FONDAPARINUX SODIUM

Fondaparinux Sodium Solution is supplied as a sterile, preservative-free injectable solution for subcutaneous use.

Each single-dose, prefilled syringe of Fondaparinux Sodium Solution, affixed with an automatic needle protection system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5.0 mg of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux sodium in 0.6 mL, or 10.0 mg of fondaparinux sodium in 0.8 mL of an isotonic solution of sodium chloride and water for injection. The final drug product is a clear and colorless to slightly yellow liquid with a pH between 5.0 and 8.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Anti-Xa Activity: The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin or LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately three hours.

12.3 Pharmacokinetics

Absorption: Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, C_max of 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L. In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), and 10 mg (body weight >100 kg) once daily, the body–weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.

Distribution: In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells.

Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.

Elimination: In individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours. The elimination half-life is 17 to 21 hours.

12.4 Special Populations

Renal Impairment: Fondaparinux elimination is prolonged in patients with renal impairment since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal impairment (CrCl 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30 to 50 mL/min), and approximately 55% lower in patients with severe renal impairment (<30 mL/min) compared to patients with normal renal function. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients. [See Contraindications (4) and Warnings and Precautions (5.2).]

Hepatic Impairment: Following a single, subcutaneous dose of 7.5 mg of Fondaparinux Sodium Solution in patients with moderate hepatic impairment (Child-Pugh Category B), C_max and AUC were decreased by 22% and 39%, respectively, compared to subjects with normal liver function. The changes from baseline in pharmacodynamic parameters, such as aPTT, PT/INR, and antithrombin III, were similar in normal subjects and in patients with moderate hepatic impairment. Based on these data, no dosage adjustment is recommended in these patients. However, a higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects [see Use in Specific Populations (8.7)]. The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment. [See Dosage and Administration (2.4).]

Pediatric: The pharmacokinetics of fondaparinux have not been investigated in pediatric patients.[See Contraindications (4), Warnings and Precautions (5.3), and Pediatric Use (8.4).]

Geriatric: Fondaparinux elimination is prolonged in patients older than 75 years. In studies evaluating fondaparinux sodium 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients older than 75 years as compared to patients younger than 65 years. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients. [See Use in Specific Populations (8.5).]

Patients Weighing Less Than 50 kg: Total clearance of fondaparinux sodium is decreased by approximately 30% in patients weighing less than 50 kg [see Dosage and Administration (2.3) and Contraindications (4)].

Gender: The pharmacokinetic properties of fondaparinux sodium are not significantly affected by gender.

Race: Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopedic surgery.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium.

Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK^+/-) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test.

At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

14.1 Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, Fondaparinux Sodium Solution 2.5 mg SC once daily was compared to enoxaparin sodium 40 mg SC once daily, which is not approved for use in patients undergoing hip fracture surgery. A total of 1,711 patients were randomized and 1,673 were treated. Patients ranged in age from 17 to 101 years (mean age 77 years) with 25% men and 75% women. Patients were 99% Caucasian, 1% other races. Patients with multiple traumas affecting more than one organ system, serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from the trial. Fondaparinux Sodium Solution was initiated after surgery in 88% of patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients (mean 18 hours). For both drugs, treatment was continued for 7 ± 2 days. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported up to Day 11. The efficacy data are provided in Table 7 and demonstrate that under the conditions of the trial Fondaparinux Sodium Solution was associated with a VTE rate of 8.3% compared with a VTE rate of 19.1% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 39%, 70%; P <0.001). Major bleeding episodes occurred in 2.2% of patients receiving Fondaparinux Sodium Solution and 2.3% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

^a N = all evaluable hip fracture surgery patients. Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip fracture surgery of the upper third of the femur), with an adequate efficacy assessment up to Day 11.

^b P value versus enoxaparin sodium <0.001.

^c P value versus enoxaparin sodium: NS.

