Arixtra

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Spinal or epidural hematomas [see Warnings and Precautions (5.1 )] • Hemorrhage [see Warnings and Precautions (5.2 )] • Renal impairment and bleeding risk [see Warnings and Precautions (5.3 )] • Body weight <50 kg and bleeding risk [see Warnings and Precautions (5.4 )] • Thrombocytopenia [see Warnings and Precautions (5.5) ] The most serious adverse reactions associated with the use of ARIXTRA are bleeding complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information below is based on data from 8,877 patients exposed to ARIXTRA in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Hemorrhage During administration of ARIXTRA, the most common adverse reactions were bleeding complications [see Warnings and Precautions (5.2) ]. Hip Fracture, Hip Replacement, and Knee Replacement Surgery The rates of major bleeding events reported during 3 active-controlled peri-operative VTE prophylaxis trials with enoxaparin sodium in hip fracture, hip replacement, or knee replacement surgery (N = 3,616) and in an extended VTE prophylaxis trial (n = 327) with ARIXTRA 2.5 mg are provided in Table 2. Table 2. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) ARIXTRA 2.5 mg SC once daily N = 3,616 Enoxaparin Sodium Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. , Not approved for use in patients undergoing hip fracture surgery. N = 3,956 ARIXTRA 2.5 mg SC once daily N = 327 Placebo SC once daily N = 329 Major bleeding Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) ≥2. 96 (2.7%) 75 (1.9%) 8 (2.4%) 2 (0.6%) Hip fracture 18/831 (2.2%) 19/842 (2.3%) 8/327 (2.4%) 2/329 (0.6%) Hip replacement 67/2,268 (3.0%) 55/2,597 (2.1%) — — Knee replacement 11/517 (2.1%) 1/517 (0.2%) — — Fatal bleeding 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%) Non-fatal bleeding at critical site 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%) Re-operation due to bleeding 12 (0.3%) 10 (0.3%) 2 (0.6%) 2 (0.6%) BI ≥2 BI ≥2: Overt bleeding associated only with a bleeding index (BI) ≥2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values]. 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0.0%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 109 (3.0%) 116 (2.9%) 5 (1.5%) 2 (0.6%) A separate analysis of major bleeding across all randomized, controlled, peri-operative, prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery according to the time of the first injection of ARIXTRA after surgical closure was performed in patients who received ARIXTRA only post-operatively. In this analysis, the incidences of major bleeding were as follows: <4 hours was 4.8% (5/104), 4 to 6 hours was 2.3% (28/1,196), 6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (≥75%) of the major bleeding events occurred during the first 4 days after surgery. Abdominal Surgery In a randomized study of patients undergoing abdominal surgery, ARIXTRA 2.5 mg once daily (n = 1,433) was compared with dalteparin 5,000 IU once daily (n = 1,425). Bleeding rates are shown in Table 3. Table 3. Bleeding in the Abdominal Surgery Study ARIXTRA 2.5 mg SC once daily Dalteparin Sodium 5,000 IU SC once daily N = 1,433 N = 1,425 Major bleeding Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) ≥2. 49 (3.4%) 34 (2.4%) Fatal bleeding 2 (0.1%) 2 (0.1%) Non-fatal bleeding at critical site 0 (0.0%) 0 (0.0%) Other non-fatal major bleeding Surgical site 38 (2.7%) 26 (1.8%) Non-surgical site 9 (0.6%) 6 (0.4%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 31 (2.2%) 23 (1.6%) The rates of major bleeding according to the time interval following the first ARIXTRA injection were as follows: <6 hours was 3.4% (9/263) and 6 to 8 hours was 2.9% (32/1112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism The rates of bleeding events reported during a dose-response trial (n = 111) and an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) and an active-controlled trial with heparin in PE treatment (n = 1,092) with ARIXTRA are provided in Table 4. Table 4. Bleeding Bleeding rates are during the study drug treatment period (approximately 7 days). Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration. in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies ARIXTRA N = 2,294 Enoxaparin Sodium N = 1,101 Heparin aPTT adjusted IV N = 1,092 Major bleeding Major bleeding was defined as clinically overt: –and/or contributing to death – and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland – and/or associated with a fall in hemoglobin level ≥2 g/dL – and/or leading to a transfusion ≥2 units of packed red blood cells or whole blood. 28 (1.2%) 13 (1.2%) 12 (1.1%) Fatal bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%) Non-fatal bleeding at a critical site 3 (0.1%) 0 (0.0%) 2 (0.2%) Intracranial bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%) Retro-peritoneal bleeding 0 (0.0%) 0 (0.0%) 1 (0.1%) Other clinically overt bleeding Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood ≥2 units. 22 (1.0%) 13 (1.2%) 10 (0.9%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 70 (3.1%) 33 (3.0%) 57 (5.2%) 6.2 Local Reactions Local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of ARIXTRA. 6.3 Elevations of Serum Aminotransferases In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment with ARIXTRA 2.5 mg once daily versus 3.2% and 3.9% of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin sodium. These elevations are reversible and may be associated with increases in bilirubin. In the extended prophylaxis clinical trial, no significant differences in AST and ALT levels between ARIXTRA 2.5 mg and placebo-treated patients were observed. In the DVT and PE treatment clinical trials, asymptomatic increases in AST and ALT levels greater than 3 times the upper limit of normal of the laboratory reference range were reported in 0.7% and 1.3% of patients, respectively, during treatment with ARIXTRA. In comparison, these increases were reported in 4.8% and 12.3% of patients, respectively, in the DVT treatment trial during treatment with enoxaparin sodium 1 mg/kg every 12 hours and in 2.9% and 8.7% of patients, respectively, in the PE treatment trial during treatment with aPTT adjusted heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like ARIXTRA should be interpreted with caution. 6.4 Other Adverse Reactions Other adverse reactions that occurred during treatment with ARIXTRA in clinical trials with patients undergoing hip fracture, hip replacement, or knee replacement surgery are provided in Table 5. Table 5. Adverse Reactions Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, and Knee Replacement Surgery Studies Adverse Reactions Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) ARIXTRA 2.5 mg SC once daily Enoxaparin Sodium Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. , Not approved for use in patients undergoing hip fracture surgery. ARIXTRA 2.5 mg SC once daily Placebo SC once daily N = 3,616 N = 3,956 N = 327 N = 329 Anemia 707 (19.6%) 670 (16.9%) 5 (1.5%) 4 (1.2%) Insomnia 179 (5.0%) 214 (5.4%) 3 (0.9%) 1 (0.3%) Wound drainage increased 161 (4.5%) 184 (4.7%) 2 (0.6%) 0 (0.0%) Hypokalemia 152 (4.2%) 164 (4.1%) 0 (0.0%) 0 (0.0%) Dizziness 131 (3.6%) 165 (4.2%) 2 (0.6%) 0 (0.0%) Purpura 128 (3.5%) 137 (3.5%) 0 (0.0%) 0 (0.0%) Hypotension 126 (3.5%) 125 (3.2%) 1 (0.3%) 0 (0.0%) Confusion 113 (3.1%) 132 (3.3%) 4 (1.2%) 1 (0.3%) Bullous eruption Localized blister coded as bullous eruption. 112 (3.1%) 102 (2.6%) 0 (0.0%) 1 (0.3%) Hematoma 103 (2.8%) 109 (2.8%) 7 (2.1%) 1 (0.3%) Post-operative hemorrhage 85 (2.4%) 69 (1.7%) 2 (0.6%) 2 (0.6%) The most common adverse reaction in the abdominal surgery trial was post-operative wound infection (4.9%), and the most common adverse reaction in the VTE treatment trials was epistaxis (1.3%). 6.5 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARIXTRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of ARIXTRA by subcutaneous (SC) injection [see Warnings and Precautions (5.1) ]. Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported in the postmarketing experience and cases of elevated aPTT temporally associated with bleeding events have been reported following administration of ARIXTRA (with or without concomitant administration of other anticoagulants) [see Warnings and Precautions (5.5) ]. Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of ARIXTRA [see Contraindications (4) ] .

