Fondaparinux Sodium

Fondaparinux sodium injection is a Factor Xa inhibitor (anticoagulant) indicated for:

• Prophylaxis of deep vein thrombosis (DVT) in adult 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) in adult patients when administered in conjunction with warfarin sodium. ( 1.2 , 1.3 )
• Treatment of venous thromboembolism (VTE) in pediatric patients aged 1 year or older weighing at least 10 kg. ( 1.4 )

1.1 Prophylaxis of Deep Vein Thrombosis in Adult Patients Fondaparinux sodium injection is indicated for the prophylaxis of deep vein thrombosis (DVT) in adults, 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 in Adult Patients Fondaparinux sodium injection is indicated for the treatment of acute deep vein thrombosis in adults when administered in conjunction with warfarin sodium.

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

1.4 Treatment of Venous Thromboembolism in Pediatric Patients Fondaparinux sodium injection is indicated for the treatment of venous thromboembolism (VTE) in pediatric patients aged 1 year or older weighing at least 10 kg .

Injection: Single-dose, prefilled syringes containing clear to practically clear and colorless liquid containing either 2.5 mg/0.5 mL, 5 mg/0.4 mL, 7.5 mg/0.6 mL, or 10 mg/0.8 mL of fondaparinux sodium. Single-dose, prefilled syringes containing 2.5 mg/0.5 mL, 5 mg/0.4 mL, 7.5 mg/0.6 mL, or 10 mg/0.8 mL of fondaparinux sodium. ( 3 )

Fondaparinux sodium injection is contraindicated in the following conditions:

• Severe renal impairment (creatinine clearance [CrCl] less than 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 less than 50 kg (venous thromboembolism [VTE] prophylaxis in adults 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 less than 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 less than 50 kg (venous thromboembolism prophylaxis in adults 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 adult patients with low body weight less than 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 (6.2) ]. Conditions associated with increased bleeding in pediatric patients include systemic lupus erythematosus, Wilms tumor, antiphospholipid syndrome, antithrombin III deficiency, Factor V Leiden, malignancy, pancytopenia, indwelling chest tubes, thoracotomy, invasive infections, hypertensive encephalopathy, intestinal lymphangiectasia and von Willebrand disease . 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 in Adult Patients Fondaparinux sodium increases the risk of bleeding in adult 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 adult patients receiving fondaparinux sodium for VTE surgical prophylaxis is provided in Table 4. In these patient populations, the following is recommended:

• Do not use fondaparinux sodium for VTE prophylaxis and treatment in patients with CrCl less than 30 mL/min [see Contraindications (4) ].
• Fondaparinux sodium may cause prolonged anticoagulation in patients with CrCl 30 mL/min to 50 mL/min. Table 4. Incidence of Major Bleeding in Adult 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. Degree of Renal Impairment Population Timing of Dose Normal % (n/N) Mild % (n/N) Moderate % (n/N) Severe % (n/N) CrCl (mL/min) Greater than or equal to 80 Greater than or equal to 50 to less than 80 Greater than or equal to 30 to less than 50 Less than 30 Orthopedic surgery Hip fracture, hip replacement, and knee replacement surgery prophylaxis. Overall 1.6% (25/1,565) 2.4% (31/1,288) 3.8% (19/504) 4.8% (4/83) 6 hours 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 hours 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 days 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) ].

5.4 Body Weight Less than 50 kg and Bleeding Risk in Adults Fondaparinux sodium increases the risk for bleeding in adults who weigh less than 50 kg, compared to adults with higher weights. In adults who weigh less than 50 kg:

• Do not administer fondaparinux sodium as prophylactic therapy for adults undergoing hip fracture, hip replacement, or knee replacement surgery and abdominal surgery [see Contraindications (4) ] . In randomized clinical trials of VTE prophylaxis in adults during the peri-operative period following hip fracture, hip or knee replacement surgery, and abdominal surgery, major bleeding occurred at a higher rate among adults with a body weight less than 50 kg compared to those with a body weight greater than 50 kg (5.4% versus 2.1% in adults undergoing hip fracture, hip replacement, or knee replacement surgery; 5.3% versus 3.3% in adults undergoing abdominal surgery).