14.2 Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with Fondaparinux Sodium Solution 2.5 mg once daily for 7 ± 1 days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3-week double-blind period. Three hundred twenty-six (326) patients and 330 patients were randomized to receive Fondaparinux Sodium Solution 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. Patients ranged in age from 23 to 96 years (mean age 75 years) and were 29% men and 71% women. Patients were 99% Caucasian and 1% other races. Patients with multiple traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180 micromol/L) were excluded from the trial. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported for up to 24 days following randomization. The efficacy data are provided in Table 8 and demonstrate that extended prophylaxis with Fondaparinux Sodium Solution was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], P <0.0001). Major bleeding rates during the 3-week extended prophylaxis period for Fondaparinux Sodium Solution occurred in 2.4% of patients receiving Fondaparinux Sodium Solution and 0.6% of placebo-treated patients [see Adverse Reactions (6.1)].

^a N = all randomized evaluable hip fracture surgery patients. Evaluable patients were those who were treated in the post-randomization period, with an adequate efficacy assessment for up to 24 days following randomization.

^b P value versus placebo <0.001

^c P value versus placebo = 0.021.

^d P value versus placebo = NS.

14.3 Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery

In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, Fondaparinux Sodium Solution 2.5 mg SC once daily was compared to either enoxaparin sodium 30 mg SC every 12 hours (Study 1) or to enoxaparin sodium 40 mg SC once a day (Study 2). In Study 1, a total of 2,275 patients were randomized and 2,257 were treated. Patients ranged in age from 18 to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% black, <1% Asian, and 2% others. In Study 2, a total of 2,309 patients were randomized and 2,273 were treated. Patients ranged in age from 24 to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99% Caucasian, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from both trials. In Study 1, Fondaparinux Sodium Solution was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, Fondaparinux Sodium Solution was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients. The first post-operative enoxaparin sodium dose was given within 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hours. For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are provided in Table 9. Under the conditions of Study 1, Fondaparinux Sodium Solution was associated with a VTE rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk reduction of 26% (95% CI: -11%, 53%; P = NS). Under the conditions of Study 2, fondaparinux sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; P <0.001). For the 2 studies combined, the major bleeding episodes occurred in 3.0% of patients receiving Fondaparinux Sodium Solution and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

^a N = all evaluable hip replacement surgery patients. Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip replacement surgery), with an adequate efficacy assessment up to Day 11.

^b VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

^c P value versus enoxaparin sodium: NS.

^d P value versus enoxaparin sodium in study 1: <0.05.

^e P value versus enoxaparin sodium in study 2: <0.001.

^f P value versus enoxaparin sodium in study 2: <0.01.

14.4 Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery

In a randomized, double-blind, clinical trial in patients undergoing knee replacement surgery (i.e., surgery requiring resection of the distal end of the femur or proximal end of the tibia), Fondaparinux Sodium Solution 2.5 mg SC once daily was compared to enoxaparin sodium 30 mg SC every 12 hours. A total of 1,049 patients were randomized and 1,034 were treated. Patients ranged in age from 19 to 94 years (mean age 68 years) with 41% men and 59% women. Patients were 88% Caucasian, 8% black, <1% Asian, and 3% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from the trial. Fondaparinux Sodium Solution was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 to 24 hours (mean 21 hours) after surgery in 96% of patients. For both drugs, treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 10 and demonstrate that under the conditions of the trial, Fondaparinux Sodium Solution was associated with a VTE rate of 12.5% compared with a VTE rate of 27.8% for enoxaparin sodium for a relative risk reduction of 55% (95% CI: 36%, 70%; P <0.001). Major bleeding episodes occurred in 2.1% of patients receiving Fondaparinux Sodium Solution and 0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

^a N = all evaluable knee replacement surgery patients. Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., knee replacement surgery), with an adequate efficacy assessment up to Day 11.

^b VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

^c P value versus enoxaparin sodium <0.001.

^d P value versus enoxaparin sodium: NS.

14.5 Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk included the following: Those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 60 years with or without additional risk factors; and those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 40 years with additional risk factors. Risk factors included neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure.

In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery, Fondaparinux Sodium Solution 2.5 mg SC once daily started postoperatively was compared to dalteparin sodium 5,000 IU SC once daily, with one 2,500 IU SC preoperative injection and a 2,500 IU SC first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 to 93 years (mean age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1% Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from the trial. Sixty-nine percent (69%) of study patients underwent cancer-related abdominal surgery. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 11 and demonstrate that prophylaxis with Fondaparinux Sodium Solution was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium (P = NS).

