FONDAPARINUX: 2,230 Adverse Event Reports & Safety Profile

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

AND USAGE 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. ( 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.

AND ADMINISTRATION For subcutaneous use, do not mix with other injections or infusions. ( 2.1 ) Prophylaxis of deep vein thrombosis in adults: Fondaparinux sodium 2.5 mg subcutaneously once daily after hemostasis has been established. The initial dose should be given no earlier than 6 hours to 8 hours after surgery and continued for 5 days 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 in adults: Fondaparinux sodium 5 mg (body weight less than 50 kg), 7.5 mg (50 kg to 100 kg), or 10 mg (greater than 100 kg) subcutaneously once daily. Treatment should continue for at least 5 days until INR 2 to 3 is achieved with warfarin sodium. ( 2.4 ) Treatment of venous thromboembolism in pediatric patients weighing at least 10 kg: Fondaparinux sodium 0.1 mg/kg subcutaneously once daily. ( 2.5)

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. Monitor routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood periodically <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span>.

2.2 Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and Knee Replacement Surgery in Adults In adult 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 hours 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 days 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14)]</span>.

2.3 Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery in Adults In adult 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 hours 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 days 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 Adults In adult patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of fondaparinux sodium injection is 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 kg to 100 kg), or 10 mg (body weight greater than 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 days to 9 days; up to 26 days of fondaparinux sodium injection was administered in clinical trials <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) , Adverse Reactions (6) , and Clinical Studies (14) ]</span>.

2.5 Venous Thromboembolism Treatment in Pediatric Patients Aged 1 Year or Older Weighing at Least 10 kg For patients weighing 10 kg to 20 kg, the recommended initial dose is 0.1 mg/kg subcutaneously once daily. There is no available prefilled syringe for patients in this weight range, and a patient specific dose should be prepared (see section

2.8 Instructions for Preparation of Individual Pediatric Doses in Pharmacies). The dose should be exact and rounded to the nearest 0.1 mg (see Table 1).

Table

1: Recommended Initial Dose of Fondaparinux Sodium Injection for Treatment of VTE in Pediatric Patients Weighing 10 kg to 20 kg Body Weight (kg)

Initial Dose

10 kg to 20 kg Dosing should be exact and rounded to the nearest 0.1 mg For patients weighing over 20 kg, the recommended initial dose is 0.1 mg/kg subcutaneously once daily with doses rounded to the nearest prefilled syringe according to Table 2. There is no available information for dosing pediatric patients who weigh less than 10 kg.

Table

2: Recommended Prefilled Syringe Selection for Initial Dose of Fondaparinux Sodium Injection for Treatment of VTE in Pediatric Patients Weighing More Than 20 kg Body Weight (kg)

Prefilled Syringe Selection

Greater than 20 kg to 40 kg* 2.5 mg/0.5 mL Greater than 40 kg to 60 kg* 5 mg/0.4 mL Greater than 60 kg* 7.5 mg/0.6 mL *Whenever possible, patients weighing more than 20 kg should receive a full prefilled syringe for dosing. If therapeutic levels are not achievable using the prefilled syringe available strengths and dose adjustments are needed, a patient specific dose may be prepared (see section

2.8 Instructions for Preparation of Individual Pediatric Doses in Pharmacies). Monitor fondaparinux levels 2 hours to 4 hours after the second or third dose and then weekly for a month followed by every 1 month to 3 months for the duration of treatment using a fondaparinux-based anti-Xa assay with a therapeutic goal range of 0.5 mg/L to 1 mg/L. Dosing adjustments may be necessary to achieve peak blood concentration within the therapeutic target of 0.5 mg/L to 1 mg/L (see Table 3). Do not exceed the maximum dose of 7.5 mg/day.

Table

3: Recommended Dose Adjustments Fondaparinux-Based Anti-Xa Level (mg/L)

Dose Adjustment

Less than 0.3 mg/L Increase dose by 0.03 mg/kg* 0.3 mg/L to 0.49 mg/L Increase dose by 0.01 mg/kg* 0.5 mg/L to 1 mg/L No change 1.01 mg/L to 1.2 mg/L Decrease dose by 0.01 mg/kg* Greater than 1.2 mg/L Decrease dose by 0.03 mg/kg* *Adjust the dose to the nearest 0.1 mg. There is no adequate data to support the use of fondaparinux sodium injection in pediatric patients below 1 year of age.

2.6 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 injection therapy. Observe these patients closely for signs and symptoms of bleeding <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.4)]</span> .

2.7 Instructions for Use for Prefilled Syringe Fondaparinux sodium injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. Fondaparinux sodium injection 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 Hypak TM SCF 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: 1. Wipe the surface of the injection site with an alcohol swab. 2. Hold the syringe with either hand and use your other hand to pull the rigid needle shield straight off the needle ( Figure 1 ). Discard the needle shield. 3. Do not try to remove the air bubbles from the syringe before giving the injection. 4. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. 5. 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 ( Figure 2 ).

Figure

1 Figure 2 6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 3) . 7. Push the plunger to the bottom of the syringe. This will ensure you have injected all the contents of the syringe (Figure 4) .