5.5 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% 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 (6.2) ]. […]

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

• Spinal or epidural hematomas [see Warnings and Precautions (5.1) ]
• Hemorrhage [see Warnings and Precautions (5.2) ]
• Renal impairment and bleeding risk [see Warnings and Precautions (5.3) ]
• Body weight less than 50 kg and bleeding risk [see Warnings and Precautions (5.4) ]
• Thrombocytopenia [see Warnings and Precautions (5.5) ] The most serious adverse reactions associated with the use of fondaparinux sodium are bleeding complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults 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 5. Table 5. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg subcutaneously once daily N = 3,616 Enoxaparin Sodium Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily. , Not approved for use in patients undergoing hip fracture surgery. N = 3,956 Fondaparinux Sodium 2.5 mg subcutaneously once daily N = 327 Placebo subcutaneously once daily N = 329 Major bleeding Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g., intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) greater than or equal to 2. 96 (2.7%) 75 (1.9%) 8 (2.4%) 2 (0.6%) Hip fracture 18/831 (2.2%) 19/842 (2.3%) 8/327 (2.4%) 2/329 (0.6%) Hip replacement 67/2,268 (3.0%) 55/2,597 (2.1%) — — Knee replacement 11/517 (2.1%) 1/517 (0.2%) — — Fatal bleeding 0 (0%) 1 (less than 0.1%) 0 (0%) 0 (0%) Non-fatal bleeding at critical site 0 (0%) 1 (less than 0.1%) 0 (0%) 0 (0%) Re-operation due to bleeding 12 (0.3%) 10 (0.3%) 2 (0.6%) 2 (0.6%) BI greater than or equal to 2 BI greater than or equal to 2: Overt bleeding associated only with a bleeding index (BI) greater than or equal to 2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values]. 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 109 (3%) 116 (2.9%) 5 (1.5%) 2 (0.6%) A separate analysis of major bleeding across all randomized, controlled, peri-operative, prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery according to the time of the first injection of fondaparinux sodium after surgical closure was performed in patients who received fondaparinux sodium only post-operatively. In this analysis, the incidences of major bleeding were as follows: less than 4 hours was 4.8% (5/104), 4 to 6 hours was 2.3% (28/1,196), 6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (greater than or equal to 75%) of the major bleeding events occurred during the first 4 days after surgery. Abdominal Surgery In a randomized study of patients undergoing abdominal surgery, fondaparinux sodium 2.5 mg once daily (n = 1,433) was compared with dalteparin 5,000 IU once daily (n = 1,425). Bleeding rates are shown in Table 6. Table 6. Bleeding in the Abdominal Surgery Study Fondaparinux Sodium 2.5 mg subcutaneously once daily Dalteparin Sodium 5,000 IU subcutaneously once daily N = 1,433 N = 1,425 Major bleeding Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) greater than or equal to 2. 49 (3.4%) 34 (2.4%) Fatal bleeding 2 (0.1%) 2 (0.1%) Non-fatal bleeding at critical site 0 (0%) 0 (0%) Other non-fatal major bleeding Surgical site 38 (2.7%) 26 (1.8%) Non-surgical site 9 (0.6%) 6 (0.4%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 31 (2.2%) 23 (1.6%) The rates of major bleeding according to the time interval following the first fondaparinux sodium injection were as follows: less than 6 hours was 3.4% (9/263) and 6 hours to 8 hours was 2.9% (32/1,112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism The rates of bleeding events reported during a dose-response trial (n = 111) and an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) and an active-controlled trial with heparin in PE treatment (n = 1,092) with fondaparinux sodium are provided in Table 7. Table 7. Bleeding Bleeding rates are during the study drug treatment period (approximately 7 days). Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration. in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies Fondaparinux Sodium N = 2,294 Enoxaparin Sodium N = 1,101 Heparin aPTT adjusted IV N = 1,092 Major bleeding Major bleeding was defined as clinically overt: – and/or contributing to death – and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland – and/or associated with a fall in hemoglobin level greater than or equal to 2 g/dL – and/or leading to a transfusion greater than or equal to 2 units of packed red blood cells or whole blood. 28 (1.2%) 13 (1.2%) 12 (1.1%) Fatal bleeding 3 (0.1%) 0 (0%) 1 (0.1%) Non-fatal bleeding at a critical site 3 (0.1%) 0 (0%) 2 (0.2%) Intracranial bleeding 3 (0.1%) 0 (0%) 1 (0.1%) Retro-peritoneal bleeding 0 (0%) 0 (0%) 1 (0.1%) Other clinically overt bleeding Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood greater than or equal to 2 units. 22 (1%) 13 (1.2%) 10 (0.9%) Minor bleeding Minor bleeding was defined as clinically overt bleeding that was not major. 70 (3.1%) 33 (3%) 57 (5.2%) Local Reactions Local irritation (injection site bleeding, rash, and pruritus) has occurred following subcutaneous injection of fondaparinux sodium. Elevations of Serum Aminotransferases In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment with fondaparinux sodium 2.5 mg once daily versus 3.2% and 3.9% of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin sodium. These elevations are reversible and may be associated with increases in bilirubin. […]