^a N = all evaluable abdominal surgery patients. Evaluable patients were those who were randomized and had an adequate efficacy assessment up to Day 10; non-treated patients and patients who did not undergo surgery did not get a VTE assessment.

^b VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day 10.

^c P value versus dalteparin sodium: NS.

14.6 Treatment of Deep Vein Thrombosis

In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, Fondaparinux Sodium Solution 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (Fondaparinux Sodium Solution treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of patients in both groups were discharged home from the hospital while receiving study treatment. A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from 18 to 95 years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2 days, and both treatment groups received vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 12.

^a VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to Day 97. The 95% confidence interval for the treatment difference for total VTE was: (-1.8% to 1.5%).

During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and 10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%).

14.7 Treatment of Pulmonary Embolism

In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, Fondaparinux Sodium Solution 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) SC once daily (Fondaparinux Sodium Solution treatment regimen) was compared to heparin IV bolus (5,000 USP units) followed by a continuous IV infusion adjusted to maintain 1.5 to 2.5 times aPTT control value. Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the trial. All patients started study treatment in hospital. Approximately 15% of patients were discharged home from the hospital while receiving Fondaparinux Sodium Solution therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from 18 to 97 years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm³ were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range 7 ± 2 days, and both treatment groups received vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 13.

^a VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to Day 97. The 95% confidence interval for the treatment difference for total VTE was: (-3.0% to 0.5%).

During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and 19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%).

16 HOW SUPPLIED/STORAGE AND HANDLING

Fondaparinux SodiumSolution is available in the following strengths and package sizes:

2.5 mg Fondaparinux Sodium Solution in 0.5 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.

5 mg Fondaparinux Sodium Solution in 0.4 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.

7.5 mg Fondaparinux Sodium Solution in 0.6 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.

10 mg Fondaparinux Sodium Solution in 0.8 mL single-dose prefilled syringe, affixed with a 27-gauge x ½-inch needle and an automatic needle protection system with white plunger rod.

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (17.2)

17.1 Patient Advice

If the patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDS, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematomas, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur, the patients should contact his or her physician immediately.

The use of aspirin and other NSAIDS may enhance the risk of hemorrhage. Their use should be discontinued prior to Fondaparinux Sodium Solution therapy whenever possible; if co-administration is essential, the patient’s clinical and laboratory status should be closely monitored. [See Drug Interactions (7).]

If patients must self-administer Fondaparinux Sodium Solution (e.g., if Fondaparinux Sodium Solution is used at home), they should be advised of the following:

• •Fondaparinux Sodium Solution should be given by subcutaneous injection. Patients must be instructed in the proper technique for administration.
• •As with all anticoagulants, the most important risk with Fondaparinux Sodium Solution administration is bleeding. Patients should be counseled on signs and symptoms of possible bleeding.
• •It may take them longer than usual to stop bleeding.
• •They may bruise and/or bleed more easily when they are treated with Fondaparinux Sodium Solution.
• •They should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions (5.1, 5.4)].
• •To tell their physicians and dentists they are taking Fondaparinux Sodium Solution and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.1)].
• •To tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs. [See Drug Interactions (7).]

Keep out of the reach of children.

17.2 FDA-Approved Patient Labeling

Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information.

Manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured for:

Apotex Corp.

Weston, FL 33326

FND-AP:3PI

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

----------------------------------------------------------------------------------------

PATIENT INFORMATION

Fondaparinux Sodium Solution for Injection (fon-da-PEH-rih-nux)

Read the Patient Information that comes with Fondaparinux Sodium Solution before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Fondaparinux Sodium Solution, ask your doctor or pharmacist.

What is the most important information I should know about Fondaparinux Sodium Solution?

Certain medical procedures involving the spine, such as an epidural (pain medication given through the spine), spinal anesthesia, or spinal puncture, may be used during your hospital stay. If you need any of these procedures while receiving Fondaparinux Sodium Solution, heparins, heparinoids, or low-molecular weight heparins (anticoagulants), you may be at risk for having a blood clot (hematoma) in or around your spine. This type of clot is very serious, as it can cause long-term and possibly permanent paralysis (loss of the ability to move).

