fondaparinux sodium

1 INDICATIONS AND USAGE 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 ) 1.1 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. 1.2 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. 1.3 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.

2 DOSAGE AND ADMINISTRATION For subcutaneous use, do not mix with other injections or infusions. ( 2.1 ) 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. ( 2.2 , 2.3 ) Treatment of deep vein thrombosis and pulmonary embolism:fondaparinux sodium 5 mg (body wright < 50 kg), 7.5mg (50 to 100 kg), or 100 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 fondaparinux sodium injection. Administer fondaparinux sodium injection 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 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. [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 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. 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 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. [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 fondaparinux sodium therapy. Observe these patients closely for signs and symptoms of bleeding. [See Clinical Pharmacology ( 12.4 ).] 2.6 Instructions for Use Fondaparinux sodium injection is provided in a single-dose, prefilled syringe affixed with an automatic …

5 WARNINGS AND PRECAUTIONS Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur. ( 5.1 ) Patient 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 ) The packaging (needle guard) contains dry natural rubber and may cause allergic reactions in latex sensitive individuals ( 5.7 ) 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 [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. 5.2 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) [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 ) ]. 5.3 Renal Impairment and Bleeding Risk 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: In patients who weigh less than 50 kg: 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) Degree of Renal Impairment Population Timing of Dose Normal % (n/N) Mild % (n/N) Moderate % (n/N) Severe % (n/N) CrCl (mL/min) ≥…

4 CONTRAINDICATIONS Fondaparinux sodium injection is contraindicated in the following conditions:( 4 ) 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 injection. 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 injection.

7 DRUG INTERACTIONS 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 )

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with fondaparinux sodium and adverse development 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 risk 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 Consideration) . 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 Consideration 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 the 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 specification addressed as delivery approached [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 receied only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of fondaparinux sodium in umbilical cord plasma was approximately 1/10th the level of fondaparinux sodium 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 development 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 dose 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 fondaparinux sodium to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with 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.

6 ADVERSE REACTIONS The following serious 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 clinically significant adverse reactions associated with the use of fondaparinux sodium are bleeding complications. ( 6.1 ) Mild local irritation (injection site bleeding, rash and pruritus) may occur following subcutaneous injection. ( 6.2 ) Anemia, insomnia, increased wound drainage, hypokalemia, dizziness,hypotension, confusion, bullous eruption, hematoma, post-operative hemorrhage, and purpura may occur. ( 6.4 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA), Inc. at 1-877-993-8779 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 fondaparinux sodium in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Hemorrhage During administration of fondaparinux sodium, 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 fondaparinux sodium 2.5 mg are provided in Table 2. Hip Fracture, Hip Replacement, and Knee Replacement Surgery: The rates of major bleeding events reported during the hip fracture, hip replacement, or knee replacement surgery clinical trials with fondaparinux sodium 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 (Day 1 to Day 7 ± Prophylaxis 1 post-surgery) Extended (Day 8 to Day 28 Prophylaxis ± 2 post-surgery) Fondaparinux Sodium 2.5 mg SC once daily N = 3,616 Enoxaparin Sodium a, b N = 3,956 Fondaparinux Sodium 2.5 mg SC once daily N = 327 Placebo SC once daily N = 329 Major bleeding c 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 d 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0.0%) Minor bleeding e 109 (3.0%) 116 (2.9%) 5 (1.5%) 2 (0.6%) a Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. b Not approved for use in patients undergoing hip fracture surgery. c 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. d 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]. e Minor bleeding was defined as clinically overt bleeding that was not major. A separate analysis of major bleeding across …