Data from FDA - Curated by Marshall Pearce - Last updated 06 November 2017

Indication(s)

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.

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Advisory information

contraindications
4 CONTRAINDICATIONS Fondaparinux sodium injection is contraindicated in the following conditions: Severe renal impairment (creatinine clearance [CrCl] <30 mL/min). [SeeWarnings 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) [seeWarnings 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.
Adverse reactions
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 serious adverse reactions associated with the use of fondaparinux sodium are bleeding complications. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 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. Table 2. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) 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 bleedingc 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 ≥2d 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0.0%) Minor bleedinge 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 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: <4 hours was 4.8% (5/104), 4 to 6 hours was 2.3% (28/1,196), 6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (≥75%) of the major bleeding events occurred during the first 4 days after surgery. Abdominal Surgery: In a randomized study of patients undergoing abdominal surgery, 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 3. Table 3. Bleeding in the Abdominal Surgery Study Fondaparinux Sodium 2.5 mg SC once daily Dalteparin Sodium 5,000 IU SC once daily N = 1,433 N = 1,425 Major bleedinga 49 (3.4%) 34 (2.4%) Fatal bleeding 2 (0.1%) 2 (0.1%) Non-fatal bleeding at critical site 0 (0.0%) 0 (0.0%) Other non-fatal major bleeding Surgical site Non-surgical site 38 (2.7%) 9 (0.6%) 26 (1.8%) 6 (0.4%) Minor bleedingb 31 (2.2%) 23 (1.6%) a Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) ≥2. b Minor bleeding was defined as clinically overt bleeding that was not major. The rates of major bleeding according to the time interval following the first fondaparinux sodium injection were as follows: <6 hours was 3.4% (9/263) and 6 to 8 hours was 2.9% (32/1112). Treatment of Deep Vein Thrombosis and Pulmonary Embolism: The rates of bleeding events reported during a dose-response trial (n = 111) and an active controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) and an active-controlled trial with heparin in PE treatment (n = 1,092) with fondaparinux sodium injection are provided in Table 4. Table 4. Bleedinga 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 b 28 (1.2%) 13 (1.2%) 12 (1.1%) Fatal bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%) Non-fatal bleeding at a critical site 3 (0.1%) 0 (0.0%) 2 (0.2%) Intracranial bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%) Retro-peritoneal bleeding 0 (0.0%) 0 (0.0%) 1 (0.1%) Other clinically overt bleeding c 22 (1.0%) 13 (1.2%) 10 (0.9%) Minor bleeding d 70 (3.1%) 33 (3.0%) 57 (5.2%) a 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. b Major bleeding was defined as clinically overt: –and/or contributing to death – and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland – and/or associated with a fall in hemoglobin level ≥2 g/dL – and/or leading to a transfusion ≥2 units of packed red blood cells or whole blood. c Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood ≥2 units. d Minor bleeding was defined as clinically overt bleeding that was not major. 6.2 Local Reactions Local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of fondaparinux sodium. 6.3 Elevations of Serum Aminotransferases In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment with 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 the extended prophylaxis clinical trial, no significant differences in AST and ALT levels between fondaparinux sodium 2.5 mg and placebo-treated patients were observed. In the DVT and PE treatment clinical trials, asymptomatic increases in AST and ALT levels greater than 3 times the upper limit of normal of the laboratory reference range were reported in 0.7% and 1.3% of patients, respectively, during treatment with fondaparinux sodium. In comparison, these increases were reported in 4.8% and 12.3% of patients, respectively, in the DVT treatment trial during treatment with enoxaparin sodium 1 mg/kg every 12 hours and in 2.9% and 8.7% of patients, respectively, in the PE treatment trial during treatment with aPTT adjusted heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like fondaparinux sodium should be interpreted with caution. 6.4 Other Adverse Reactions Other adverse reactions that occurred during treatment with fondaparinux sodium in clinical trials with patients undergoing hip fracture, hip replacement, or knee replacement surgery are provided in Table 5. Table 5. Adverse Reactions Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, and Knee Replacement Surgery Studies Adverse Reactions Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery) Fondaparinux Sodium 2.5 mg SC once daily Enoxaparin Sodiuma,b Fondaparinux Sodium 2.5 mg SC once daily Placebo SC once daily N = 3,616 N = 3,956 N = 327 N = 329 Anemia 707 (19.6%) 670 (16.9%) 5 (1.5%) 4 (1.2%) Insomnia 179 (5.0%) 214 (5.4%) 3 (0.9%) 1 (0.3%) Wound drainage increased 161 (4.5%) 184 (4.7%) 2 (0.6%) 0 (0.0%) Hypokalemia 152 (4.2%) 164 (4.1%) 0 (0.0%) 0 (0.0%) Dizziness 131 (3.6%) 165 (4.2%) 2 (0.6%) 0 (0.0%) Purpura 128 (3.5%) 137 (3.5%) 0 (0.0%) 0 (0.0%) Hypotension 126 (3.5%) 125 (3.2%) 1 (0.3%) 0 (0.0%) Confusion 113 (3.1%) 132 (3.3%) 4 (1.2%) 1 (0.3%) Bullous eruptionc 112 (3.1%) 102 (2.6%) 0 (0.0%) 1 (0.3%) Hematoma 103 (2.8%) 109 (2.8%) 7 (2.1%) 1 (0.3%) Post-operative hemorrhage 85 (2.4%) 69 (1.7%) 2 (0.6%) 2 (0.6%) 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 Localized blister coded as bullous eruption. The most common adverse reaction in the abdominal surgery trial was post-operative wound infection (4.9%), and the most common adverse reaction in the VTE treatment trials was epistaxis (1.3%). 