Figure

3 Figure 4 8. Remove the syringe from the injection site keeping your finger on the plunger. Orient the needle away from you and others, and activate the safety shield by firmly pushing the plunger ( Figure 5 ). The protective sleeve will automatically cover the needle and an audible “click” will be heard to confirm shield activation ( Figure 6 ). Once safety shield is activated, discard the syringe into the sharps container.

Figure

5 Figure 6 9. You will know that the syringe has worked when: The needle is pulled back into the security sleeve and the spring expands fully. You may also hear or feel a soft click when the plunger rod is released fully. image description image description image description image description image description image description

2.8 Instructions for Preparation of Individual Pediatric Doses in Pharmacies For pediatric patients weighing 10 kg to 20 kg, a patient-specific dose may be prepared by a pharmacist under aseptic conditions per the instructions below. These instructions may also be used to prepare pediatric patient-specific doses for patients weighing over 20 kg when dose adjustments are needed and therapeutic levels are not achievable using the prefilled syringe available strengths. Prior to preparing fondaparinux sodium injection, visually inspect fondaparinux sodium prefilled syringe to ensure the solution is clear and free of particulate matter.

General Aseptic Preparation Practices

Strictly observe aseptic technique when preparing patient specific pediatric doses of fondaparinux sodium injection. To prevent accidental contamination, prepare fondaparinux sodium injection according to aseptic standards, including but not limited to:

• Prepare fondaparinux sodium injection in an ISO Class 5 laminar airflow (LAF) hood
• Ensure that the dose preparation area, including the LAF hood, has appropriate environmental specifications, confirmed by periodic monitoring.
• Ensure that personnel are appropriately trained in aseptic manipulations of sterile products.
• Ensure that personnel wear appropriate clothing and gloves.
• Ensure that gloves and surfaces are disinfected. All steps should be completed in accordance with aseptic techniques: 1. Determine the total dose and volume per the duration, and the appropriate number of fondaparinux sodium injection prefilled syringes. One fondaparinux sodium injection prefilled syringe is used in cases where the total required dose is less than 0.5 mL. Where the total dose required is greater than or equal to 0.5 mL, only two fondaparinux sodium injection prefilled syringes may be pooled together. The maximum number of fondaparinux sodium injection prefilled syringes that may be pooled together is two. Do not combine fondaparinux sodium injection prefilled syringes of different concentrations in one injection to give the prescribed dose. 2. Gather the required supplies including the appropriate fondaparinux sodium injection prefilled syringe(s), a sterile, closed/sealed, empty glass vial (recommended 5 mL), and required number of suitable sized graduated tuberculin sterile syringes with 27 gauge x ½” staked needles or sterile needles (if not pre-attached to syringe). 3. Verify the required supplies are correct and within expiry date. Ensure only the materials required for the preparation are present in the work area. 4. While wearing sterile gloves, clean the LAF hood and wipe it down with sterile 70% alcohol. Ensure the LAF hood is within specification and continually monitored. 5. Ensure equipment and consumables are cleaned with isopropyl alcohol (IPA). 6. Before transferring into the LAF hood, clean all supplies including ancillary items (such as vial holder jigs, syringe cap holder jigs, sharps containers) with IPA. 7. Perform all the dose preparation steps within the LAF hood. 8. Pre-sterilize gloves with IPA. While wearing sterile gloves, hold the fondaparinux sodium injection prefilled syringe with either gloved hand and use your other gloved hand to twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle. Discard the needle guard. 9. Dispense the full contents of the fondaparinux sodium injection prefilled syringe into the vial by fully depressing the plunger. 10. When you have injected all the contents of the fondaparinux sodium injection prefilled syringe, the plunger should be released. The plunger will then rise automatically while the needle retracts into the security sleeve. Discard the fondaparinux sodium injection prefilled syringe into a sharps container. 11. Take an empty graduated tuberculin sterile syringe and attach a suitable sterile needle if not already supplied pre-attached. 12. Remove needle cap. 13. Withdraw required dose from vial into the tuberculin syringe. 14. Replace needle cap over the needle. Clean the external surfaces of the filled tuberculin syringe with IPA. 15. Repeat steps 11 to 14 as required for the appropriate number of tuberculin syringes necessary for the patient. 16. Label each fondaparinux sodium injection tuberculin syringe with patient specific information (e.g., dosing instructions, patient information), storage information (e.g., store refrigerated between 36°F to 46°F (2°C to 8°C), do not freeze, and the beyond use date). The beyond use date should be the earlier of the product expiration date of the fondaparinux sodium injection prefilled syringe or 30 days after preparation of the tuberculin syringe. 17. Prepared tuberculin syringes may be dispensed in an empty plastic bag.

Include Patient

Information and Instructions for Use for the tuberculin syringe within the plastic bag to be dispensed to patients. They may be stored at refrigerated temperatures between 36°F to 46°F (2°C to 8°C) for up to the beyond use date. Do not freeze. Do not store the pediatric preparations at room temperature as they are growth promoting at room temperature. Discard unused portion.

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. Monitor routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood periodically <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span>.

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.

