Fondaparinux sodium injection 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-glucopyranuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-Osulfo-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: Fondaparinux sodium is supplied as a sterile, preservative-free injectable solution for subcutaneous use. Each single-dose, prefilled syringe of fondaparinux sodium, affixed with an active needle protection system, contains 2.5 mg of fondaparinux sodium, USP in 0.5 mL, 5.0 mg of fondaparinux sodium, USP in 0.4 mL, 7.5 mg of fondaparinux sodium, USP in 0.6 mL, or 10.0 mg of fondaparinux sodium, USP in 0.8 mL of an isotonic solution of sodium chloride, 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 5.5 and 8.0.

Fondaparinux sodium injection 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. Treatment of DVT or acute pulmonary embolism (PE) when administered in conjunction with warfarin

Prophylaxis of Deep Vein Thrombosis Fondaparinux sodium injection 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

Treatment of Acute Deep Vein Thrombosis Fondaparinux sodium injection is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium

Treatment of Acute Pulmonary Embolism Fondaparinux sodium injection is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital.

Single-dose, prefilled syringes containing either 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux sodium. Injection: Single-dose, prefilled syringes containing 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux sodium.

For subcutaneous use, do not mix with other injections or infusions. Prophylaxis of deep vein thrombosis: Fondaparinux sodium 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. Treatment of deep vein thrombosis and pulmonary embolism: Fondaparinux sodium 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

Important Dosing Information Do not mix other medications or solutions with fondaparinux sodium injection. Administer fondaparinux sodium injection only subcutaneously. Discard unused portion

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 fondaparinux sodium injection 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 fondaparinux sodium injection 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. 2.3 Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery In patients undergoing abdominal surgery, the recommended dose of fondaparinux sodium injection 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 fondaparinux sodium injection 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 fondaparinux sodium injection was administered in clinical trials

Deep Vein Thrombosis and Pulmonary Embolism Treatment In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of fondaparinux sodium injection 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 (fondaparinux sodium treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with fondaparinux sodium injection for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of fondaparinux sodium injection is 5 to 9 days; up to 26 days of fondaparinux sodium injection was administered in clinical trials. 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 fondaparinux sodium therapy. Observe these patients closely for signs and symptoms of bleeding. 2.6 Instructions for Use Fondaparinux sodium injection is provided in a single-dose, prefilled syringe affixed with an active needle protection system. Fondaparinux sodium is administered by subcutaneous injection. It must not be administered by intramuscular injection. Fondaparinux sodium injection 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 fondaparinux sodium injection to ensure the solution is clear and free of particulate matter. The following instructions are specific to the Preventis TM injection system and may differ from the directions for other injection systems. 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 fondaparinux sodium: STEP 1: Wipe the surface of the injection site with an alcohol swab. Remove the needle shield by pulling it straight off the syringe (Figure 1). Discard the needle shield. STEP 2: Do not try to remove the air bubbles from the syringe before giving the injection. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection time. Hold the syringe with your thumb on the top pad of the plunger and keep your index and middle fingers on the finger-grips of the syringe barrel. Pay attention to avoid pricking yourself with the exposed needle. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 2). Push the plunger to the bottom of the syringe. This will ensure you have injected all the contents of the syringe. STEP 3: Remove the syringe from the injection site keeping your finger on the plunger (Figure 3). STEP 4: Orient the needle away from you and others, and activate the safety shield by firmly pushing the plunger. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (Figure 4). STEP 5: Immediately discard the syringe into the sharps container (Figure 5).

Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur Patients taking fondaparinux sodium injection with risk factors for bleeding are at increased risk of hemorrhage. Bleeding risk is increased in renal impairment and in patients with low body weight <50 kg Thrombocytopenia can occur with administration of fondaparinux sodium. Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended. 5.1 Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events may be higher with post-operative use of indwelling epidural catheters or concomitant use of other drugs affecting hemostasis such as NSAIDs . In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of fondaparinux sodium by subcutaneous (SC) injection. Optimal timing between the administration of fondaparinux sodium and neuraxial procedures is not known. Monitor patients undergoing these procedures for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel or bladder dysfunction. Consider the potential risks and benefits before neuraxial intervention in patients anticoagulated or who may be anticoagulated for thromboprophylaxis

Hemorrhage Fondaparinux sodium increases the risk of hemorrhage in patients at risk for bleeding, including conditions such as congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy, or shortly after brain, spinal, or ophthalmological surgery. Cases of elevated aPTT temporally associated with bleeding events have been reported following administration of fondaparinux sodium (with or without concomitant administration of other anticoagulants) . Do not administer agents that enhance the risk of hemorrhage with fondaparinux sodium unless essential for the management of the underlying condition, such as vitamin K antagonists for the treatment of VTE. If co-administration is essential, closely monitor patients for signs and symptoms of bleeding. Do not administer the initial dose of fondaparinux sodium earlier than 6 to 8 hours after surgery. Administration earlier than 6 hours after surgery increases risk of major bleeding

