Factor Xa Inhibition in the Management of Venous Thromboembolism: Important Safety Information. Important Safety Information (cont d)

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1 Factor Xa Inhibition in the Management of Venous Thromboembolism: The Role of Fondaparinux WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants a history of traumatic or repeated epidural or spinal puncture a history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. XRA9R Important Safety Information CONTRAINDICATIONS ARIXTRA is contraindicated in the following conditions: Severe renal impairment (creatinine clearance < ml/min) in prophylaxis or treatment of venous thromboembolism. Active major bleeding. Bacterial endocarditis. Thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux sodium. Body weight < kg (venous thromboembolism prophylaxis only). Important Safety Information (cont d) WARNINGS AND PRECAUTIONS Use with caution in patients who have conditions or who are taking concomitant medications that increase risk of hemorrhage. Bleeding risk is increased in renal impairment and in patients with low body weight. Thrombocytopenia can occur with administration of ARIXTRA. Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended The packaging (needle guard) contains dry natural rubber and may cause allergic reactions in latex sensitive individuals

2 Incidence and Consequences of Venous Thromboembolism (VTE) Incidence More than, hospitalizations occur each year due to VTE % of hospital deaths can be attributed to pulmonary embolism (PE) per year Overall mortality rate within month of diagnosis % for PE Consequences % for deep vein thrombosis (DVT) Acute PE Recurrent VTE : Highest within first - months 7% within years following initial treatment % within years following initial treatment Post-thrombotic syndrome (PTS). Rosamond W et al. Circulation. 8;7:e-e.. Heit JA. J Thromb Haemost. ;:-7.. Prandoni P et al. Haematologica. 997;8:-8.. Bradjes DPM. Lancet. 997;9:79-7. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and National Quality Forum (NQF) Measures VTE is preventable and it is the most common preventable cause of hospital death. JCAHO/NQF VTE Measures Effective Screening Prevention Treatment JCAHO and NQF have paired to provide a framework of measures for effective screening, prevention, and treatment for persons at risk of VTE. NQF VTE Measures 8. Accessed February,.. NQF Project Brief. Accessed February,. Patient Characteristics and Surgical Risk Factors for VTE VTE Patient Characteristics, Surgical Risk Factors Major surgery Prolonged immobility Previous VTE Obesity Varicose veins Increasing age Paralysis Smoking Pregnancy Estrogen use Malignancy Cancer therapy Procedure Duration of procedure Surgical site Surgical technique Anesthesia Presence of infection Postoperative immobilization. Geerts WH et al. Chest. ;( suppl):8s-s.. Heit JA et al. Arch Intern Med. ;: Geerts WH et al. Chest. ;9( suppl):s-7s.

3 Mechanisms of Anticoagulation Intrinsic system (surface contact) XII XI XIIa XIa Extrinsic system (tissue damage) Tissue factor IX IXa VIIa VII Unfractionated heparin, VIII Low molecular-weight heparins, VIIIa X Xa Vitamin K antagonists Direct thrombin inhibitors, Factor Xa inhibitors, V Va II Fibrinogen IIa (Thrombin) Fibrin. Adapted with permission from Petitou M et al. Nature. 99;(9 suppl):-.. Hirsh J, Fuster V. Circulation. 99;89:9-8.. Hirsh J et al. Chest. ;9( suppl):s-9s.. Nutescu EA et al. Pharmacotherapy. ;(7 Pt ):8S-87S.. Bauer KA. J Thromb Thrombolysis. ;: ARIXTRA (fondaparinux sodium) Is a Nonheparin, Selective Factor Xa Inhibitor Intrinsic pathway Extrinsic pathway AT AT AT Xa Xa II IIa Fibrinogen ARIXTRA reversibly binds AT, causing a conformational change Fibrin clot AT affinity for Factor Xa increases, enhancing inhibitory effect of AT by X Thrombin (IIa) generation is inhibited, leading to reduced thrombus development AT: antithrombin. : ARIXTRA. Adapted from Turpie AG et al. N Engl J Med. ;:9-. Prescribing Information for ARIXTRA. 8 Differentiating Biochemical Properties of ARIXTRA First and only FDA-approved selective Factor Xa inhibitor Unique mechanism of action ARIXTRA acts selectively on Factor Xa Small, synthetic compound Small size prevents interaction with thrombin Made exclusively by chemical synthesis NOT derived from animal sources, Batch-to-batch consistency Not made from any heparin products. Lassen et al. Lancet. ;9:7-7.. Comp PC. Pharmacotherapy. ;: Data on file, GlaxoSmithKline. 9