4 CONTRAINDICATIONS ARIXTRA is contraindicated in the following conditions: • Severe renal impairment (creatinine clearance [CrCl] <30 mL/min) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6) ]. • Active major bleeding. • Bacterial endocarditis. • Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium. • Body weight <50 kg (venous thromboembolism [VTE] prophylaxis only) [see Warnings and Precautions (5.4) ]. • History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to ARIXTRA. ARIXTRA is contraindicated in the following conditions: ( 4 ) • Severe renal impairment (creatinine clearance <30 mL/min) in prophylaxis or treatment of venous thromboembolism. • Active major bleeding. • Bacterial endocarditis. • Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium. • Body weight <50 kg (venous thromboembolism prophylaxis only). • History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to ARIXTRA.

11 DESCRIPTION ARIXTRA (fondaparinux sodium injection, USP) is a sterile solution containing fondaparinux sodium. It is a synthetic and specific inhibitor of activated Factor X (Xa). Fondaparinux sodium is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra-nuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside, decasodium salt. The molecular formula of fondaparinux sodium is C 31 H 43 N 3 Na 10 O 49 S 8 and its molecular weight is 1728. The structural formula is provided below: ARIXTRA is supplied as a sterile, preservative-free injectable solution for subcutaneous use. Each single-dose, prefilled syringe of ARIXTRA, 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 and water for injection. May also contain sodium hydroxide and/or hydrochloric acid as pH adjusters. The final drug product is a clear and colorless to slightly yellow liquid with a pH between 5.0 and 8.0. Fondaparinux Sodium Structural Formula