Renal Impairment and Bleeding Risk Fondaparinux sodium increases the risk of bleeding in patients with impaired renal function due to reduced clearance . The incidence of major bleeding by renal function status reported in clinical trials of patients receiving fondaparinux sodium for VTE surgical prophylaxis is provided in Table 1. In these patient populations, the following is recommended: Do not use fondaparinux sodium for VTE prophylaxis and treatment in patients with CrCl <30 mL/min . Fondaparinux sodium may cause prolonged anticoagulation in patients with CrCl 30 to 50 mL/min. Table 1. Incidence of Major Bleeding in Patients Treated With Fondaparinux Sodium by Renal Function Status for Surgical Prophylaxis and Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Population Timing of Dose Degree of Renal Impairment Normal % (n/N) Mild % (n/N) Moderate % (n/N) Severe % (n/N) CrCl (mL/min) ≥ 80 ≥ 50 - <80 ≥ 30 - <50 <30 Orthopedic surgery a Overall 1.6% (25/1,565) 2.4% (31/1,288) 3.8% (19/504) 4.8% (4/83) 6-8 hours after surgery 1.8% (16/905) 2.2% (15/675) 2.3% (6/265) 0% (0/40) Abdominal surgery Overall 2.1% (13/606) 3.6% (22/613) 6.7% (12/179) 7.1% (1/14) 6-8 hours after surgery 2.1% (10/467) 3.3% (16/481) 5.8% (8/137) 7.7% (1/13) DVT and PE Treatment 0.4% (4/1,132) 1.6% (12/733) 2.2% (7/318) 7.3% (4/55) Assess renal function periodically in patients receiving fondaparinux sodium. Discontinue the drug immediately in patients who develop severe renal impairment while on therapy. After discontinuation of fondaparinux sodium, 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 fondaparinux sodium may persist even longer in patients with renal impairment

Body Weight <50 kg and Bleeding Risk Fondaparinux sodium increases the risk for bleeding in patients who weigh less than 50 kg, compared to patients with higher weights. In patients who weigh less than 50 kg: Do not administer fondaparinux sodium as prophylactic therapy for patients undergoing hip fracture, hip replacement, or knee replacement surgery and abdominal surgery . During the randomized clinical trials of VTE prophylaxis in the peri-operative period following hip fracture, hip replacement, or knee replacement surgery and abdominal surgery, major bleeding occurred at a higher rate among patients with a body weight <50 kg compared to those with a body weight >50 kg (5.4% versus 2.1% in patients undergoing hip fracture, hip replacement, or knee replacement surgery; 5.3% versus 3.3% in patients undergoing abdominal surgery)

Thrombocytopenia Thrombocytopenia can occur with the administration of fondaparinux sodium. Thrombocytopenia of any degree should be monitored closely. Discontinue fondaparinux sodium if the platelet count falls below 100,000/mm 3 . Moderate thrombocytopenia (platelet counts between 100,000/mm 3 and 50,000/mm 3 ) occurred at a rate of 3.0% in patients given fondaparinux sodium 2.5 mg in the peri-operative hip fracture, hip replacement, or knee replacement surgery and abdominal surgery clinical trials. Severe thrombocytopenia (platelet counts less than 50,000/mm 3 ) occurred at a rate of 0.2% in patients given fondaparinux sodium 2.5 mg in these clinical trials. During extended prophylaxis, no cases of moderate or severe thrombocytopenia were reported. Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the fondaparinux sodium treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the fondaparinux sodium treatment regimen in the DVT and PE treatment clinical trials. Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported with the use of fondaparinux sodium in postmarketing experience. 5.6 Monitoring: Laboratory Tests Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of fondaparinux sodium and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of fondaparinux sodium. If unexpected changes in coagulation parameters or major bleeding occur during therapy with fondaparinux sodium, discontinue fondaparinux sodium. In postmarketing experience, isolated occurrences of aPTT elevations have been reported following administration of fondaparinux sodium . Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with fondaparinux sodium. The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux). The activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low molecular weight heparins.

In clinical studies performed with fondaparinux sodium, 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, fondaparinux sodium 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 fondaparinux sodium unless these agents are essential. If co-administration is necessary, monitor patients closely for hemorrhage. 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 fondaparinux sodium unless essential. If co-administration is necessary,monitor patients closely for hemorrhage.