In clinical studies performed with fondaparinux sodium, the concomitant use of oral anticoagulants (warfarin sodium), 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 sodium, 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 )

• 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 )

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing reports have not reported a clear association with fondaparinux sodium and adverse developmental outcomes. Fondaparinux sodium plasma concentrations obtained from four women treated with fondaparinux sodium injection 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 times 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 seconds and 50.9 seconds. The patient who did not have elevated anti-factor Xa activity had received only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of fondaparinux sodium in umbilical cord plasma was approximately 1/10 th the level of fondaparinux sodium in maternal plasma. None of the infants experienced adverse effects. Animal Data Embryo-fetal development studies have been conducted with fondaparinux sodium in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) administered from days 6 to 17 of gestation and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) administered from days 6 to 18 of gestation. These studies have revealed no evidence of adverse developmental outcomes when fondaparinux sodium was administered to pregnant rats and rabbits during organogenesis. Additionally, there were no effects on pre- and postnatal development in a study conducted in rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area).

8.2 Lactation Risk Summary There are no data on the presence of fondaparinux sodium in human milk, or the effects on milk production. Limited clinical data during lactation preclude a clear determination of the risk of 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.

8.4 Pediatric Use The safety and effectiveness of fondaparinux sodium for the treatment of venous thromboembolism have been established in pediatric patients aged 1 year and older weighing at least 10 kg. Use of fondaparinux sodium for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, safety, and efficacy data in pediatric patients aged 0.3 years and older [see Adverse Reactions (6.1) , Clinical Pharmacology (12.4) , and Clinical Studies (14.8) ] . The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults. The safety and effectiveness of fondaparinux sodium have not been established in pediatric patients for the treatment of venous thromboembolism who are younger than 1 year old, weigh less than 10 kg, or with any category of renal or hepatic impairment. The safety and effectiveness of fondaparinux sodium have not been established in pediatric patients for the prophylaxis of DVT and treatment of DVT or PE in conjunction with warfarin sodium.

8.5 Geriatric Use Over 3,000 patients 65 years and older have received fondaparinux sodium in randomized clinical trials for the treatment or prophylaxis of DVT and PE. There were over 2,000 patients 65 years of age and older in the orthopedic surgery clinical studies for prophylaxis of DVT and PE [see Clinical Studies (14) ] . Of the total number of fondaparinux sodium-treated patients in these orthopedic surgery studies, 1,111 (30.9%) were 65 years of age to 74 years of age, while 1,227 (34.2%) were 75 years of age and older. No overall differences in effectiveness of fondaparinux sodium have been observed between patients 65 years of age and older and younger adult patients. Serious adverse events were more frequent in patients 65 years of age and older. When using fondaparinux sodium in elderly patients, pay 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 geriatric 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 9. Table 9. Incidence of Major Bleeding in Patients Treated with Fondaparinux Sodium by Age Age Less than 65 years % (n/N) 65 years to 74 years % (n/N) Greater than or equal to 75 years % (n/N) Orthopedic surgery Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis. […]

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.