 2, ARIXTRA(r) was initiated 6 +- 2 hours (mean 6.25 hrs) after surgery in 86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients. The first post-operative enoxaparin sodium dose was given before 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hrs. For both studies, both study treatments were continued for 7 +- 2 days. Efficacy results are provided in Table 17 below. Major bleeding episodes for both drugs are provided in Tables 1 and 2 (see ADVERSE REACTIONS).

Table 17 Efficacy Results of study in the prophylaxis of thromboembolic events following hip replacement surgery

A

1. Patients randomized to ARIXTR (r)

that hemostasis had been achieved.

2.5 mg were to receive the first injection 6 +- 2 hours after surgery providing

Patients randomized to enoxaparin sodium were to receive the first injection between 12 and 24 hours after surgery.

Patients randomized to enoxaparin sodium were to receive the first injection 12 hours prior to surgery except in the case of spinal anesthesia. The first post-operative enoxaparin sodium dose was to be given between 12 to 24 hours

after surgery.

Evaluable patients were those who were treated and underwent the appropriate surgery (i.e. elective hip replacement surgery), with an adequate efficacy assessment up to Day 11.

VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

p-value versus enoxaparin sodium: NS

Number in parentheses indicates 95% confidence interval

p-value versus enoxaparin sodium in study 1: <0.05

p-value versus enoxaparin sodium in study 2: <0.01

Prophylaxis of Thromboembolic Events following Knee Replacement Surgery

Table 18 Summary of patient demographics for clinical trials in the prophylaxis of thromboembolic events following knee replacement surgery

In a randomized, double-blind, clinical trial in patients undergoing knee replacement surgery (i.e., surgery requiring resection of the distal end of the femur or proximal end of the tibia), ARIXTRA(r) 2.5 mg SC once daily was compared to enoxaparin sodium 30 mg SC every 12 hours. A total of 1049 patients were randomized and 1034 were treated. Patients ranged in age from 19 to 94 years (mean age 68 years) with 41% men and 59% women. Patients were 88% Caucasian, 8% Black, <1% Asian, and 3% others. Patients with serum creatinine level more than 180 umol/L (2 mg/dL), or platelet count less than 100,000/mm3 were excluded from the trial. ARIXTRA(r) was initiated 6 +- 2 hours (mean 6.25 hrs) after surgery in 94% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 21 hrs) after surgery in 96% of patients. For both drugs, treatment was continued to 7 +- 2 days. Efficacy results are provided in Table 19 below. Major bleeding episodes for both drugs are provided in Tables 1 and 2 (see ADVERSE REACTIONS).

Table 19 Efficacy Results of study in the prophylaxis of thromboembolic events following knee replacement surgery

A

1. Patients randomized to ARIXTR (r)

had been achieved.

mg received the first injection 6 +- 2 hours after surgery providing that hemostasis

Patients randomized to enoxaparin sodium received the first injection at 21 +- 2 hours after surgery closure providing that hemostasis had been achieved.

Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., knee replacement surgery),

with an adequate efficacy assessment up to Day 11.

VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

p-value <0.001

Number in parentheses indicates 95% confidence interval

p-value: NS

Treatment of Deep Vein Thrombosis And Pulmonary Embolism

The ARIXTRA(r) clinical program in treatment of venous thromboembolism was designed to demonstrate the efficacy of ARIXTRA(r) for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Over 4874 patients were studied in controlled Phase II and III clinical studies.

Treatment of Deep Vein Thrombosis

Table 20 Summary of patient demographics for clinical trial in the treatment of Deep Vein Thrombosis

In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT, ARIXTRA(r) 5 mg (body weight < 50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight > 100 kg) SC once daily (ARIXTRA(r) treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours in both hospitalized and non-hospitalized patients. Outpatient and home treatment of ARIXTRA(r) was permitted, and approximately 32% of patients were discharged home from the hospital while receiving fondaparinux therapy. A total of 2205 patients were randomized and 2192 were treated. Patients ranged in age from 18-95 years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% Black and 1% other races. For both groups, treatment continued for at least 5 days, and both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 +- 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. Treatment with ARIXTRA(r) was associated with a VTE rate of 3.9% compared with a VTE rate of 4.1% for enoxaparin sodium. The efficacy data are provided in Table 21 below.