2 DOSAGE AND ADMINISTRATION • For subcutaneous use, do not mix with other injections or infusions. ( 2.1 ) • Prophylaxis of deep vein thrombosis: ARIXTRA 2.5 mg subcutaneously once daily after hemostasis has been established. The initial dose should be given no earlier than 6 to 8 hours after surgery and continued for 5 to 9 days. For patients undergoing hip fracture surgery, extended prophylaxis up to 24 additional days is recommended. ( 2.2 , 2.3 ) • Treatment of deep vein thrombosis and pulmonary embolism: ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (50 to 100 kg), or 10 mg (>100 kg) subcutaneously once daily. Treatment should continue for at least 5 days until INR 2 to 3 achieved with warfarin sodium. ( 2.4 ) 2.1 Important Dosing Information Do not mix other medications or solutions with ARIXTRA. Administer ARIXTRA only subcutaneously. Discard unused portion. 2.2 Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and Knee Replacement Surgery In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of therapy is 5 to 9 days; up to 11 days of therapy was administered in clinical trials. In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24 additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days (peri-operative and extended prophylaxis) was administered in clinical trials [see Warnings and Precautions (5.6) , Adverse Reactions (6) , and Clinical Studies (14) ]. 2.3 Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery In patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 10 days of ARIXTRA was administered in clinical trials. 2.4 Deep Vein Thrombosis and Pulmonary Embolism Treatment In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of ARIXTRA is 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) by subcutaneous injection once daily (ARIXTRA treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with ARIXTRA for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection was administered in clinical trials [see Warnings and Precautions (5.6) , Adverse Reactions (6) , and Clinical Studies (14) ]. 2.5 Hepatic Impairment No dose adjustment is recommended in patients with mild to moderate hepatic impairment, based upon single-dose pharmacokinetic data. Pharmacokinetic data are not available for patients with severe hepatic impairment. Patients with hepatic impairment may be particularly vulnerable to bleeding during ARIXTRA therapy. Observe these patients closely for signs and symptoms of bleeding [see Clinical Pharmacology (12.4) ]. 2.6 Instructions for Use ARIXTRA Injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be administered by intramuscular injection. ARIXTRA is intended for use under a physician’s guidance. Patients may self-inject only if their physician determines that it is appropriate and the patients are trained in subcutaneous injection techniques. Prior to administration, visually inspect ARIXTRA to ensure the solution is clear and free of particulate matter. To avoid the loss of drug when using the prefilled syringe, do not expel the air bubble from the syringe before the injection. Administration should be made in the fatty tissue, alternating injection sites (e.g., between the left and right anterolateral or the left and right posterolateral abdominal wall). To administer ARIXTRA: 1. Wipe the surface of the injection site with an alcohol swab. 2. Hold the syringe with either hand and use your other hand to twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle (Figure 1). Discard the needle guard. 3. Do not try to remove the air bubbles from the syringe before giving the injection. 4. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. 5. Hold the syringe with your thumb on the top pad of the plunger rod and your next 2 fingers on the finger grips on the syringe barrel. Pay attention to avoid sticking yourself with the exposed needle (Figure 2). 6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 3). 7. Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have injected all the contents of the syringe (Figure 4). 8. When you have injected all the contents of the syringe, the plunger should be released. The plunger will then rise automatically while the needle withdraws from the skin and retracts into the security sleeve. Discard the syringe into the sharps container. 9. You will know that the syringe has worked when: • The needle is pulled back into the security sleeve and the white safety indicator appears above the upper body. • You may also hear or feel a soft click when the plunger rod is released fully. Figure 1 and 2 Figure 3 and 4

1 INDICATIONS AND USAGE ARIXTRA is a Factor Xa inhibitor (anticoagulant) indicated for: • Prophylaxis of deep vein thrombosis (DVT) in patients undergoing hip fracture surgery (including extended prophylaxis), hip replacement surgery, knee replacement surgery, or abdominal surgery. ( 1.1 ) • Treatment of DVT or acute pulmonary embolism (PE) when administered in conjunction with warfarin. ( 1.2 , 1.3 ) 1.1 Prophylaxis of Deep Vein Thrombosis ARIXTRA ® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): • in patients undergoing hip fracture surgery, including extended prophylaxis; • in patients undergoing hip replacement surgery; • in patients undergoing knee replacement surgery; • in patients undergoing abdominal surgery who are at risk for thromboembolic complications. 1.2 Treatment of Acute Deep Vein Thrombosis ARIXTRA is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium. 1.3 Treatment of Acute Pulmonary Embolism ARIXTRA is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital.

10 OVERDOSAGE There is no known antidote for ARIXTRA. Overdose of ARIXTRA may lead to hemorrhagic complications. Discontinue treatment and initiate appropriate therapy if bleeding complications associated with overdosage occur. Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of ARIXTRA can increase by 20% during hemodialysis.

