DailyMed Label: Fondaparinux Sodium

DailyMed Label: FONDAPARINUX SODIUM

2024

DailyMed Prescription

FONDAPARINUX SODIUM

FONDAPARINUX SODIUM

Eugia US LLC

NDC: 55150-230

NDC: 55150-231

NDC: 55150-232

NDC: 55150-233

NDC: 55150-230

NDC: 55150-231

NDC: 55150-232

NDC: 55150-233

NDC: 55150-230

NDC: 55150-231

NDC: 55150-232

NDC: 55150-233

NDC: 55150-230

NDC: 55150-230

NDC: 55150-231

NDC: 55150-231

NDC: 55150-232

NDC: 55150-232

NDC: 55150-233

NDC: 55150-233

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. Fondaparinux sodium USP is a white to almost white, hygroscopic powder. 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 injection, USP is supplied as a sterile, preservative-free injectable solution for subcutaneous use. Each single-dose, prefilled syringe of fondaparinux sodium injection, USP, affixed with an automatic needle protection system, contains 2.5 mg of fondaparinux sodium USP (equivalent to 2.18 mg fondaparinux) in 0.5 mL, 5 mg of fondaparinux sodium USP (equivalent to 4.36 mg fondaparinux) in 0.4 mL, 7.5 mg of fondaparinux sodium USP (equivalent to 6.54 mg fondaparinux) in 0.6 mL, or 10 mg of fondaparinux sodium USP (equivalent to 8.73 mg fondaparinux) in 0.8 mL of an isotonic solution of sodium chloride and water for injection. Also contain hydrochloric acid and sodium hydroxide as pH adjusters. The final drug product is a sterile, clear, colorless to slightly yellow solution, free from visible particles with a pH between 5.0 and 8.0. Fondaparinux Sodium Chemical Structure

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. (1.1) Treatment of DVT or acute pulmonary embolism (PE) when administered in conjunction with warfarin.  (1.2,   1.3) 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. Fondaparinux sodium injection is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium. 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.

For subcutaneous use, do not mix with other injections or infusions. ( 2.1 ) Prophylaxis of deep vein thrombosis: Fondaparinux sodium injection 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: Fondaparinux sodium injection 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 ) Do not mix other medications or solutions with fondaparinux sodium injection. Administer fondaparinux sodium injection only subcutaneously. Discard unused portion. In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of fondaparinux sodium 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 [see Warnings and Precautions (5.6) , Adverse Reactions (6) , and Clinical Studies (14) ]. In patients undergoing abdominal surgery, the recommended dose of fondaparinux sodium 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. In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of fondaparinux sodium 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 [see Warnings and Precautions (5.6) , Adverse Reactions (6) , and Clinical Studies (14) ]. 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 injection therapy. Observe these patients closely for signs and symptoms of bleeding [see Clinical Pharmacology (12.4) ]. Fondaparinux sodium injection is provided in a single-dose, prefilled syringe affixed with an automatic 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 injection: STEP 1: Wipe the surface of the injection site with an alcohol swab. Remove the needle shield by pulling it straight off the needle (Figure 1). Discard the needle shield.                               Figure 1 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. 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. 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.                                 Figure 2 STEP 3: Remove the syringe from the injection site keeping your finger on the plunger rod (Figure 3).                             Figure 3 STEP 4: Orienting the needle away from you and others, activate the safety shield by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation (Figure 4).                             Figure 4 STEP 5: Immediately dispose the syringe in the nearest sharps collector (Figure 5).                              Figure 5 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

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)

Fondaparinux sodium injection 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 fondaparinux sodium. Fondaparinux sodium injection 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 fondaparinux sodium.

Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur. ( 5.1 ) Patients taking fondaparinux sodium with risk factors for bleeding are at increased risk of hemorrhage. ( 5.2 ) Bleeding risk is increased in renal impairment and in patients with  low body weight <50 kg. ( 5.3 , 5.4 ) Thrombocytopenia can occur with administration of fondaparinux sodium. ( 5.5 ) Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended. ( 5.6 ) 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 [see Boxed Warning ] . 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. 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) [see Adverse Reactions (6.5) ]. 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 [see  Dosage and Administration (2) and Adverse Reactions (6.1) ]. Fondaparinux sodium increases the risk of bleeding in patients with impaired renal function due to reduced clearance [see Clinical Pharmacology (12.4) ]. 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 [see Contraindications (4) ]. 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) CrCl = creatinine clearance.  a   Hip fracture, hip replacement, and knee replacement surgery prophylaxis.   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 to <80 ≥ 30 to <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 to 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 to 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 [see Clinical Pharmacology (12.4) ]. 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 [see Contraindications (4) ]. 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 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 [see Adverse Reactions (6.5) ]. 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, occurrences of aPTT elevations have been reported following administration of fondaparinux sodium [see Adverse Reactions (6.5) ] . 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 [see  Clinical Pharmacology (12.2,   12.3) ].

The following clinically significant adverse reactions are described elsewhere in the labeling:

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 [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 fondaparinux sodium unless essential. If co-administration is necessary, monitor patients closely for hemorrhage. ( 7 )

Safety and effectiveness of fondaparinux sodium in pediatric patients have not been established. Because the risk for bleeding  during treatment with fondaparinux sodium is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of fondaparinux sodium in the pediatric population.  (4,   5.4 ) Because elderly patients are more likely to have reduced renal function, fondaparinux sodium 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) 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 fondaparinux sodium 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 to 4% and 15 to 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). 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 fondaparinux sodium to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fondaparinux sodium and any potential adverse effects on the breastfed infant from fondaparinux sodium or from the underlying maternal condition. Safety and effectiveness of fondaparinux sodium in pediatric patients have not been established. Because risk for bleeding during treatment with fondaparinux sodium is increased in adults who weigh <50 kg, bleeding may be a particular safety concern for use of fondaparinux sodium in the pediatric population [see Warnings and Precautions (5.4) ]. In clinical trials the efficacy of fondaparinux sodium 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 fondaparinux sodium 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 fondaparinux sodium 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 fondaparinux sodium 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 fondaparinux sodium 2.5 mg, serious adverse events increased with age for patients receiving fondaparinux sodium. The incidence of major bleeding in clinical trials of fondaparinux sodium by age is provided in Table 6. Table 6. Incidence of Major Bleeding in Patients Treated With Fondaparinux Sodium by Age a   Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis.   Age <65 years % (n/N) 65 to 74 years % (n/N) ≥ 75 years % (n/N)   Orthopedic surgery a        Extended prophylaxis 1.8% (23/1,253) 1.9% (1/52) 2.2% (24/1,111) 1.4% (1/71) 2.7% (33/1,277) 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) Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of fondaparinux sodium [see  Contraindications (4) and Warnings and Precautions (5.3) ] . Assess renal function periodically in patients receiving fondaparinux sodium. Discontinue fondaparinux sodium 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 [see Clinical Pharmacology (12.4) ]. Following a single, subcutaneous dose of 7.5 mg of fondaparinux sodium 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) ].

Fondaparinux sodium injection, USP is a sterile, clear, colorless to slightly yellow solution, free from visible particles and is available in the following strengths and package sizes: 2.5 mg per 0.5 mL 2.5 mg fondaparinux sodium injection, USP in 0.5 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with blue plunger rod. Single-Dose Syringes, in a carton of 2                                                                               NDC 55150-230-02 Single-Dose Syringes, in a carton of 10                                                                             NDC 55150-230-10 5 mg per 0.4 mL 5 mg fondaparinux sodium injection, USP in 0.4 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with orange plunger rod. Single-Dose Syringes, in a carton of 2                                                                               NDC 55150-231-02 Single-Dose Syringes, in a carton of 10                                                                             NDC 55150-231-10 7.5 mg per 0.6 mL 7.5 mg fondaparinux sodium injection, USP in 0.6 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with magenta plunger rod. Single-Dose Syringes, in a carton of 2                                                                               NDC 55150-232-02 Single-Dose Syringes, in a carton of 10                                                                             NDC 55150-232-10 10 mg per 0.8 mL 10 mg fondaparinux sodium injection, USP in 0.8 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with violet plunger rod. Single-Dose Syringes, in a carton of 2                                                                               NDC 55150-233-02 Single-Dose Syringes, in a carton of 10                                                                             NDC 55150-233-10 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. The container closure is not made with natural rubber latex. PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

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. 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. 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. 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 fondaparinux sodium 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.