4 Biochemical Properties of ARIXTRA Inhibition of thrombin generation (%) 7 ARIXTRA Effectively Inhibits Thrombin Generation Anti-Factor Xa (units/ml) Factor Xa inhibition results in linear, dose-dependent inhibition of thrombin generation Nonheparin anticoagulant with a rapid onset of action Provides patients a quick anticoagulant response Allows once-daily dosing without aptt monitoring Concentration of ARIXTRA (µg/ml) Rapid Onset of Action of ARIXTRA T max C max Half-life hours. µg/ml 7 to hours Bioavailability % 8 8 Time (hours) aptt = activated partial thromboplastin time.. Adapted with permission from Lormeau JC, Herault JP. Thromb Haemost. 99;7: Donat F et al. Clin Pharmacokinet. ;(suppl ):-9. Benefits of ARIXTRA ARIXTRA is the st available FDA-approved, nonheparin, injectable anticoagulant ARIXTRA Always dosed once-daily Synthetic, nonheparin compound Specific Factor Xa inhibition Rapid onset of action Does not inactivate thrombin st FDA-approved in unique class Important Safety Information ARIXTRA is contraindicated in the following conditions: Severe renal impairment (creatinine clearance < ml/min) in prophylaxis or treatment of venous thromboembolism. Body weight < kg (venous thromboembolism prophylaxis only). Bleeding risk is increased in renal impairment and in patients with low body weight.

5 Clinical Development of ARIXTRA in PE and DVT: Evaluated in More Than, Patients Indication Trial Population Comparator Orthopedic surgery No. randomized Year completed Penthifra Hip fracture Enoxaparin Penthifra Plus Hip fracture extended prophylaxis Placebo Pentathlon Hip replacement Enoxaparin 7 Ephesus Hip replacement Enoxaparin 9 Pentamaks Knee replacement Enoxaparin 9 Abdominal surgery Treatment of acute VTE PEGASUS Abdominal Dalteparin 97 surgery* APOLLO Abdominal IPC ± ES 9 surgery* MATISSE DVT Acute DVT Enoxaparin MATISSE PE Acute PE UFH *In patients at high risk of VTE. IPC = Intermittent pneumatic compression. ES = Elastic stockings. 8 ACCP Guidelines for Antithrombotic and Thrombolytic Therapy The American College of Chest Physicians (ACCP) has successfully provided high-quality clinical practice guidelines for over years Extensive review of literature for management of thromboembolic disorders Grading system has been revised for the purposes of consistency and comparison with other guidelines Less confusion compared with other recommendations This grading system is used by many organizations: American College of Physicians American Thoracic Society World Health Organization Clinicians are most interested in the best course of action when considering a treatment, therefore the strength of the recommendation is integrated into the grading system. Baumann MH, Gutterman DD. Chest. ;9:-;. Hirsh et al. Chest. 8;:7S-9S;. Guyatt GH et al. Chest. 8;S-S. ACCP Grades of Recommendation Strength of recommendation is determined by considering the benefit vs the harm and the quality of evidence Grade : Strong recommendation indicating that benefits outweigh the harms, burdens, or costs Grade : Weaker recommendation, less certainty of benefits Grade A: Quality, randomized, controlled trials with unbiased results Grade B: Randomized, controlled trials with inconsistent results, poor study design, and/or biased results Grade C: Low-quality evidence or observational studies Guyatt GH et al. Chest. 8;S-S.