7 DRUG INTERACTIONS In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In addition, ARIXTRA 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 therapy with ARIXTRA unless these agents are essential. If co-administration is necessary, monitor patients closely for hemorrhage [see Warnings and Precautions (5.2) ]. In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200 micromolar i.e., 350 mg/L) was 17 to 28%. Inhibition of the other isozymes evaluated (CYPs 1A2, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0 to 16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro , fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes. Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected. Discontinue agents that may enhance the risk of hemorrhage prior to initiation of therapy with ARIXTRA unless essential. If co-administration is necessary, monitor patients closely for hemorrhage. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time. 12.2 Pharmacodynamics 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 LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately three hours. 12.3 Pharmacokinetics Absorption Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, C max of 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L. 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 to 100 kg), and 10 mg (body weight >100 kg) once daily, the body–weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L. Distribution In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells. Metabolism In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function. Elimination In individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours. The elimination half-life is 17 to 21 hours. 12.4 Special Populations Renal Impairment Fondaparinux elimination is prolonged in patients with renal impairment 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 impairment (CrCl 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30 to 50 mL/min), and approximately 55% lower in patients with severe renal impairment (<30 mL/min) compared to patients with normal renal function. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients [see Contraindications (4) and Warnings and Precautions (5.3) ]. Hepatic Impairment Following a single, subcutaneous dose of 7.5 mg of ARIXTRA in patients with moderate hepatic impairment (Child-Pugh Category B), C max and AUC were decreased by 22% and 39%, respectively, compared to subjects with normal liver function. The changes from baseline in pharmacodynamic parameters, such as aPTT, PT/INR, and antithrombin III, were similar in normal subjects and in patients with moderate hepatic impairment. Based on these data, no dosage adjustment is recommended in these patients. However, a higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects [see Use in Specific Populations (8.7) ] . The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.5) ]. Pediatric The pharmacokinetics of fondaparinux have not been investigated in pediatric patients [see Contraindications (4) , Warnings and Precautions (5.4) , and Pediatric Use (8.4) ]. Geriatric Fondaparinux elimination is prolonged in patients older than 75 years. 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 older than 75 years as compared to patients younger than 65 years. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients [see Use in Specific Populations (8.5) ]. 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 (2.4) and Contraindications (4) ] . Gender The pharmacokinetic properties of fondaparinux sodium are not significantly affected by gender. Race Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopedic surgery.

12.1 Mechanism of Action The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time.

12.2 Pharmacodynamics 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 LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately three hours.

12.3 Pharmacokinetics Absorption Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, C max of 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L. 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 to 100 kg), and 10 mg (body weight >100 kg) once daily, the body–weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L. Distribution In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells. Metabolism In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function. Elimination In individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours. The elimination half-life is 17 to 21 hours.

20200820

11

3 DOSAGE FORMS AND STRENGTHS Injection: Single-dose, prefilled syringes containing either 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux sodium. Single-dose, prefilled syringes containing 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux sodium. ( 3 )

Arixtra fondaparinux sodium FONDAPARINUX SODIUM FONDAPARINUX SODIUM CHLORIDE WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Arixtra fondaparinux sodium FONDAPARINUX SODIUM FONDAPARINUX SODIUM CHLORIDE WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Arixtra fondaparinux sodium FONDAPARINUX SODIUM FONDAPARINUX SODIUM CHLORIDE WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Arixtra fondaparinux sodium FONDAPARINUX SODIUM FONDAPARINUX SODIUM CHLORIDE WATER SODIUM HYDROXIDE HYDROCHLORIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium. Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/- ) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test. At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium. Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK +/- ) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test. At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.

NDA021345

Arixtra

fondaparinux sodium

67457-592

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL – 2.5 mg/0.5 mL NDC 67457-592-10 Arixtra® (fondaparinux sodium injection, USP) 2.5 mg/0.5 mL For Subcutaneous Injection PHARMACIST: Dispense the accompanying Patient Information Leaflet to each patient. Rx only Contains 10 Single-Dose, Prefilled Syringes Affixed with an Automatic Needle Protection System Contents: Each single-dose prefilled syringe contains 2.5 mg of fondaparinux sodium, USP in 0.5 mL of an isotonic solution of sodium chloride and water for injection. May also contain sodium hydroxide and/or hydrochloric acid as pH adjusters. The needle guard of the prefilled syringe of ARIXTRA contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals. Recommended Dose: 2.5 mg subcutaneous injection, once daily. See package insert. Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Discard unused portion. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Made in France MI:592:10C:R6 Mylan.com Arixtra Injection 2.5 mg/0.5 mL Carton Label

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) 17.1 Patient Advice If the patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDS, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematomas, such as back pain, tingling, numbness (especially in the lower limbs), muscular weakness, and stool or urine incontinence. If any of these symptoms occur, the patients should contact his or her physician immediately. The use of aspirin and other NSAIDS may enhance the risk of hemorrhage. Their use should be discontinued prior to ARIXTRA therapy whenever possible; if co-administration is essential, the patient’s clinical and laboratory status should be closely monitored [see Drug Interactions (7) ]. If patients must self-administer ARIXTRA (e.g., if ARIXTRA is used at home), they should be advised of the following: • ARIXTRA should be given by subcutaneous injection. Patients must be instructed in the proper technique for administration. • The most important risk with ARIXTRA administration is bleeding. Patients should be counseled on signs and symptoms of possible bleeding. • It may take them longer than usual to stop bleeding. • They may bruise and/or bleed more easily when they are treated with ARIXTRA. • They should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions (5.2 , 5.5 )] . • To tell their physicians and dentists they are taking ARIXTRA and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.2) ]. • To tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions (7) ]. Keep out of the reach of children. 17.2 FDA-Approved Patient Labeling Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Aspen Notre Dame de Bondeville Notre Dame de Bondeville, France MI:ARXTIJ:R6p