If you receive Fondaparinux Sodium Solution after an epidural or spinal anesthetic is used, as the anesthesia for your surgery, your doctor will watch you closely for problems with feeling (sensation) and being able to move. Tell your doctor right away if you have any of these signs and symptoms, especially in your legs and feet:

• •tingling
• •numbness
• •muscle weakness

Because the risk of bleeding may be higher, tell your doctor before taking Fondaparinux Sodium Solution if you:

• •are also taking certain other medicines that affect blood clotting such as aspirin, an NSAID (for example, ibuprofen or naproxen), clopidogrel, or warfarin sodium.
• •have bleeding problems.
• •had problems in the past with pain medication given through the spine.
• •have had surgery to your spine.
• •have a spinal deformity.

What is Fondaparinux Sodium Solution?

Fondaparinux Sodium Solution is a prescription medicine that “thins your blood” (also known as an anticoagulant). Fondaparinux Sodium Solution is used to:

• •help prevent blood clots from forming in patients who have had certain surgeries of the hip, knee, or the stomach area (abdominal surgery)
• •treat people who have blood clots in their legs or blood clots that travel to their lungs

It is not known if Fondaparinux Sodium Solution is safe and effective for use in children younger than 18 years of age.

Who should not take Fondaparinux Sodium Solution?

Do not take Fondaparinux Sodium Solution if you have:

• •certain kidney problems
• •active bleeding problems
• •an infection in your heart
• •low platelet counts and if you test positive for a certain antibody while you are taking Fondaparinux Sodium Solution
• •had a serious allergic reaction to Fondaparinux Sodium Solution

People who weigh less than 110 pounds (50 kg) should not use Fondaparinux Sodium Solution to prevent blood clots from forming after surgery.

What should I tell my doctor before taking Fondaparinux Sodium Solution?

Tell your doctor about all of your medical conditions, including if you:

• •have had any bleeding problems (such as stomach ulcers)
• •have had a stroke
• •have had recent surgeries, including eye surgery
• •have diabetic eye disease
• •have kidney problems
• •have uncontrolled high blood pressure
• •have a latex allergy. The packaging (needle guard) for Fondaparinux Sodium Solution contains dry natural rubber.
• •are pregnant. It is not known if Fondaparinux Sodium Solution will harm your unborn baby. If you are pregnant, talk to your doctor about the best way for you to prevent or treat blood clots.
• •are breast-feeding. It is not known if Fondaparinux Sodium Solution passes into breast milk.

Tell your doctor about all the medicines you take including prescriptions and non-prescription medicines, vitamins, and herbal supplements. Some medicines can increase your risk of bleeding. Especially tell your doctor if you take:

• •aspirin
• •NSAIDS (such as ibuprofen or naproxen)
• •other blood thinner medicines, such as clopidogrel or warfarin

See “What is the most important information I should know about Fondaparinux Sodium Solution?” Do not start taking any new medicines without first talking to your doctor.

Know the medicines you take. Tell all your doctors and dentist that you take Fondaparinux Sodium Solution, especially if you need to have any kind of surgery or a dental procedure. Keep a list of your medicines and show it to all your doctors and pharmacist before you start a new medicine.

How should I take Fondaparinux Sodium Solution?

• •Take Fondaparinux Sodium Solution exactly as prescribed by your doctor.
• •Fondaparinux Sodium Solution is given by injection under the skin (subcutaneous injection). See “How should I give an injection of Fondaparinux Sodium Solution?”
• •If your doctor tells you that you may give yourself injections of Fondaparinux Sodium Solution at home, you will be shown how to give the injections first before you do them on your own.
• •Tell your doctor if you have any bleeding or bruising while taking Fondaparinux Sodium Solution.
• •If you miss a dose of Fondaparinux Sodium Solution, take your dose as soon as you remember. Do not take 2 doses at the same time.
• •If you take too much Fondaparinux Sodium Solution, call your doctor right away.
• •Do not use Fondaparinux Sodium Solution if:
  • ∘the solution appears discolored (the solution should normally appear clear),
  • ∘you see any particles in the solution, or
  • ∘the syringe is damaged.