REACTIONS 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 Sandoz Inc. at 1-800-525-8747 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 a, b N = 3,956 Fondaparinux Sodium 2.5 mg subcutaneously once daily N = 327 Placebo subcutaneously 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%) 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 d 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0%) Minor bleeding e 109 (3%) 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) greater than or equal to 2. d 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]. 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: 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 a 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 Non-surgical site 38 (2.7%) 9 (0.6%) 26 (1.8%) 6 (0.4%) Minor bleeding b 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) greater than or equal to 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 injection of fondaparinux sodium 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 a 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%) 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 c 22 (1%) 13 (1.2%) 10 (0.9%) Minor bleeding d 70 (3.1%) 33 (3%) 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 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. c 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. d Minor bleeding was defined as clinically overt bleeding that was not major.

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 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.

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 8.

Table

8: 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 subcutaneously once daily Enoxaparin Sodium a, b Fondaparinux Sodium 2.5 mg subcutaneously once daily Placebo subcutaneously 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%) 214 (5.4%) 3 (0.9%) 1 (0.3%) Wound drainage increased 161 (4.5%) 184 (4.7%) 2 (0.6%) 0 (0%)

Hypokalemia

152 (4.2%) 164 (4.1%) 0 (0%) 0 (0%)

Dizziness

131 (3.6%) 165 (4.2%) 2 (0.6%) 0 (0%)

Purpura

128 (3.5%) 137 (3.5%) 0 (0%) 0 (0%)

Hypotension

126 (3.5%) 125 (3.2%) 1 (0.3%) 0 (0%)

Confusion

113 (3.1%) 132 (3.3%) 4 (1.2%) 1 (0.3%) Bullous eruption c 112 (3.1%) 102 (2.6%) 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%).

Clinical Trials

Experience in Pediatric Patients Safety data for use of fondaparinux sodium in the treatment of VTE in pediatric patients aged 1 year or older is available from Study FDPX-IJS-7001.

In

Study FDPX-IJS-7001 (n = 366), the median duration of treatment with fondaparinux sodium injection, including fondaparinux sodium, was 85 days (range 1 day to 3,768 days). The incidence of major bleeding events, defined as per the ISTH criteria, was the primary safety outcome of interest in Study FDPX-IJS-7001. Seven patients (1.9%) had composite major bleeding events: 1 patient (0.3%) had clinically overt bleeding (associated with a decrease in hemoglobin of at least 20 g/L (2 g/dL) in a 24-hour period), 3 patients (0.8%) had bleeding that was retroperitoneal, pulmonary, intracranial, or otherwise involved the central nervous system, and 3 patients (0.8%) had major bleeding that required surgical intervention in an operating suite. Major bleeding events resulted in the interruption of fondaparinux sodium injection treatment for 4 patients and the discontinuation of fondaparinux sodium injection for 3 patients. All major bleeding events were reported in patients between the ages of greater than or equal to 2 years to less than 18 years. Eleven patients (3%) had non-major bleeding events: 8 patients (2.2%) had overt bleeding for which a blood product was administered, and which was not directly attributable to the patient’s underlying medical condition and 4 patients (1.1%) had bleeding that required medical or surgical intervention to restore hemostasis other than in an operating room. All non-major bleeding events warranted either interruption or withdrawal of fondaparinux sodium injection treatment except for 1 patient for whom the action taken with fondaparinux was not reported. All non-major bleeding events were reported in patients between the ages of greater than or equal to 2 years to less than 18 years. Overall, 65 patients (18%) had composite minor bleeding events: 64 patients (18%) had overt or macroscopic evidence of bleeding that did not fulfill the criteria for either major bleeding or clinically relevant, non-major bleeding and two patients (0.5%) had non-major menstrual bleeding which resulted in a medical consultation and/or intervention.

Other Adverse Reactions

Other adverse reactions that occurred during treatment with fondaparinux sodium injection in pediatric studies included: anemia, thrombocytopenia, allergic reactions, generalized skin associated events, abnormal liver function, hypokalemia, and hypotension.

6.2 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5)]</span> . Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of fondaparinux sodium <span class="opacity-50 text-xs">[see Contraindications (4)]</span> . Elevations of hepatic transaminases have been reported in pediatric patients with elevations greater than 10x ULN.

AND PRECAUTIONS

• 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)

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 <span class="opacity-50 text-xs">[see Boxed Warning]</span> . 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) <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2) and Adverse Reactions (6.1)]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.4)]</span>. 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)

Population

Timing of Dose Degree of Renal Impairment 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 a 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) CrCl = creatinine clearance. a Hip fracture, hip replacement, and knee replacement surgery prophylaxis. CrCl=creatinine clearance. a Hip fracture, hip replacement, and knee replacement surgery prophylaxis. 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/mm3. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) 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/mm3) 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>.

5.6 Monitoring: Laboratory Tests Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of fondaparinux sodium and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of fondaparinux sodium. If unexpected changes in coagulation parameters or major bleeding occur during therapy with fondaparinux sodium, discontinue fondaparinux sodium. In postmarketing experience, occurrences of aPTT elevations have been reported following administration of fondaparinux sodium <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2, 12.3)]</span>.

INTERACTIONS 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)