6 Summary of ACCP Recommendations VTE treatment Fondaparinux LMWH UFH VKA Treatment of DVT (When administered in conjunction with warfarin) Treatment of PE (When administered in conjunction with warfarin and when initial therapy is started in the hospital) VTE prophylaxis A A A * A A A * Elective hip replacement A A Elective knee replacement A A Hip fracture surgery A B Hip fracture surgery with extended prophylaxis Abdominal surgery (In patients at risk of thromboembolic complications) B (LDUH) A (adjusted dose) A (adjusted dose) B (adjusted dose) A C C A A A (LDUH) * When used in conjunction with warfarin. Abdominal surgery indication is included generally in section.. and.. in ACCP guidelines regarding general surgery on pages 9S-9S. Hirsh et al. Chest. 8;:7S-9S. 8 Recommendations for the Treatment of Venous Thromboembolism (VTE) A grade of A signifies a strong recommendation based on high-quality evidence Treatment of Deep Vein Thrombosis (DVT) In patients with acute DVT, fondaparinux, low molecular-weight heparin (LMWH), or unfractionated heparin (UFH) in combination with vitamin K antagonist (VKA) are recommended for treatment with a grade of A In patients with acute DVT, initiation of a VKA plus ARIXTRA, LMWH, or UFH is recommended on the first treatment day rather than delayed initiation of VKA (Grade A) Treatment of Pulmonary Embolism (PE) Fondaparinux, LMWH, or UFH in combination with VKA are recommended for the treatment of confirmed PE with a grade of A In patients with acute PE, initiation of a VKA plus ARIXTRA, LMWH, or UFH is recommended on the first treatment day rather than delayed initiation of VKA (Grade A) Hirsh et al. Chest. 8;:7S-9S. 7 MATISSE Studies: ARIXTRA for the Treatment of PE and DVT Objectives: Noninferiority studies designed to demonstrate the effectiveness of ARIXTRA in the treatment of PE and DVT, Primary efficacy outcome: incidence of symptomatic recurrent VTE during -month study period Primary safety outcome: incidence of major bleeding during initial treatment period PE study To evaluate the efficacy and safety of subcutaneous ARIXTRA QD compared with intravenous UFH in the treatment of acute, symptomatic PE DVT study To evaluate the efficacy and safety of ARIXTRA QD compared with enoxaparin BID in the treatment of acute, symptomatic DVT. Büller HR et al. N Engl J Med. ;9:9-7.. Büller HR et al. Ann Intern Med. ;:

7 MATISSE PE Study: Study Design Randomized, Open-label, Multicenter Study Eligibility and randomization (n = ) ARIXTRA (., 7., or. mg) daily* (n = ) Treatment continued for at least days Vitamin K antagonists (started within 7 hours of treatment and continued for up to months) *. mg in patients < kg 7. mg in patients kg kg. mg in patients > kg UFH IU IV bolus followed by IU/ hour continuous IV infusion (n = ) Treatment continued for at least days Vitamin K antagonists (started within 7 hours of treatment and continued for up to months) Until the international normalized ratio was >. for consecutive days. Büller HR et al. N Engl J Med. ;9: MATISSE PE Study: Patient Characteristics Characteristic ARIXTRA (n = ) UFH (n = ) Mean age, yr ±. ±.7 Male/female / 77/ Mean body weight, kg 8 ± ± 9. Previous VTE 9 (.7%) (.%) Known prothrombotic state 8 (.%) (.7%) Surgery or trauma (< months ago) 8 (.%) (.%) Büller HR et al. N Engl J Med. ;9:9-7. MATISSE PE Study: ARIXTRA Was at Least as Effective as UFH in Treating PE Patients with recurrent venous thromboembolic events (%).8 An absolute difference of -. (9% CI -. to.) for all recurrent VTE shows ARIXTRA was as effective as UFH P = NS ARIXTRA (n = )... UFH (n = )... n = n = n = n = 7 n = n = n = n = All VTE DVT only Fatal PE Nonfatal PE. Primary outcome Secondary outcomes NS = not significant. Patients were also treated with vitamin K antagonist within 7 hours after the first administration of the study drug; VTE was a composite of symptomatic, recurring, nonfatal VTE, or fatal PE occurring throughout entire study.. Büller HR et al. N Engl J Med. ;9:9-7. 7