Table 21 Efficacy of ARIXTRA(r) Injection In the Treatment of Deep Vein Thrombosis

1. Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration.

2. VTE was a composite of symptomatic recurrent VTE or fatal VTE reported up to Day 97.

3. The 95% confidence interval for the treatment difference for total VTE was: -1.8% to 1.5%.

Treatment of Pulmonary Embolism

Table 22 Summary of patient demographics for clinical trial in the treatment of Pulmonary Embolism

In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, ARIXTRA(r) 5 mg (body weight < 50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight > 100 kg) SC once daily (ARIXTRA(r) treatment regimen) was compared to heparin IV bolus (5000 units) followed by a continuous IV infusion adjusted to maintain 1.5-2.5 times aPTT control value. Outpatient and home treatment of ARIXTRA(r) was permitted, and approximately 15% of patients were discharged home from the hospital while receiving fondaparinux therapy. A total of 2213 patients were randomized and 2184 were treated. Patients ranged in age from 18-97 years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% Black and 1% other races. For both groups, treatment continued for at least 5 days, and both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 +- 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. Treatment with ARIXTRA(r) was associated with a VTE rate of 3.8% compared with a VTE rate of 5.0% for unfractionated heparin. The efficacy data are provided in Table 23 below.

Table 23 Efficacy of ARIXTRA(r) Injection In the Treatment of Pulmonary Embolism

1. Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration.

2. VTE was a composite of symptomatic recurrent VTE or fatal VTE reported up to Day 97.

3. The 95% confidence interval for the treatment difference for total VTE was: -3.0% to 0.5%.

Management of Unstable Angina or Non-ST Segment Elevation Myocardial Infarction (UA/NSTEMI)

In a randomized, double-blind, outcome trial, OASIS 5, 20 078 subjects presenting to hospital with suspected UA/NSTEMI acute coronary syndrome and at least 2 of 3 risk criteria (aged >=60 years, troponin T or I or CK-MB above the upper limit of normal, or ECG changes compatible with ischemia) were randomized to ARIXTRA(r) (n=10 057) or enoxaparin (n=10 021) within 24 hours of the most recent episode of symptoms. Patients were to be eligible for anticoagulation treatment.

Table 24 Summary of Patient Demographics in OASIS 5 1,2

1. 45% of subjects had UA, and 55% had NSTEMI.

2. Approximately 40% and 17% of patients had mild (creatinine clearance 50 to <80 mL/min) or moderate (creatinine clearance 30 to <50 mL/min) renal insufficiency, respectively, at randomization.

Patients received standard medical care for UA/NSTEMI including aspirin, clopidogrel/ ticlopidine, GPIIb/IIIa inhibitors, as well as percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, where appropriate. Patients undergoing PCI received either a single pre-procedural dose of ARIXTRA(r) intravenously (ARIXTRA(r) treatment arm) or unfractionated heparin intravenously (enoxaparin treatment arm) using an algorithm based on the time of the previous subcutaneous dose and whether GPIIb/IIIa inhibitors were planned. Subcutaneous study drug was resumed after PCI if possible. Patients undergoing CABG surgery had study drug temporarily stopped 24 hours prior to surgery and restarted 48 hours post surgery, if possible. The objective of the study was to determine whether ARIXTRA(r) was non-inferior to enoxaparin within 9 days of randomization based on the primary composite endpoint of death, myocardial infarction (MI) and refractory ischemia (RI) (see Table 25).

Table 25 Efficacy of ARIXTRA(r) in the Treatment of UA/NSTEMI up to Day 9 in OASIS 5 (All Randomized Patients)

1. Patients randomized to ARIXTRA(r) received 2.5 mg fondaparinux SC once daily for up to 8 days or discharge

2. Patients randomized to enoxaparin sodium received 1 mg/kg enoxaparin SC twice daily (once daily if creatinine clearance was between 20 mL/min and 30 mL/min) for 2-8 days or until clinically stable

3. The primary endpoint was a composite of death, myocardial infarction (MI) and refractory ischemia (RI) within

9 days of randomization.

p=0.003, one-sided non-inferiority

ARIXTRA(r) was as effective as enoxaparin in reducing the risk of death, MI or refractory ischemia at Day 9 (see Tables 25 and 26.) The treatment effect observed for the components was consistent with that for the overall composite endpoint (see Table 25). At 6 month follow-up, the benefit of ARIXTRA(r) was maintained (Table 26).