14 CLINICAL STUDIES 14.1 Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, ARIXTRA 2.5 mg SC once daily was compared to enoxaparin sodium 40 mg SC once daily, which is not approved for use in patients undergoing hip fracture surgery. A total of 1,711 patients were randomized and 1,673 were treated. Patients ranged in age from 17 to 101 years (mean age 77 years) with 25% men and 75% women. Patients were 99% Caucasian, 1% other races. Patients with multiple traumas affecting more than one organ system, serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from the trial. ARIXTRA was initiated after surgery in 88% of patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients (mean 18 hours). For both drugs, treatment was continued for 7 ± 2 days. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported up to Day 11. The efficacy data are provided in Table 7 and demonstrate that under the conditions of the trial ARIXTRA was associated with a VTE rate of 8.3% compared with a VTE rate of 19.1% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 39%, 70%; P <0.001). Major bleeding episodes occurred in 2.2% of patients receiving ARIXTRA and 2.3% of enoxaparin sodium patients [see Adverse Reactions (6.1) ]. Table 7. Efficacy of ARIXTRA in the Peri-operative Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery Endpoint Peri-operative Prophylaxis (Day 1 to Day 7 ± 2 post-surgery) ARIXTRA 2.5 mg SC once daily Enoxaparin Sodium 40 mg SC once daily n/N N = all evaluable hip fracture surgery 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. % (95% CI) n/N % (95% CI) VTE 52/626 8.3% P value versus enoxaparin sodium <0.001. (6.3, 10.8) 119/624 19.1% (16.1, 22.4) All DVT 49/624 7.9% (5.9, 10.2) 117/623 18.8% (15.8, 22.1) Proximal DVT 6/650 0.9% (0.3, 2.0) 28/646 4.3% (2.9, 6.2) Symptomatic PE 3/831 0.4% P value versus enoxaparin sodium: NS. (0.1, 1.1) 3/840 0.4% (0.1, 1.0) 14.2 Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with ARIXTRA 2.5 mg once daily for 7 ± 1 days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3‑week double-blind period. Three hundred twenty-six (326) patients and 330 patients were randomized to receive ARIXTRA 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. 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 with multiple traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180 micromol/L) were excluded from the trial. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported for up to 24 days following randomization. The efficacy data are provided in Table 8 and demonstrate that extended prophylaxis with ARIXTRA 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 = [98.7; 87.1], P <0.0001). Major bleeding rates during the 3-week extended prophylaxis period for ARIXTRA occurred in 2.4% of patients receiving ARIXTRA and 0.6% of placebo-treated patients [see Adverse Reactions (6.1) ]. Table 8. Efficacy of ARIXTRA Injection in the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery Endpoint Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) ARIXTRA 2.5 mg SC once daily Placebo SC once daily n/N N = all randomized evaluable hip fracture surgery patients. Evaluable patients were those who were treated in the post-randomization period, with an adequate efficacy assessment for up to 24 days following randomization . % (95% CI) n/N % (95% CI) VTE 3/208 1.4% P value versus placebo <0.001 (0.3, 4.2) 77/220 35.0% (28.7, 41.7) All DVT 3/208 1.4% (0.3, 4.2) 74/218 33.9% (27.7, 40.6) Proximal DVT 2/221 0.9% (0.1, 3.2) 35/222 15.8% (11.2, 21.2) Symptomatic VTE (all) 1/326 0.3% P value versus placebo = 0.021. (0.0, 1.7) 9/330 2.7% (1.3, 5.1) Symptomatic PE 0/326 0.0% P value versus placebo = NS. (0.0, 1.1) 3/330 0.9% (0.2, 2.6) 14.3 Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, ARIXTRA 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). In Study 1, a total of 2,275 patients were randomized and 2,257 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 2,309 patients were randomized and 2,273 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 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from both trials. In Study 1, ARIXTRA was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) 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 within 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hours. For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are provided in Table 9. Under the conditions of Study 1, ARIXTRA was associated with a VTE rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk reduction of 26% (95% CI: -11%, 53%; P = NS). Under the conditions of Study 2, fondaparinux sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; P <0.001). For the 2 studies combined, the major bleeding episodes occurred in 3.0% of patients receiving ARIXTRA and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1) ] . Table 9. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery Endpoint Study 1 n/N N = all evaluable hip replacement surgery patients. Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip replacement surgery), with an adequate efficacy assessment up to Day 11. % (95% CI) Study 2 n/N % (95% CI) ARIXTRA 2.5 mg SC once daily Enoxaparin Sodium 30 mg SC every 12 hr ARIXTRA 2.5 mg SC once daily Enoxaparin Sodium 40 mg SC once daily VTE VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. 48/787 6.1% P value versus enoxaparin sodium: NS. (4.5, 8.0) 66/797 8.3% (6.5, 10.4) 37/908 4.1% P value versus enoxaparin sodium in study 2: <0.001. (2.9, 5.6) 85/919 9.2% (7.5, 11.3) All DVT 44/784 5.6% P value versus enoxaparin sodium in study 1: <0.05. (4.1, 7.5) 65/796 8.2% (6.4, 10.3) 36/908 4.0% (2.8, 5.4) 83/918 9.0% (7.3, 11.1) Proximal DVT 14/816 1.7% (0.9, 2.9) 10/830 1.2% (0.6, 2.2) 6/922 0.7% P value versus enoxaparin sodium in study 2: <0.01. (0.2, 1.4) 23/927 2.5% (1.6, 3.7) Symptomatic PE 5/1,126 0.4% (0.1, 1.0) 1/1,128 0.1% (0.0, 0.5) 2/1,129 0.2% (0.0, 0.6) 2/1,123 0.2% (0.0, 0.6) 14.4 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 2.5 mg SC once daily was compared to enoxaparin sodium 30 mg SC every 12 hours. A total of 1,049 patients were randomized and 1,034 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 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from the trial. ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 to 24 hours (mean 21 hours) after surgery in 96% of patients. For both drugs, treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 10 and demonstrate that under the conditions of the trial, ARIXTRA was associated with a VTE rate of 12.5% compared with a VTE rate of 27.8% for enoxaparin sodium for a relative risk reduction of 55% (95% CI: 36%, 70%; P <0.001). Major bleeding episodes occurred in 2.1% of patients receiving ARIXTRA and 0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1) ]. Table 10. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery Endpoint ARIXTRA 2.5 mg SC once daily Enoxaparin Sodium 30 mg SC every 12 hours n/N N = all evaluable knee replacement surgery patients. 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. % (95% CI) n/N % (95% CI) VTE VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. 45/361 12.5% P value versus enoxaparin sodium <0.001. (9.2, 16.3) 101/363 27.8% (23.3, 32.7) All DVT 45/361 12.5% (9.2, 16.3) 98/361 27.1% (22.6, 32.0) Proximal DVT 9/368 2.4% P value versus enoxaparin sodium: NS. (1.1, 4.6) 20/372 5.4% (3.3, 8.2) Symptomatic PE 1/517 0.2% (0.0, 1.1) 4/517 0.8% (0.2, 2.0) 14.5 Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications Abdominal surgery patients at risk included the following: Those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 60 years with or without additional risk factors; and those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 40 years with additional risk factors. Risk factors included neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure. In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery, ARIXTRA 2.5 mg SC once daily started postoperatively was compared to dalteparin sodium 5,000 IU SC once daily, with one 2,500 IU SC preoperative injection and a 2,500 IU SC first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 to 93 years (mean age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1% Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from the trial. Sixty-nine percent (69%) of study patients underwent cancer-related abdominal surgery. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 11 and demonstrate that prophylaxis with ARIXTRA was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium ( P = NS). Table 11. Efficacy of ARIXTRA In Prophylaxis of Thromboembolic Events Following Abdominal Surgery Endpoint ARIXTRA 2.5 mg SC once daily Dalteparin Sodium 5,000 IU SC once daily n/N N = all evaluable abdominal surgery patients. Evaluable patients were those who were randomized and had an adequate efficacy assessment up to Day 10; non-treated patients and patients who did not undergo surgery did not get a VTE assessment. % (95% CI) n/N % (95% CI) VTE VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day 10. 47/1,027 4.6% P value versus dalteparin sodium: NS. (3.4, 6.0) 62/1,021 6.1% (4.7, 7.7) All DVT 43/1,024 4.2% (3.1, 5.6) 59/1,018 5.8% (4.4, 7.4) Proximal DVT 5/1,076 0.5% (0.2, 1.1) 5/1,077 0.5% (0.2, 1.1) Symptomatic VTE 6/1,465 0.4% (0.2, 0.9) 5/1,462 0.3% (0.1, 0.8) 14.6 Treatment of Deep Vein Thrombosis In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of patients in both groups were discharged home from the hospital while receiving study treatment. A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from 18 to 95 years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2 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 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 12. Table 12. Efficacy of ARIXTRA in the Treatment of Deep Vein Thrombosis (All Randomized) Endpoint ARIXTRA 5, 7.5, or 10 mg SC once daily N = 1,098 Enoxaparin Sodium 1 mg/kg SC every 12 hours N = 1,107 n % (95% CI) n % (95% CI) Total VTE VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to Day 97. The 95% confidence interval for the treatment difference for total VTE was: (-1.8% to 1.5%). 43 3.9% (2.8, 5.2) 45 4.1% (3.0, 5.4) DVT only 18 1.6% (1.0, 2.6) 28 2.5% (1.7, 3.6) Non-fatal PE 20 1.8% (1.1, 2.8) 12 1.1% (0.6, 1.9) Fatal PE 5 0.5% (0.1, 1.1) 5 0.5% (0.1, 1.1) During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and 10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%). 14.7 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 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to heparin IV bolus (5,000 USP units) followed by a continuous IV infusion adjusted to maintain 1.5 to 2.5 times aPTT control value. Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the trial. All patients started study treatment in hospital. Approximately 15% of patients were discharged home from the hospital while receiving ARIXTRA therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from 18 to 97 years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm 3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range 7 ± 2 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 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 13. Table 13. Efficacy of ARIXTRA in the Treatment of Pulmonary Embolism (All Randomized) Endpoint ARIXTRA 5, 7.5, or 10 mg SC once daily N = 1,103 Heparin aPTT adjusted IV N = 1,110 n % (95% CI) n % (95% CI) Total VTE VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to Day 97. The 95% confidence interval for the treatment difference for total VTE was: (‑3.0% to 0.5%). 42 3.8% (2.8, 5.1) 56 5.0% (3.8, 6.5) DVT only 12 1.1% (0.6, 1.9) 17 1.5% (0.9, 2.4) Non-fatal PE 14 1.3% (0.7, 2.1) 24 2.2% (1.4, 3.2) Fatal PE 16 1.5% (0.8, 2.3) 15 1.4% (0.8, 2.2) During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and 19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%).