8 MATISSE DVT Study: Study Design Double-blind, Randomized, Multicenter Study Eligibility and randomization (n = ) ARIXTRA (., 7., or. mg) daily* (n = 98) Treatment continued for at least days Vitamin K antagonists (started within 7 hours of treatment and continued for up to months) Enoxaparin ( mg/kg) BID (n = 7) Treatment continued for at least days Vitamin K antagonists (started within 7 hours of treatment and continued for up to months) *. mg in patients < kg 7. mg in patients kg kg. mg in patients > kg Until the international normalized ratio was >. for consecutive days. Büller HR et al. Ann Intern Med. ;: MATISSE DVT Study: Patient Characteristics Characteristic ARIXTRA (n = 98) Enoxaparin (n = 7) Mean age, yr. ±.7. ±. Male/female 8/7 78/9 Mean body weight, kg 79. ± ± 7. Previous VTE 7 (.9%) 8 (.%) Known prothrombotic state 8 (.%) (.7%) Surgery or trauma (< months ago) (.9%) (.7%) Büller HR et al. Ann Intern Med. ;: MATISSE DVT Study: ARIXTRA Was at Least as Effective as Enoxaparin in Treating DVT Patients with recurrent venous thromboembolic events (%) An absolute difference of -. (9% CI -.8 to.) for all recurrent VTE shows ARIXTRA is as effective as enoxaparin P = NS... ARIXTRA (n = 98) Enoxaparin (n = 7).. n = n = n = 8 n = 8 n = n = n = n = All VTE DVT only Fatal PE Nonfatal PE.8. Primary outcome Secondary outcomes VTE was a composite of symptomatic, recurring, nonfatal VTE, or fatal PE occurring throughout entire study.. Büller HR et al. Ann Intern Med. ;:

9 Patients (%) ARIXTRA Had Major Bleeding Rates Similar to UFH/ Enoxaparin in Patients With PE/DVT 8 Absolute difference (9% CI). P = NS... Patients (%) n = n = n = 9 n = 9 n = n = n = n = Major bleeding. (-.7 to.) Major bleeding* results from Pegasus and APOLLO MATISSE PE ARIXTRA (N = 9) UFH (N = 9) P = NS Major and nonmajor bleeding -.8 (-.7 to.) 8. P = NS. Major bleeding -. (-. to.8) Bleeding during initial treatment is shown. MATISSE DVT ARIXTRA (N = 9) Enoxaparin (N = ) P = NS.7. Major and nonmajor bleeding -. (-. to.) * Major bleeding was defined as being clinically apparent and associated with a decrease of g/dl or more in the hemoglobin level, leading to the transfusion of or more units of red cells or whole blood, being retroperitoneal or intracranial, occurring in a critical organ, or contributing to death. Mean duration of initial treatment in MATISSE PE study:. days ±. ARIXTRA;.9 ±. days UFH. Mean duration of initial treatment in MATISSE DVT study: 7. days ±. ARIXTRA; 7. days ±. enoxaparin.. Büller HR et al. N Engl J Med. ;9:9-7.. Büller HR et al. Ann Intern Med. ;: ARIXTRA for the Prophylaxis of VTE: In Patients Following Major Orthopedic Surgery* and at Risk Undergoing Abdominal Surgery *Major orthopedic surgery included elective hip replacement, hip fracture, and knee replacement surgeries. At-risk patients were > years of age, or between the ages of and years, with or more additional risk factors for VTE or who were undergoing abdominal surgery with general anesthesia expected to last > minutes. 8 Recommendations for Orthopedic Surgery Elective Hip Replacement Fondaparinux, LMWH, or adjusted-dose VKA are recommended as an anticoagulant option for elective hip replacement surgery with a grade of A Elective Knee Replacement Fondaparinux, LMWH, or adjusted-dose VKA are recommended for thrombophylaxis for elective knee replacement surgery with a grade of A Hirsh et al. Chest. 8;:7S-9S. 7 9