Table 26 Efficacy of ARIXTRA(r) for the Prevention of Death, MI or RI in UA/NSTEMI up to Day 180 in OASIS 5 (All Randomized Patients)

1. Patients randomized to ARIXTRA(r) received 2.5 mg fondaparinux SC once daily for up to 8 days or discharge.

2. Patients randomized to enoxaparin sodium received 1 mg/kg enoxaparin SC twice daily (once daily if creatinine clearance was between 20 mL/min and 30 mL/min) for 2-8 days or until clinically stable.

3. The primary endpoint was a composite of death, myocardial infarction (MI) and refractory ischemia (RI) within

9 days of randomization.

p=0.003, one-sided non-inferiority

In the management of UA/NSTEMI with ARIXTRA(r), the risk of all cause mortality up to Day 180 is reported in Table 27.

Table 27 Efficacy of ARIXTRA(r) for the Prevention of All Cause Mortality in UA/NSTEMI up to Day 180 in OASIS 5 (All Randomized Patients)

1. Patients randomized to ARIXTRA(r) received 2.5 mg fondaparinux SC once daily for up to 8 days or discharge.

2. Patients randomized to enoxaparin sodium received 1 mg/kg enoxaparin SC twice daily (once daily if creatinine clearance was between 20 mL/min and 30 mL/min) for 2-8 days or until clinically stable.

The rates of major bleeding episodes for UA/NSTEMI patients treated with ARIXTRA(r) vs. enoxaparin are provided in Tables 5 and 6 (see ADVERSE REACTIONS). In patients undergoing PCI during the initial hospitalization, the relative effects of ARIXTRA(r) and enoxaparin on death, MI or refractory ischemia and on major bleeding at Day 9 were consistent with that observed for the overall population (see Tables 28 and 29). However, in patients undergoing PCI, the incidence of guiding catheter thrombosis, although rare, was higher in patients treated with ARIXTRA(r) compared to enoxaparin (see WARNINGS AND PRECAUTIONS, Risk of catheter thrombosis during PCI, and ADVERSE REACTIONS, Risk of catheter thrombosis during PCI).

Table 28 Efficacy of ARIXTRA(r) by PCI Usage during Initial Hospitalisation up to Day 9 and Day 180 in OASIS 5 (All Randomised Patients)

Table 29 Adjudicated Major Bleeding by PCI Usage during Initial Hospitalisation (As Treated Patients) in OASIS 5

1 The on therapy period was from the start of dosing at randomisation until 2 days post the last injection

Management of ST segment Elevation Myocardial Infarction (STEMI)

In a randomized, double-blind, outcome trial, OASIS 6, ARIXTRA(r) was compared to usual care (placebo or UFH) in 12 092 subjects presenting to hospital with STEMI acute coronary syndrome within 12 hours of symptom onset. Randomization was stratified according to whether UFH was indicated based on the judgement of the investigator. A total of 5658 patients were enrolled in Stratum 1 who received ARIXTRA(r) (n=2823) or placebo (n=2835) and 6434 patients were enrolled in Stratum 2 who received ARIXTRA(r) (n=3213) or UFH (n=3221).

Table 30 Summary of Patient Demographics in OASIS 61

Approximately 40% and 14% of patients had mild (creatinine clearance 50 to <80 mL/min) or moderate (creatinine clearance 30 to <50 mL/min) renal insufficiency, respectively, at randomization.

The primary adjudicated endpoint was a composite of death and reinfarction (recurrent myocardial infarction) within 30 days of randomization. The results for ARIXTRA(r) compared to control (UFH or placebo combined) at Day 30 were 9.7% vs. 11.1% for death or myocardial reinfarction (p=0.008), 7.8% vs. 8.9% for death (all cause mortality) (p=0.023), and 2.3% vs. 2.8% for myocardial reinfarction (p=0.069) (see Table 31).