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.

In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, fondaparinux sodium 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. Fondaparinux sodium 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 fondaparinux sodium 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 fondaparinux sodium and 2.3% of enoxaparin sodium patients [see Adverse Reactions (6.1) ]. Table 7. Efficacy of Fondaparinux Sodium in the Peri-operative Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery  a   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. b   P value versus enoxaparin sodium <0.001. c   P value versus enoxaparin sodium: NS.  Endpoint Peri-operative Prophylaxis (Day 1 to Day 7 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg SC once daily Enoxaparin Sodium 40 mg SC once daily   n/N a % (95% CI) n/N a % (95% CI)  VTE 52/626 8.3% b (6.3, 10.8) 119/624 19.1% (16.1, 22.4)  All DVT 49/624 7.9% b (5.9, 10.2) 117/623 18.8% (15.8, 22.1)  Proximal DVT 6/650 0.9% b (0.3, 2.0) 28/646 4.3% (2.9, 6.2)  Symptomatic PE 3/831 0.4% c (0.1, 1.1) 3/840 0.4% (0.1, 1.0) In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with fondaparinux sodium 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 fondaparinux sodium 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 fondaparinux sodium was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], P <0.0001). Major bleeding rates during the 3-week extended prophylaxis period for fondaparinux sodium occurred in 2.4% of patients receiving fondaparinux sodium and 0.6% of placebo-treated patients [see Adverse Reactions (6.1) ]. Table 8. Efficacy of Fondaparinux Sodium Injection in the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery  a   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. b   P value versus placebo <0.001 c   P value versus placebo = 0.021. d   P value versus placebo = NS.  Endpoint Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg SC once daily Placebo SC once daily n/N a % (95% CI) n/N a % (95% CI)  VTE 3/208 1.4% b (0.3, 4.2) 77/220 35.0% (28.7, 41.7)  All DVT 3/208 1.4% b (0.3, 4.2) 74/218 33.9% (27.7, 40.6)  Proximal DVT 2/221 0.9% b (0.1, 3.2) 35/222 15.8% (11.2, 21.2)  Symptomatic VTE (all) 1/326 0.3% c (0.0, 1.7) 9/330 2.7% (1.3, 5.1)  Symptomatic PE 0/326 0.0% d (0.0, 1.1) 3/330 0.9% (0.2, 2.6) In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, fondaparinux sodium 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, fondaparinux sodium 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, fondaparinux sodium 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, fondaparinux sodium 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 fondaparinux sodium and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1) ] . Table 9. Efficacy of Fondaparinux Sodium in the Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery  a   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. b   VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. c   P value versus enoxaparin sodium: NS. d   P value versus enoxaparin sodium in study 1: <0.05. e   P value versus enoxaparin sodium in study 2: <0.001. f   P value versus enoxaparin sodium in study 2: <0.01.  Endpoint Study 1 n/N a % (95% CI) Study 2 n/N a % (95% CI) Fondaparinux Sodium 2.5 mg SC once daily Enoxaparin Sodium 30 mg SC every 12 hr Fondaparinux Sodium 2.5 mg SC once daily Enoxaparin Sodium 40 mg SC once daily VTE b 48/787 6.1% c (4.5, 8.0) 66/797 8.3% (6.5, 10.4) 37/908 4.1% e (2.9, 5.6) 85/919 9.2% (7.5, 11.3) All DVT 44/784 5.6% d (4.1, 7.5) 65/796 8.2% (6.4, 10.3) 36/908 4.0% e (2.8, 5.4) 83/918 9.0% (7.3, 11.1) Proximal DVT 14/816 1.7% c (0.9, 2.9) 10/830 1.2% (0.6, 2.2) 6/922 0.7% f (0.2, 1.4) 23/927 2.5% (1.6, 3.7) Symptomatic PE 5/1,126 0.4% c (0.1, 1.0) 1/1,128 0.1% (0.0, 0.5) 2/1,129 0.2% c (0.0, 0.6) 2/1,123 0.2% (0.0, 0.6) 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), fondaparinux sodium 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. Fondaparinux sodium 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, fondaparinux sodium 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 fondaparinux sodium and 0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1) ]. Table 10. Efficacy of Fondaparinux Sodium in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery  a   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. b   VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11. c   P value versus enoxaparin sodium <0.001. d   P value versus enoxaparin sodium: NS.  Endpoint Fondaparinux Sodium 2.5 mg SC once daily Enoxaparin Sodium 30 mg SC every 12 hours   n/N a % (95% CI) n/N a % (95% CI) VTE b 45/361 12.5% c (9.2, 16.3) 101/363 27.8% (23.3, 32.7) All DVT 45/361 12.5% c (9.2, 16.3) 98/361 27.1% (22.6, 32.0) Proximal DVT 9/368 2.4% d (1.1, 4.6) 20/372 5.4% (3.3, 8.2) Symptomatic PE 1/517 0.2% d (0.0, 1.1) 4/517 0.8% (0.2, 2.0) 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, fondaparinux sodium 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 fondaparinux sodium 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 Fondaparinux Sodium In Prophylaxis of Thromboembolic Events Following Abdominal Surgery  a   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. b   VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day 10. c   P value versus dalteparin sodium: NS.  Endpoint Fondaparinux Sodium 2.5 mg SC once daily Dalteparin Sodium 5,000 IU SC once daily n/N a % (95% CI) n/N a % (95% CI)  VTE b 47/1,027 4.6% c (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) In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, fondaparinux sodium 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 (fondaparinux sodium 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 Fondaparinux Sodium in the Treatment of Deep Vein Thrombosis (All Randomized)  a   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%).  Endpoint Fondaparinux Sodium 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 a 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%). In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, fondaparinux sodium 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 (fondaparinux sodium treatment regimen) was compared to heparin intravenous bolus (5,000 USP units) followed by a continuous intravenous 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 fondaparinux sodium 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 Fondaparinux Sodium in the Treatment of Pulmonary Embolism (All Randomized)  a   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%).  Endpoint Fondaparinux Sodium 5, 7.5, or 10 mg SC once daily N = 1,103 Heparin aPTT adjusted intravenous N = 1,110   n % (95% CI) n % (95% CI)  Total VTE a 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%).