10 8 Recommendations for Orthopedic Surgery Hip Fracture Surgery For hip fracture surgery, fondaparinux received a recommendation with a grade of A for thrombophylaxis, while LMWH, LDUH, and adjusted-dose VKA both received grades of B Hip Fracture Surgery with Extended Prophylaxis Extended thrombophylaxis ( days up to days after surgery) for hip fracture surgery is recommended using fondaparinux (Grade A), LMWH (Grade C), or VKA (Grade C) Hirsh et al. Chest. 8;:7S-9S. 8 ARIXTRA Significantly Reduced the Rate of VTE Compared With Enoxaparin Following Major Orthopedic Surgery* Incidence of venous thromboembolic events up to Day (%) 8 ARIXTRA Reduced the Rate of VTE by.%.8 *Major orthopedic surgery included elective hip replacement, hip fracture, and knee replacement surgeries. In of the studies, ARIXTRA reduced the rate of VTE by %, %, and % vs enoxaparin (P<.). - In the fourth study, ARIXTRA reduced VTE by % vs enoxaparin (P = NS). Individual study data not shown. ARIXTRA is contraindicated in patients < kg for VTE prophylaxis..turpie AG et al. Arch Intern Med. ;:8-8.. Eriksson BI et al. N Engl J Med. ;:98-.. Bauer KA et al. N Engl J Med. ;:-.. Lassen MR et al. Lancet. ;9:7-7.. Turpie AG et al. Lancet. ;9:7-7. P <..7 (8/ 8) (7/ 7). (7/ 77). (/ 98) ARIXTRA Enoxaparin VTE DVT Proximal DVT Distal DVT Primary outcome Secondary outcomes A meta-analysis of randomized, double-blind clinical trials. (/ 7).9 (8/ 77. (/ 7).8 (9/ 79 9 Positive Bleeding Index Largely Accounts for Higher Bleeding Incidence* ARIXTRA (N = ) Enoxaparin (N = ) Patients (%) n = n = 9 n = n = 8 n= n = n = 8 n = n = n = Major bleeding Bleeding Led to Critical Fatal in perioperative index of re-operation organ prophylaxis trials Type of Major Bleeding *Perioperative orthopedic prophylaxis (Day to Day 7 ± postsurgery). Does not include extended prophylaxis (Day 8 to Day 8 ± postsurgery). Bleeding Index is calculated as the number of packed red blood cells or whole blood transfused plus prebleeding minus postbleeding hemoglobin (g/dl) values. Turpie AG et al. Arch Intern Med. ;:8-8.