Table 31 Efficacy of ARIXTRA(r) in the treatment of STEMI up to Day 30 in OASIS 6 (All Randomized Patients)

1. Patients randomized to ARIXTRA(r) received an IV bolus injection of 2.5 mg followed by 2.5 mg by SC injection daily for up to 8 days or discharge.

2. Patients randomized to UFH received an IV bolus injection 60 IU/kg followed by an infusion of 12 IU/kg/hr for 24 to 48 hours.

3. The hazard ratio, ARIXTRA(r) versus control, was adjusted for treatment group and strata.

4. Adjusted hazard ratio p-value.

5. The primary endpoint was a composite of death and reinfarction within 30 days of randomization.

6. Placebo patients did not receive unfractionated heparin as an anticoagulant.

The treatment effect was greater with ARIXTRA(r) than with control (UFH or placebo combined) in reducing the risk of death or reinfarction at Day 30 (see Table 31). The treatment effect observed for the components was consistent with that for the overall composite endpoint (see Table 31). At 6 month follow-up, the benefit of ARIXTRA(r) was maintained (see Table 32).

Table 32 Efficacy of ARIXTRA(r) for the Prevention of Death or Reinfarction in STEMI up to 6 months in OASIS 6 (All Randomized Patients)

1. Patients randomized to ARIXTRA(r) received an IV bolus injection of 2.5 mg followed by 2.5 mg by SC injection daily for up to 8 days or discharge.

2. Patients randomized to UFH received an IV bolus injection 60 IU/kg followed by an infusion of 12 IU/kg/hr for 24 to 48 hours.

3. The hazard ratio, ARIXTRA(r) versus control, was adjusted for treatment group and strata.

4. Adjusted hazard ratio p-value.

5. The primary endpoint was a composite of death and reinfarction within 30 days of randomization.

Placebo patients did not receive unfractionated heparin as an anticoagulant.

In the management of STEMI with ARIXTRA(r), the risk of all cause mortality up to Day 180 is reported in Table 33.

Table 33 Efficacy of ARIXTRA(r) for the Prevention of Adjudicated Death (All Cause Mortality) in STEMI up to 6 months in OASIS 6 (All Randomized Patients)

Patients randomized to ARIXTRA(r) received an IV bolus injection of 2.5 mg followed by 2.5 mg by SC injection daily for up to 8 days or discharge.

Patients randomized to UFH received an IV bolus injection 60 IU/kg followed by an infusion of 12 IU/kg/hr for 24 to 48 hours.

The hazard ratio, ARIXTRA(r) versus control, was adjusted for treatment group and strata.

Adjusted hazard ratio p-value.

Placebo patients did not receive unfractionated heparin as an anticoagulant.

The results for the primary endpoint (death or reinfarction) at Day 30 by reperfusion strategy are presented in Table 34.

Table 34 Efficacy of ARIXTRA(r) for the Prevention of Adjudicated Death or Reinfarction in STEMI up to Day 30 in OASIS 6 by Initial Reperfusion Strategy (All Randomized Patients)

1. p-value versus control: 0.008

2. Patients not undergoing primary PCI

3. UFH Not Indicated

4. UFH Indicated

The rates of major bleeding episodes for STEMI patients treated with ARIXTRA(r) vs. control (UFH/placebo) are provided in Table 7 (see ADVERSE REACTIONS). The results for major bleeding by initial reperfusion strategy are presented in Table 35.

Table 35 Major Bleeding in the OASIS 6 study by Initial Reperfusion Strategy (As Treated Patients)

1. Patients not undergoing primary PCI

2. UFH Not Indicated

3. UFH Indicated

DETAILED PHARMACOLOGY

Effect on thrombosis in animal models

Fondaparinux has potent dose-dependent antithrombotic activity in a variety of models of experimental thrombosis. The inhibitory activity varies according to the nature of the thrombotic stimulus and the location of the thrombus i.e. venous (low shear) and arterial (high shear). Antithrombotic activity is generally achieved at concentrations below those required to saturate plasma ATIII concentrations, with the exception of the inhibition of the thromboplastin-induced thromboembolism which occurs at doses far above antithrombin III-saturating levels. The duration of the antithrombotic activity is correlated with that of anti-factor Xa activity.