8.5 Geriatric Use In clinical trials the efficacy of ARIXTRA in the elderly (65 years or older) was similar to that seen in patients younger than 65 years; however, serious adverse events increased with age. When using ARIXTRA in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication) [see Warnings and Precautions (5.2) ]. Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to ARIXTRA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, assess renal function prior to ARIXTRA administration [see Contraindications (4) , Warnings and Precautions (5.3) , and Clinical Pharmacology (12.4) ]. In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving ARIXTRA 2.5 mg, serious adverse events increased with age for patients receiving ARIXTRA. The incidence of major bleeding in clinical trials of ARIXTRA by age is provided in Table 6. Table 6. Incidence of Major Bleeding in Patients Treated With ARIXTRA by Age Age <65 years % (n/N) 65 to 74 years % (n/N) ≥75 years % (n/N) Orthopedic surgery Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis. 1.8% (23/1,253) 2.2% (24/1,111) 2.7% (33/1,277) Extended prophylaxis 1.9% (1/52) 1.4% (1/71) 2.9% (6/204) Abdominal surgery 3.0% (19/644) 3.2% (16/507) 5.0% (14/282) DVT and PE treatment 0.6% (7/1,151) 1.6% (9/560) 2.1% (12/583)

8.4 Pediatric Use Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Because risk for bleeding during treatment with ARIXTRA is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of ARIXTRA in the pediatric population [see Warnings and Precautions (5.4) ].

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with fondaparinux sodium and adverse developmental outcomes. Fondaparinux sodium plasma concentrations obtained from four women treated with ARIXTRA during pregnancy and their newborn infants demonstrated low placental transfer of fondaparinux sodium (see Data ). There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with use of anticoagulants (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis at doses 32 and 65 times, respectively, the recommended human dose based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reactions Fondaparinux sodium has been demonstrated to cross the placenta in humans (see Data ). Use of anticoagulants, including fondaparinux sodium, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2 , 5.4 , 5.6) ]. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Fondaparinux sodium use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Pregnant women receiving fondaparinux sodium should be carefully monitored for evidence of bleeding or unexpected changes in coagulation parameters. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Warnings and Precautions (5.1 , 5.6) ]. Data Human Data In a study of five pregnant women treated with fondaparinux sodium during the third trimester of pregnancy at a dose of 2.5 mg/day, four of the women had elevated anti-factor Xa activity noted in the cord blood. Anti-factor Xa clotting times in these four cases were between 37.5 and 50.9 seconds. The patient who did not have elevated anti-factor Xa activity had received only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of fondaparinux sodium in umbilical cord plasma was approximately 1/10 th the level of fondaparinux sodium in maternal plasma. None of the infants experienced adverse effects. Animal Data Embryo-fetal development studies have been conducted with fondaparinux sodium in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) administered from days 6 to 17 of gestation and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) administered from days 6 to 18 of gestation. These studies have revealed no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis. Additionally, there were no effects on pre and postnatal development in a study conducted in rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area).