11 Proper Timing of First Injection ( to 8 hours) Following Surgery Significantly Reduced Incidence of Major Bleeding.8 Patients with a bleeding index (%)...8. (/) (/89) (/7) (/) (9/9) Time from surgical closure to first injection (hours) Efficacy of ARIXTRA was not affected by injection timing (P =.7) When given hours after surgery, in accordance with prophylaxis recommendations, the incidence of major bleeding with ARIXTRA was reduced Adapted from Kwong LM, Muntz JE. Am J Orthop. ;(suppl ):-. 8 Recommendations for General Surgery General Surgery With Risk Characteristics Fondaparinux, LMWH, or LDUH are recommended for thromboprophylaxis in patients in benign disease at moderate risk undergoing general surgery with a grade of A For patients at higher risk during general surgery in cancer patients, fondaparinux, LMWH, or LDUH tid are recommended for thromboprophylaxis with a grade of A Please note: While the guidelines recommend fondaparinux for general surgery, ARIXTRA is not FDA-approved for general surgery. ARIXTRA is indicated for the prophylaxis of VTE in patients undergoing abdominal surgery at risk of thromboembolic complications. Abdominal surgery indication is included generally in section.. and.. in ACCP guidelines regarding general surgery on pages 9S-9S. Hirsh et al. Chest. 8;:7S-9S. PEGASUS Study: Study Design Randomized, Double-blind Clinical Trial ARIXTRA (. mg) QD (n = ) Eligibility and randomization (n = 8) Start hours post-op Double-blind Treatment 7 ± days Inclusion criteria High-risk* abdominal surgery under general anesthesia Surgery duration > min (incision to closure) Dalteparin IU pre-op and post-op IU once-daily post-op (n = ) Start hours pre-op Venogram Day - Follow-up Day ± *Age > years with or without additional risk factor for VTE; or age > years with at least additional risk factor for VTE. For VTE prophylaxis, ARIXTRA is contraindicated in patients < kg undergoing surgery. Agnelli G et al. Br J Surg. ;9:-.

12 APOLLO Study: Study Design Randomized, double-blind clinical trial with ARIXTRA in combination with mechanical prophylaxis ARIXTRA (. mg) QD + IPC ± ES (n = ) Eligibility and randomization (n = 9) Prophylaxis up to 7 ± days Start ARIXTRA or placebo -8 hr postoperatively (QD) after incision closure and established hemostasis Placebo + IPC ± ES (n = 9) Inclusion criteria Patients > yrs and > kg undergoing abdominal surgery Surgery duration > min (incision to closure) Venogram Day - Follow-up Day ± For VTE prophylaxis, ARIXTRA is contraindicated in patients < kg undergoing surgery. Turpie AG et al. J Thromb Haemost. 7;:8-8. ARIXTRA Provided Proven Protection From VTE in Patients at High Risk* Undergoing Abdominal Surgery Patients with venous thromboembolic events (%) 7 PEGASUS APOLLO ARIXTRA (n = 7) Dalteparin (n = ).. Patients with venous thromboembolic events (%) n = 7 n = n = 7 n = VTE VTE ARIXTRA was as effective as dalteparin in the prevention of VTE ARIXTRA in combination with IPC reduced the risk of VTE 7 ARIXTRA (n = ) Placebo (n = 8) P =...7 *> years with or without additional risk factors for VTE, or > years with at least one additional risk factor for VTE, and undergoing abdominal surgery with general anesthesia expected to last > minutes.. Agnelli G et al. Br J Surg. ;9:-.. Turpie AG et al. J Thromb Haemost. 7;:8-8. Major Bleeding Results from PEGASUS and APOLLO in Patients at High Risk Undergoing Abdominal Surgery Patients (% PEGASUS APOLLO ARIXTRA (n = ) Dalteparin (n = ) ARIXTRA (n = ) Placebo (n = ) P =... Patients (%) P =.. n = 9 n =. n = n = Major bleeding * Major bleeding * 97.% of patients who received ARIXTRA were free from major bleeding when the dose was administered hours after surgery. *During the treatment period: from the first injection -8 hours after surgery to days following last injection. Major bleeding was defined as any of the following: fatal, retroperitoneal, intracranial, intraspinal, or involving any other critical organ leading to intervention; bleeding at the surgical site leading to intervention; and/or with a bleeding index.. Agnelli G et al. Br J Surg. ;9:-.. Turpie AG et al. J Thromb Haemost. 7;:8-8.