Safety Pharmacology:

Fondaparinux sodium

Showed no relevant effects on the central nervous systemDid not affect body weight, body temperature and gastro-intestinal motilityHad no significant effect on electrolyte balanceDid not induce relevant changes in cardiovascular and respiration parametersDid not affect coagulation time, defined as aPTT and PT (see PRECAUTIONS - Coagulation Tests), blood cell counts, hemoglobin concentration and hematocrit in animalsHad little effect on bleeding in the subdermal bleeding model in the rat and in the ear bleeding model in the rabbit at doses that are 25 times higher than the dose resulting in the saturation of antithrombin III (0.8 mg/kg)Did not bind to Human Platelet Factor 4 (unlike heparin) and did not cross-react with Heparin Induced Thrombocytopenic (HIT) sera from HIT-patients. On the basis of these data, no antibody-induced thrombocytopenia is anticipated with fondaparinux in humansDid not influence lipid metabolism through the release of triglyceride lipase activity in rats (unlike heparin)

TOXICOLOGY

Acute Toxicity

Single subcutaneous or intravenous doses of 40 mg/kg were well tolerated in mice, rats and monkeys. No lethal effects were observed. This dose represents up to 1200 times the recommended human dose.

Long Term Toxicity

Repeated dose toxicity studies were performed in rats and monkeys at dose levels of 0.4, 2 and 10 mg/kg/d, up to 12, 60 and 300 times the recommended human doses. Fondaparinux had low toxicity and induced mainly an increase of the trauma-related hemorrhage. Small numbers of animal deaths were due to hemorrhage and hematomas. These were primarily attributed to repeated injection traumas and to the pharmacological activity of the compound. In monkey studies, some large hematomas were also observed at handling sites, blood puncture and anaesthetic injection sites.

Carcinogenicity

Fondaparinux has not been tested for its carcinogenic potential in long-term animal studies.

Mutagenicity

Fondaparinux was not mutagenic in the in vitro Ames Test nor the mouse lymphoma cell (L5178Y/TK+/2) forward mutation test. Fondaparinux was not clastogenic in the human lymphocyte chromosomal aberration test, rat hepatocyte unscheduled DNA synthesis (UDS) test or in the in vivo rat micronucleus test.

Reproduction and Teratology

Fondaparinux at doses up to 10 mg/kg/day (i.e., doses up to 280 times the human daily doses) did not impair the reproduction parameters studied: rat mating performance and fertility, rat and rabbit gestation and embryo-fetal development and rat parturition, lactation, new-born viability and growth, F1 behaviour and reproduction and F2 fetal development. The main treatment-related findings were hematomas and hemorrhage at the injection site. The only other treatment-related finding noted was one fatality associated with hematoma and changes in liver and lungs. Very low placental transfer and very limited excretion in the milk were demonstrated in rats.

REFERENCES

1. Boneu B, Necciari J, Cariou R et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74(6):1468-73.

2. Lormeau JC, Herault JP . The effect of the synthetic pentasaccharide SR90107/Org31540 on thrombin generation ex vivo is uniquely due to ATIII- mediated neutralization of factor Xa. Thromb Haemost 1995; 74(6):1474-7.

3. Lormeau JC, Herault JP, Gaich C et al. Determination of the anti-factor Xa activity of the synthetic pentasaccharide SR90107A/Org31540 and of two structural analogues. Thromb Res 1997; 85(1):67-75.

4. Lormeau JC, Herault JP, Herbert JM . Antithrombin-mediated inhibition of factor VIIa-tissue factor complex by the synthetic pentasaccharide representing the heparin binding site to antithrombin. Thromb Haemost 1996; 76(1):5-8.

5. Eriksson BI., Bauer KA., Lassen MR., Turpie AG. Influence of the duration of fondaparinux (ARIXTRA(r)) prophylaxis in preventing venous thrombembolism following major orthopedic surgery. J. Thromb. Haemost., 2003; 1(2), 383-384.

6. The Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. N Engl J Med 2003; 349: 1695 - 702.

7. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al.

Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes. N Engl J Med. 2006; 354:1464-1476. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. OASIS- 6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006 Apr 5; 295(13):1519-30.

PART III: CONSUMER INFORMATION

PrARIXTRA(r)

fondaparinux sodium injection

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

ABOUT THIS MEDICATION

What the medication is used for:

ARIXTRA(r) is a synthetic antithrombotic agent (against blood

clotting). An antithrombotic drug helps prevent clots from forming in the blood. ARIXTRA(r) is used:

• to prevent the occurrence of venous thromboembolic events (blood clots in the blood vessels of the legs or lungs) for up to one month post-surgery in patients undergoing orthopedic surgery of the lower limbs (hip fracture, knee surgery or hip replacement surgery);

• to treat acute deep vein thrombosis (blood clots in a deep vein of the legs) and acute pulmonary embolism (blood clots in the blood vessels of the lungs);

• for the management of unstable angina or non-ST segment elevation myocardial infarction (severe chest pain and a type of heart attack);

• for the management ST segment elevation myocardial infarction (severe heart attack);

What it does:

ARIXTRA(r) contains fondaparinux sodium, a synthetic

compound, that inhibits specifically a clotting factor and plays an important role in blood coagulation. It helps to prevent the development of unwanted blood clots (thrombosis) in blood vessels and is useful in dissolving existing blood clots.

When it should not be used:

if you are allergic to fondaparinux sodium or any of its constituents;

if you have thrombocytopenia (an abnormally small number of platelets in the circulating blood) associated with a positive lab test for anti-platelet protective protein in the presence of fondaparinux sodium (see your doctor);

if you are bleeding excessively;

if you suffer from bacterial infection of the heart;

What the medicinal ingredient is:

Fondaparinux sodium

What the important nonmedicinal ingredients are:

Isotonic solution of sodium chloride, water for injection and, if necessary, sodium hydroxide or hydrochloric acid for pH

adjustment (pH 5-8).

What dosage forms it comes in:

ARIXTRA(r) is a solution for injection supplied in a sterile pre-

filled syringe with built-in automatic needle protection to help prevent needle injuries after use.

Package of 10:

Single use 2.5 mg/0.5 mL pre-filled syringes.

Packages of 2, 7 and 10:

Single use 5 mg/0.4 mL pre-filled syringe,

Single use 7.5 mg/0.6 mL pre-filled syringe,

Single use 10 mg /0.8 mL pre-filled syringe.

WARNINGS AND PRECAUTIONS

It is important that you provide your doctor with an accurate history of any serious illnesses you may have had in the past or any current medical conditions, as these may influence the action of ARIXTRA(r).

BEFORE you use ARIXTRA(r), talk to your doctor or pharmacist if:

you weigh less than 50 kg or are 75 years of age or older.

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

• you are allergic to fondaparinux sodium;

• you suffer from bacterial infection of the heart;

• you are bleeding excessively;

• you have a risk of hemorrhage (uncontrolled bleeding), such as:

• stomach ulcer;

• bleeding disorders;

• recent intracranial bleeding;

you have had recent brain, spinal column or eye surgery;

you have liver disease;

you have kidney disease.

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.

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

INTERACTIONS WITH THIS MEDICATION

Some other medicines may affect the way ARIXTRA(r) works or vice versa. Please tell your doctor or pharmacist what medicine you have recently taken, are taking or intend to take since these medicines might affect blood clotting, even those available without prescription such as acetylsalicylic acid (i.e.,

Aspirin(r)). If you should see another doctor or a dentist while you are using ARIXTRA(r), you should inform/tell them that you are using ARIXTRA(r).

The different parts of ARIXTRA(r)

1 Rigid needle guard 2 Cap

1. Plunger

2. Finger-grip

3. Security sleeve

safety syringe are:

PROPER USE OF THIS MEDICATION

Usual dose:

ARIXTRA is a prescription drug and must be used as directed. ARIXTRA(r) is given by injection under the skin (subcutaneously) into a skin fold of the lower stomach area.

For a step-by-step 'Instructions for use' please see below. Do not inject ARIXTRA(r) into muscle (intramuscularly).

While you are in the hospital, your doctor or a nurse will give your first injection. It is possible that after you go home, you may need to continue your injections of ARIXTRA(r) for a few

days.