8 USE IN SPECIFIC POPULATIONS • Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Because the risk for bleeding during treatment with ARIXTRA is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of ARIXTRA in the pediatric population. ( 4 , 5.4 ) • Because elderly patients are more likely to have reduced renal function, ARIXTRA should be used with caution in these patients. ( 8.5 ) • The risk of bleeding is increased with reduced renal or hepatic function. ( 8.6 , 8.7 ) 8.1 Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with fondaparinux sodium and adverse developmental outcomes. Fondaparinux sodium plasma concentrations obtained from four women treated with ARIXTRA during pregnancy and their newborn infants demonstrated low placental transfer of fondaparinux sodium (see Data ). There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with use of anticoagulants (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis at doses 32 and 65 times, respectively, the recommended human dose based on body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reactions Fondaparinux sodium has been demonstrated to cross the placenta in humans (see Data ). Use of anticoagulants, including fondaparinux sodium, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2 , 5.4 , 5.6) ]. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Fondaparinux sodium use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Pregnant women receiving fondaparinux sodium should be carefully monitored for evidence of bleeding or unexpected changes in coagulation parameters. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Warnings and Precautions (5.1 , 5.6) ]. Data Human Data In a study of five pregnant women treated with fondaparinux sodium during the third trimester of pregnancy at a dose of 2.5 mg/day, four of the women had elevated anti-factor Xa activity noted in the cord blood. Anti-factor Xa clotting times in these four cases were between 37.5 and 50.9 seconds. The patient who did not have elevated anti-factor Xa activity had received only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of fondaparinux sodium in umbilical cord plasma was approximately 1/10 th the level of fondaparinux sodium in maternal plasma. None of the infants experienced adverse effects. Animal Data Embryo-fetal development studies have been conducted with fondaparinux sodium in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) administered from days 6 to 17 of gestation and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) administered from days 6 to 18 of gestation. These studies have revealed no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis. Additionally, there were no effects on pre and postnatal development in a study conducted in rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area). 8.2 Lactation Risk Summary There are no data on the presence of fondaparinux sodium in human milk, or the effects on milk production. Limited clinical data during lactation preclude a clear determination of the risk of ARIXTRA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARIXTRA and any potential adverse effects on the breastfed infant from ARIXTRA or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of ARIXTRA in pediatric patients have not been established. Because risk for bleeding during treatment with ARIXTRA is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of ARIXTRA in the pediatric population [see Warnings and Precautions (5.4) ]. 8.5 Geriatric Use In clinical trials the efficacy of ARIXTRA in the elderly (65 years or older) was similar to that seen in patients younger than 65 years; however, serious adverse events increased with age. When using ARIXTRA in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication) [see Warnings and Precautions (5.2) ]. Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to ARIXTRA may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, assess renal function prior to ARIXTRA administration [see Contraindications (4) , Warnings and Precautions (5.3) , and Clinical Pharmacology (12.4) ]. In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving ARIXTRA 2.5 mg, serious adverse events increased with age for patients receiving ARIXTRA. The incidence of major bleeding in clinical trials of ARIXTRA by age is provided in Table 6. Table 6. Incidence of Major Bleeding in Patients Treated With ARIXTRA by Age Age <65 years % (n/N) 65 to 74 years % (n/N) ≥75 years % (n/N) Orthopedic surgery Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis. 1.8% (23/1,253) 2.2% (24/1,111) 2.7% (33/1,277) Extended prophylaxis 1.9% (1/52) 1.4% (1/71) 2.9% (6/204) Abdominal surgery 3.0% (19/644) 3.2% (16/507) 5.0% (14/282) DVT and PE treatment 0.6% (7/1,151) 1.6% (9/560) 2.1% (12/583) 8.6 Renal Impairment Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of ARIXTRA [see Contraindications (4) and Warnings and Precautions (5.3) ] . Assess renal function periodically in patients receiving ARIXTRA. Discontinue ARIXTRA immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, its anticoagulant effects may persist for 2 to 4 days in patients with normal renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of ARIXTRA may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4) ]. 8.7 Hepatic Impairment Following a single, subcutaneous dose of 7.5 mg of ARIXTRA in patients with moderate hepatic impairment (Child-Pugh Category B) compared to subjects with normal liver function, changes from baseline in aPTT, PT/INR, and antithrombin III were similar in the two groups. However, a higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects, especially mild hematomas at the blood sampling or injection site. The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.4) ].

16 HOW SUPPLIED/STORAGE AND HANDLING ARIXTRA (fondaparinux sodium injection, USP) is available in the following strengths: 2.5 mg ARIXTRA in 0.5 mL single-dose prefilled syringe, affixed with a 27-gauge x ½‑inch needle and an automatic needle protection system with white plunger rod. NDC 67457-592-10 10 Single Unit Syringes 5 mg ARIXTRA in 0.4 mL single-dose prefilled syringe, affixed with a 27-gauge x ½‑inch needle and an automatic needle protection system with white plunger rod. NDC 67457-593-04 10 Single Unit Syringes 7.5 mg ARIXTRA in 0.6 mL single-dose prefilled syringe, affixed with a 27-gauge x ½‑inch needle and an automatic needle protection system with white plunger rod. NDC 67457-594-06 10 Single Unit Syringes 10 mg ARIXTRA in 0.8 mL single-dose prefilled syringe, affixed with a 27-gauge x ½‑inch needle and an automatic needle protection system with white plunger rod. NDC 67457-595-08 10 Single Unit Syringes Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Discard unused portion. PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

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 non-steroidal 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 • Optimal timing between the administration of ARIXTRA and neuraxial procedures is not known. 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 [see Warnings and Precautions (5.1) and Drug Interactions (7) ]. WARNING: SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete boxed warning. 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 non-steroidal 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 [see Warnings and Precautions (5.1) and Drug Interactions (7) ].