Patient labeling is provided in the carton. Preventis TM is the trademark of Becton, Dickinson and Company. Distributed by: Eugia US LLC 279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India PATIENT INFORMATION Fondaparinux Sodium (fon'' da par' in ux soe' dee um) Injection, USP for subcutaneous use What is the most important information I should know about fondaparinux sodium? Fondaparinux sodium may cause serious side effects, including: Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like fondaparinux sodium, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if: a thin tube called an epidural catheter is placed in your back to give you certain medicine you take NSAIDs or a medicine to prevent blood from clotting you have a history of difficult or repeated epidural or spinal punctures you have a history of problems with your spine or have had surgery on your spine If you take fondaparinux sodium and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), loss of control of the bowels or bladder (incontinence). Because the risk of bleeding may be higher, tell your doctor before taking fondaparinux sodium if you: are also taking certain other medicines that affect blood clotting such as aspirin, an NSAID (for example, ibuprofen or naproxen), clopidogrel, or warfarin sodium have bleeding problems had problems in the past with pain medication given through the spine have had surgery to your spine have a spinal deformity What is fondaparinux sodium? Fondaparinux sodium is a prescription medicine that is used to: help prevent blood clots from forming in people who have had certain surgeries of the hip, knee, or the stomach area (abdominal surgery) treat people who have blood clots in their legs or blood clots that travel to their lungs, along with the blood thinner medicine warfarin. It is not known if fondaparinux sodium is safe and effective for use in children younger than 18 years of age. Who should not take fondaparinux sodium? Do not take fondaparinux sodium if you: have certain kidney problems have active bleeding problems have an infection in your heart have low platelet counts and if you test positive for a certain antibody while you are taking   fondaparinux sodium weigh less than 110 pounds (50 kg) to prevent blood clots from surgery. See, “What are the possible side effects of fondaparinux sodium?” had a serious allergic reaction to fondaparinux sodium What should I tell my doctor before taking fondaparinux sodium? Before taking fondaparinux sodium, tell your doctor about all of your medical conditions, including if you: have had any bleeding problems (such as stomach ulcers) have had a stroke have had recent surgeries, including eye surgery have diabetic eye disease have kidney or liver problems have uncontrolled high blood pressure are pregnant or plan to become pregnant. Fondaparinux sodium may harm your unborn baby. If you are pregnant, talk to your doctor about the best way for you to prevent or treat blood clots. are breastfeeding or plan to breastfeed . It is not known if fondaparinux sodium passes into breast milk. You and your doctor should decide if you will breastfeed during treatment with fondaparinux sodium. Tell your doctor about all the medicines you take including prescriptions and over-the-counter medicines, vitamins, and herbal supplements. Some medicines can increase your risk of  bleeding. See “What is the most important information I should know about fondaparinux sodium?” Do not start taking any new medicines without first talking to your doctor. Tell all your doctors and dentist that you take fondaparinux sodium, especially if you need to have any kind of surgery or a dental procedure. Keep a list of your medicines and show it to all your doctors and pharmacist before you start a new medicine. How should I take fondaparinux sodium? See the detailed Instructions for Use that comes with fondaparinux sodium for information about how to give an fondaparinux sodium injection. Take fondaparinux sodium exactly as your doctor tells you to. Fondaparinux