13 FDA-Approved VTE-related Indications for ARIXTRA FDA-approved indication ARIXTRA Enoxaparin Treatment of PE, including outpatient - When administered in conjunction with warfarin and initiated in the hospital Treatment of DVT, including outpatient - When administered in conjunction with warfarin Abdominal surgery prophylaxis - In patients at risk for thromboembolic complications Knee replacement prophylaxis Hip replacement prophylaxis Hip fracture surgery prophylaxis Hip fracture surgery extended prophylaxis Lovenox is a registered trademark of sanofi-aventis U.S. LLC.. Prescribing Information for Lovenox (enoxaparin sodium injection). 7 ARIXTRA and Surgical Care Improvement Project (SCIP) SCIP: A Partnership for Better Care SCIP is a national quality partnership of organizations committed to improving the safety of surgical care through the reduction of postoperative complications VTE measures Recommended VTE prophylaxis ordered in surgery patients Appropriate VTE prophylaxis received within hours prior to surgery to hours after surgery ARIXTRA is included as an option for Hip fracture surgery General and gynecological surgery ARIXTRA is not FDA-approved for general and gynecological surgery. ARIXTRA is indicated for abdominal surgery in patients who are at risk for thromboembolic complications Elective total knee replacement surgery Elective total hip replacement surgery SCIP Goal: To reduce the incidence of surgical complications by % by. Surgical Care Improvement Project. Accessed July, 8.. SCIP VTE- and VTE-. %FPage%FQnetTier&c=Page. Accessed February,. 8 Once-daily Dosing Across All Indications for ARIXTRA Prophylaxis of VTE Patient weight kg* ARIXTRA daily dose. mg *Contraindicated for prophylaxis in patients < kg Treatment of PE and DVT Patient weight ARIXTRA daily dose < kg mg kg- kg 7. mg > kg mg Usual duration of administration with ARIXTRA is to 9 days Following hip fracture surgery, extended prophylaxis for up to additional days is recommended Simplified fixed dosing across a broad range of weights for treatment of PE and DVT Initiate warfarin within 7 hours after starting ARIXTRA and overlap therapies. ARIXTRA should be continued for at least days and until a therapeutic INR of. to. is reached Single-dose, prefilled syringes affixed with an automatic needle protection system 9

14 Important Safety Information WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal antiinflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants a history of traumatic or repeated epidural or spinal puncture a history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Important Safety Information (cont d) CONTRAINDICATIONS ARIXTRA is contraindicated in the following conditions: Severe renal impairment (creatinine clearance < ml/min) in prophylaxis or treatment of venous thromboembolism. Active major bleeding. Bacterial endocarditis. Thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux sodium. Body weight < kg (venous thromboembolism prophylaxis only). Important Safety Information (cont d) WARNINGS AND PRECAUTIONS Use with caution in patients who have conditions or who are taking concomitant medications that increase risk of hemorrhage. Bleeding risk is increased in renal impairment and in patients with low body weight. Thrombocytopenia can occur with administration of ARIXTRA. Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended The packaging (needle guard) contains dry natural rubber and may cause allergic reactions in latex sensitive individuals

15 Conclusions: ARIXTRA for the Treatment and Prophylaxis of VTE FDA approved for a broad range of indications Proven effective and has a low incidence of major bleeding -9 In the treatment of DVT and PE In VTE prophylaxis for patients undergoing major orthopedic surgery or abdominal surgery Simple once-daily dosing across all its indications in both inpatient and outpatient settings A nonheparin anticoagulant Based on both ACCP and SCIP guidelines, ARIXTRA is recommended as an option for VTE prophylaxis and treatment - *Major orthopedic surgery included elective hip replacement, hip fracture, and knee replacement surgeries.. Büller HR et al. N Engl J Med. ;9:9-7.. Büller HR et al. Ann Intern Med. ;: Turpie AG et al. Arch Intern Med. ;:8-8.. Eriksson BI et al. N Engl J Med. ;:98-.. Bauer KA et al. N Engl J Med. ;:-.. Lassen MR et al. Lancet. ;9: Turpie AG et al. Lancet. ;9: Agnelli G et al. Br J Surg. ;9:-. 9. Turpie et al. Int Soc Thromb Haemo. 7;:8-8.. Surgical Care Improvement Project. Accessed February,.. Hirsh et al. Chest. 8;:7S-9S.. Geerts et al. Chest. 8;:8S-S.