For prevention of blood clots following orthopedic surgery: The usual dose of ARIXTRA(r) (fondaparinux sodium) is 2.5 mg once a day.

For treatment of blood clots:

The usual dose of ARIXTRA(r) is 5 mg (body weight < 50 kg),

7.5 mg (body weight 50-100 kg) or 10 mg (body weight

> 100 kg) once daily.

In the management of heart attacks or severe angina:

The usual dose of ARIXTRA(r) is 2.5 mg once daily

You should continue ARIXTRA(r) treatment for as long as your doctor has told you, since ARIXTRA(r) decreases the risk of developing more serious conditions.

Always use ARIXTRA(r) exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.

Syringe BEFORE USE Syringe AFTER USE

1. Plunger

2. Finger-grip

3. Security sleeve

Instructions for self-injection of ARIXTRA(r)

Wash your hands thoroughly with soap and water. Towel dry. When at home, there is nothing for you to prepare. The syringe

is pre-filled with the exact amount of drug required. Do not press on the plunger prior to injection.

Sit or lie down in a comfortable position. Choose a spot in the lower stomach area, at least 5 cm from your belly button (Figure 1). If injecting in the stomach area is not possible, consult your nurse or doctor for instruction. Alternate the left and right side of the stomach at each injection.

Figure 4

Clean the injection area with an alcohol swab. Hold the body of the syringe firmly in one hand.

Remove the cap that protects the plunger by pulling it off (Figure 2). Discard the plunger cap.

Figure 2

Hold the syringe firmly by the finger grip.

Insert the full length of the needle perpendicularly (at an angle of 90deg) into the skin fold (Figure 5).

Figure 5

Inject ALL of the contents of the syringe by pressing down on the plunger as far as it goes. This will activate the automatic needle protection system (Figure 6)

Remove the needle guard, by first twisting it and then pulling it in a straight line away from the body of syringe (Figure 3). Discard the needle guard.

Figure 3

Figure 6

Release the plunger and the needle will withdraw automatically from the skin and retract into the security sleeve where it will be locked permanently (Figure 7)

Important note

Do not touch the needle or allow it to come into contact with any surface prior to 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 in order to be sure that you do not lose any product.

Discard the used syringe.

Figure 7

Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger during the entire injection (Figure 4).

Overdose:

Contact your doctor or pharmacist because of the increased risk

of bleeding.

Missed Dose:

NEVER inject a double dose to make up for forgotten individual doses. If you are not sure what to do, ask your

doctor or pharmacist before you take any action.

If you stop treatment before your doctor told you to, you are at risk of developing a blood clot in a vein of your leg or in the lung. Contact your doctor or pharmacist before stopping treatment if for any reason you feel you need to stop the treatment.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

ARIXTRA(r) helps most people in the prevention of blood clots. However, like all medicines it may have unwanted effects on some people.

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

bleeding from the surgical wound

oozing of fluid from the wound, swelling around the wound

chest pain

unusual tiredness or weakness

fever, nausea, dizziness, headache, allergic reaction

rash or itching (pruritis), slight bruising (purpura), local eruption

constipation, diarrhea, vomiting, dyspepsia, abdominal pain

Mild irritation, pain, bruising and redness may occur at the site of injection.

Contact your doctor or pharmacist if you experience one or more of the above mentioned unwanted effects.

If you notice any unwanted effects not mentioned above, please inform your doctor or pharmacist.

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

HOW TO STORE IT

ARIXTRA(r) should be stored between 15-30degC. Do not freeze. Keep out of the reach and sight of children.

Do not use ARIXTRA(r) under the following conditions:

after the expiry date stated on the label and carton

if you notice that particulate matter or discoloration is present in the solution

if you notice that the syringe is damaged

if you have opened a syringe and do not intend to use it straight away.

Any unused syringe should be disposed of in a safe manner.

REPORTING SUSPECTED SIDE EFFECTS

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

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician 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: June, 2007

(c)

2007 GlaxoSmithKline Inc. All Rights Reserved

(r)

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

(r)

Aspirin is a registered trademark of BAYER

AKTIENGESELLSCHAFT