6.5 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fondaparinux sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of fondaparinux sodium by subcutaneous (SC) injection [see Warnings and Precautions (5.1)]. Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported in the postmarketing experience and cases of elevated aPTT temporally associated with bleeding events have been reported following administration of fondaparinux sodium (with or without concomitant administration of other anticoagulants) [see Warnings and Precautions (5.4)]. Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of fondaparinux sodium [see Contraindications (4) ].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Do not mix other medications or solutions with fondaparinux sodium injection. Administer fondaparinux sodium injection only subcutaneously. 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. (2.1, 2.2) Treatment of deep vein thrombosis and pulmonary embolism: Fondaparinux sodium 5 mg (body weight <50 kg), 7.5 mg (50 to 100 kg), or 10 mg (>100 kg) subcutaneously once daily. Treatment should continue for at least 5 days until INR 2 to 3 achieved with warfarin sodium. (2.3) Do not use as intramuscular injection. For subcutaneous use, do not mix with other injections or infusions. 2.1 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) ]. 2.2 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. 2.3 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) ]. 2.4 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) .] 2.5 Instructions for Use Fondaparinux sodium injection is provided in a single-dose, prefilled syringe affixed with an active needle protection system. Fondaparinux sodium is administered by subcutaneous injection. It must not be administered by intramuscular injection. Fondaparinux sodium injection is intended for use under a physician’s guidance. Patients may self-inject only if their physician determines that it is appropriate and the patients are trained in subcutaneous injection techniques. Prior to administration, visually inspect fondaparinux sodium injection to ensure the solution is clear and free of particulate matter. The following instructions are specific to the Preventis TM injection system and may differ from the directions for other injection systems. To avoid the loss of drug when using the prefilled syringe, do not expel the air bubble from the syringe before the injection. Administration should be made in the fatty tissue, alternating injection sites (e.g., between the left and right anterolateral or the left and right posterolateral abdominal wall). To administer fondaparinux sodium: STEP 1: Wipe the surface of the injection site with an alcohol swab. Remove the needle shield by pulling it straight off the syringe (Figure 1). Discard the needle shield. STEP 2: Do not try to remove the air bubbles from the syringe before giving the injection. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection time. Hold the syringe with your thumb on the top pad of the plunger and keep your index and middle fingers on the finger-grips of the syringe barrel. Pay attention to avoid pricking yourself with the exposed needle. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 2). Push the plunger to the bottom of the syringe. This will ensure you have injected all the contents of the syringe. STEP 3: Remove the syringe from the injection site keeping your finger on the plunger (Figure 3). STEP 4: Orient the needle away from you and others, and activate the safety shield by firmly pushing the plunger. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (Figure 4). STEP 5: Immediately discard the syringe into the sharps container (Figure 5).
Use in special populations
8 USE IN SPECIFIC POPULATIONS 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 sodiumshould 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 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 1/10th 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 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 ) ]. 8.5 Geriatric Use 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 Age <65 years % (n/N) 65 to 74 years % (n/N) ≥75 years % (n/N) Orthopedic surgerya 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) a Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis. 8.6 Renal Impairment 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) ]. 8.7 Hepatic Impairment 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 (2.4) and Clinical Pharmacology (12.4) .]

Interactions

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)

More information

Category Value
Authorisation number ANDA091316
Agency product number X0Q6N9USOZ
Orphan designation No
Product NDC 55111-681,55111-680,55111-678,55111-679
Date Last Revised 18-09-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 861356
Marketing authorisation holder Dr. Reddy's Laboratories Limited
Warnings WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants a history of traumatic or repeated epidural or spinal puncture a history of spinal deformity or spinal surgery Optimal timing between the administration of fondaparinux sodium and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. [See Warnings and Precautions ( 5.1 ) and Drug Interactions (7).] WARNING: SPINAL/EPIDURAL HEMATOMAS See full prescribing information for complete boxed warning. Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: · use of indwelling epidural catheters · concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants · a history of traumatic or repeated epidural or spinal puncture · a history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. [see Warnings and Precautions ( 5.1) and Drug Interactions (7).]