sodium is given by injection under the skin (subcutaneous injection). If you miss a dose of fondaparinux sodium, take your dose as soon as you remember. Do not take 2 doses at the same time. If you take too much fondaparinux sodium, call your doctor right away. If your doctor tells you that you may give yourself injections of fondaparinux sodium at home, you will be shown how to give the injections first before you do them on your own. What are possible side effects of fondaparinux sodium? Fondaparinux sodium can cause serious side effects. See “What is the most important information I should know about fondaparinux sodium?” Severe b leeding. Certain conditions can increase your risk for severe bleeding, including: some bleeding problems some gastrointestinal problems including ulcers some types of strokes uncontrolled high blood pressure diabetic eye disease soon after brain, spine, or eye surgery Certain kidney problems can also increase your risk of bleeding with fondaparinux sodium . Your doctor may check your kidney function during your treatment with fondaparinux sodium. Increased bleeding risk in people undergoing certain surgeries who weigh less than 110 pounds (50 kg). Low blood platelets (thrombocytopenia) . Low blood platelets can happen when you take fondaparinux sodium. Platelets are blood cells that help your blood to clot normally. Your doctor may check your platelet counts during your treatment with fondaparinux sodium. You may bruise or bleed more easily during your treatment with fondaparinux sodium, and it may take longer than usual for bleeding to stop. Tell your doctor if you have any signs or symptoms of bleeding, bruising or rash of dark red spots under the skin during your treatment with fondaparinux sodium. Tell your doctor if you have any bleeding, bruising, or a rash of dark spots under the skin (thrombocytopenia). The most common side effects of fondaparinux sodium include: bleeding problems bleeding, rash, and itching at the injection site (injection site reactions) sleep problems (insomnia) low red blood cell count (anemia) increased wound drainage low potassium in your blood (hypokalemia) dizziness purplish spots on skin (purpura) low blood pressure (hypotension) confusion fluid-filled blisters (bullous eruption) blood clots (hematoma) severe bleeding after surgery (post-operative hemorrhage) These are not all the possible side effects of fondaparinux sodium. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store fondaparinux sodium injection? Store fondaparinux sodium injection at 68° to 77°F (20° to 25°C). Safely throw away fondaparinux sodium injection that is out of date or no longer needed. Keep fondaparinux sodium injection and all medicines out of the reach of children. General information about the safe and effective use of fondaparinux sodium Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use fondaparinux sodium for a condition for which it was not prescribed. Do not give fondaparinux sodium to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about fondaparinux sodium that is written for healthcare professionals. What are the ingredients in fondaparinux sodium injection? Active ingredient : fondaparinux sodium Inactive ingredients : sodium chloride and water for injection. Also contain hydrochloric acid and sodium hydroxide as pH adjusters. For more information about fondaparinux sodium injection, contact Eugia US LLC at 1-866-850-2876. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: July 2023

Rx only               NDC 55150-230-00                       Mfd. in India for: Fondaparinux Sodium                                             Eugia US LLC Injection, USP                                                            E. Windsor, NJ 08520 2.5 mg per 0.5 mL                                                      Code: TS/DRUGS/13/2010                                                                                     P1433111 PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 2.5 mg per 0.5 mL - Prefilled Syringe Label