What are possible side effects of Fondaparinux Sodium Solution?

Fondaparinux Sodium Solution can cause serious side effects. See “What is the most important information I should know about Fondaparinux Sodium Solution?”

• •Severe bleeding
  Certain conditions can increase your risk for severe bleeding, including:
  -some bleeding problems
  -some gastrointestinal problems including ulcers
  -some types of strokes
  -uncontrolled high blood pressure
  -diabetic eye disease
  -soon after brain, spine, or eye surgery
  • ∘Certain kidney problems can also increase your risk of bleeding with Fondaparinux Sodium Solution. Your doctor may check your kidney function while you are taking Fondaparinux Sodium Solution.
  • ∘ People undergoing surgery who weigh less than 110 pounds. See “Who should not take Fondaparinux Sodium Solution?”
  • ∘ Low blood platelets. Low blood platelets can happen when you take Fondaparinux Sodium Solution. Platelets are blood cells that help your blood to clot normally. Your doctor may check your platelet counts while you take Fondaparinux Sodium Solution.
    You may bruise or bleed more easily while taking Fondaparinux Sodium Solution, and it may take longer than usual for bleeding to stop.
    Tell your doctor if you have any of these signs or symptoms of bleeding while taking Fondaparinux Sodium Solution.
    -any bleeding
    -bruising
    -rash of dark red spots under the skin
• • Allergic reactions (itching, swelling, or rash). See “What should I tell my doctor before taking Fondaparinux Sodium Solution?” Serious allergic reactions can happen when you take Fondaparinux Sodium Solution. If you experience swelling of the face or mouth or have difficulty in swallowing or breathing, contact your doctor right away. You should stop Fondaparinux Sodium Solution if this happens.

Other side effects include:

• • Injection site reactions. Bleeding, rash, and itching can happen at the place where you inject Fondaparinux Sodium Solution.
• • Low red blood cell counts (anemia). Your doctor may check your red blood cell counts while you are taking Fondaparinux Sodium Solution.
• • Increased liver enzyme test results. Your doctor may check your liver function while you are taking Fondaparinux Sodium Solution.
• • Sleep problems (insomnia).

These are not all the possible side effects of Fondaparinux Sodium Solution. Call your doctor if you have any side effects that bother you or don’t go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How should I store Fondaparinux Sodium Solution?

Store Fondaparinux Sodium Solution at room temperature 59°F to 86°F (15°C to 30°C). Do not freeze.

Safely, throw away Fondaparinux Sodium Solution that is out of date or no longer needed.

Keep Fondaparinux Sodium Solution and all medicines out of the reach of children.

General information about Fondaparinux Sodium Solution

Medicines are sometimes prescribed for purposes other than those described in patient information leaflets. Do not use Fondaparinux Sodium Solution for a condition for which it was not prescribed. Do not give Fondaparinux Sodium Solution to other people. It may harm them.

This leaflet summarizes the most important information about Fondaparinux Sodium Solution. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Fondaparinux Sodium Solution that is written for healthcare professionals.

What are the ingredients in Fondaparinux Sodium Solution?

Active Ingredient: fondaparinux sodium

Inactive Ingredients: sodium chloride and water for injection

How should I give an injection of Fondaparinux Sodium Solution?

Fondaparinux Sodium Solution is injected into a skin fold of the lower stomach area (abdomen). Do not inject Fondaparinux Sodium Solution into muscle. Usually a doctor or nurse will give this injection to you. In some cases you may be taught how to do this yourself. Be sure that you read, understand, and follow the step-by-step instructions in this leaflet, on how to give yourself an injection of Fondaparinux Sodium Solution.

Manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured for:

Apotex Corp.

Weston, FL 33326

October 2013

FND-AP:3PIL

PRINCIPAL DISPLAY PANEL

NDC 60505-6078-4

Fondaparinux Sodium Solution

for subcutaneous injection

2.5 mg/0.5 mL

Single Dose, Prefilled Syringes

Affixed with an Automatic Needle Protection System

For Subcutaneous Injection

10 x 0.5 mL

Contains 10 Single Dose,

Prefilled Syringes

R_x only

APOTEX CORP.

11000000009728 Rev. 5/12