ARIXTRA^® 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.

ARIXTRA is indicated for the treatment of acute deep vein thrombosis in adults when administered in conjunction with warfarin sodium.

ARIXTRA 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.

ARIXTRA is indicated for the treatment of venous thromboembolism (VTE) in pediatric patients aged 1 year or older weighing at least 10 kg.

Do not mix other medications or solutions with ARIXTRA. Administer ARIXTRA only subcutaneously. Discard unused portion.

Monitor routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood periodically [see Warnings and Precautions (5.6)].

In adult patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA 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 ARIXTRA 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 [see Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14)].

In adult patients undergoing abdominal surgery, the recommended dose of ARIXTRA 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 ARIXTRA 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 ARIXTRA was administered in clinical trials.

In adult patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of ARIXTRA 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 (ARIXTRA treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with ARIXTRA for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of ARIXTRA is 5 days to 9 days; up to 26 days of ARIXTRA injection was administered in clinical trials [see Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14)].

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).

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.

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.

There is no adequate data to support the use of ARIXTRA in pediatric patients below 1 year of age.

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 ARIXTRA therapy. Observe these patients closely for signs and symptoms of bleeding [see Clinical Pharmacology (12.4)].

ARIXTRA Injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be administered by intramuscular injection. ARIXTRA 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 ARIXTRA to ensure the solution is clear and free of particulate matter.

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 ARIXTRA:

• 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 twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle (Figure A). Discard the needle guard.

2.7 Figure A

• 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.
• 6.Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure B).

2.7 Figure B

• 7.Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have injected all the contents of the syringe (Figure C).

2.7 Figure C

• 8.When you have injected all the contents of the syringe, the plunger should be released. The plunger will then rise automatically while the needle withdraws from the skin and retracts into the security sleeve. Discard the syringe into the sharps container.
• 9.You will know that the syringe has worked when:
  • The needle is pulled back into the security sleeve and the white safety indicator appears above the upper body.
  • You may also hear or feel a soft click when the plunger rod is released fully.

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 ARIXTRA, visually inspect ARIXTRA prefilled syringe to ensure the solution is clear and free of particulate matter.

Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events may be higher with post-operative use of indwelling epidural catheters or concomitant use of other drugs affecting hemostasis such as NSAIDs [see Boxed Warning]. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of ARIXTRA by subcutaneous (SC) injection. Optimal timing between the administration of ARIXTRA 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.

ARIXTRA 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 ARIXTRA (with or without concomitant administration of other anticoagulants) [see Adverse Reactions (6.2)].

Conditions associated with increased bleeding in pediatric patients include systemic lupus erythematosus, Wilms tumor, antiphospholipid syndrome, antithrombin III deficiency, Factor V Leiden, malignancy, pancytopenia, indwelling chest tubes, thoracotomy, invasive infections, hypertensive encephalopathy, intestinal lymphangiectasia and von Willebrand disease.

Do not administer agents that enhance the risk of hemorrhage with ARIXTRA 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 ARIXTRA earlier than 6 to 8 hours after surgery. Administration earlier than 6 hours after surgery increases risk of major bleeding [see Dosage and Administration (2) and Adverse Reactions (6.1)].

ARIXTRA increases the risk of bleeding in adult patients with impaired renal function due to reduced clearance [see Clinical Pharmacology (12.4)].

The incidence of major bleeding by renal function status reported in clinical trials of adult patients receiving ARIXTRA for VTE surgical prophylaxis is provided in Table 4. In these patient populations, the following is recommended:

• Do not use ARIXTRA for VTE prophylaxis and treatment in patients with CrCl less than 30 mL/min [see Contraindications (4)].
• ARIXTRA may cause prolonged anticoagulation in patients with CrCl 30 mL/min to 50 mL/min.

Assess renal function periodically in patients receiving ARIXTRA. Discontinue the drug immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, 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 ARIXTRA may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)].

ARIXTRA 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 ARIXTRA 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).

Thrombocytopenia can occur with the administration of ARIXTRA. Thrombocytopenia of any degree should be monitored closely. Discontinue ARIXTRA 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 ARIXTRA 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 ARIXTRA 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 ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the ARIXTRA 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 ARIXTRA in postmarketing experience [see Adverse Reactions (6.2)].

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of ARIXTRA and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of ARIXTRA. If unexpected changes in coagulation parameters or major bleeding occur during therapy with ARIXTRA, discontinue ARIXTRA. In postmarketing experience, occurrences of aPTT elevations have been reported following administration of ARIXTRA [see Adverse Reactions (6.2)].

Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with ARIXTRA.

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 [see Clinical Pharmacology (12.2, 12.3)].

The packaging (needle guard) of the prefilled syringe of ARIXTRA contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals.

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 following adverse reactions have been identified during post-approval use of ARIXTRA. 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 ARIXTRA 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 ARIXTRA (with or without concomitant administration of other anticoagulants) [see Warnings and Precautions (5.5)].

Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have been reported with the use of ARIXTRA [see Contraindications (4)].

Elevations of hepatic transaminases have been reported in pediatric patients with elevations greater than 10x ULN.

The safety and effectiveness of ARIXTRA for the treatment of venous thromboembolism have been established in pediatric patients aged 1 year and older weighing at least 10 kg. Use of ARIXTRA for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, safety, and efficacy data in pediatric patients aged 0.3 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.4), and Clinical Studies (14.8)]. The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults.

The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the treatment of venous thromboembolism who are younger than 1 year old, weigh less than 10 kg, or with any category of renal or hepatic impairment.

The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the prophylaxis of DVT and treatment of DVT or PE in conjunction with warfarin sodium.

Over 3,000 patients 65 years and older have received ARIXTRA in randomized clinical trials for the treatment or prophylaxis of DVT and PE. There were over 2,000 patients 65 years of age and older in the orthopedic surgery clinical studies for prophylaxis of DVT and PE [see Clinical Studies (14)]. Of the total number of ARIXTRA-treated patients in these orthopedic surgery studies, 1,111 (30.9%) were 65 years of age to 74 years of age, while 1,227 (34.2%) were 75 years of age and older. No overall differences in effectiveness of ARIXTRA have been observed between patients 65 years of age and older and younger adult patients. Serious adverse events were more frequent in patients 65 years of age and older. When using ARIXTRA in elderly patients, pay particular attention to dosing directions and concomitant medications (especially anti-platelet medication) [see Warnings and Precautions (5.2)].

Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to ARIXTRA may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, assess renal function prior to ARIXTRA 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 ARIXTRA 2.5 mg, serious adverse events increased with age for patients receiving ARIXTRA. The incidence of major bleeding in clinical trials of ARIXTRA by age is provided in Table 9.

Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of ARIXTRA [see Contraindications (4) and Warnings and Precautions (5.3)]. Assess renal function periodically in patients receiving ARIXTRA. Discontinue ARIXTRA immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, 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 ARIXTRA may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)].

There is no adequate data to support safe and effective use of ARIXTRA in pediatric patients with renal impairment.

Following a single, subcutaneous dose of 7.5 mg of ARIXTRA 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 (2.6) and Clinical Pharmacology (12.4)]. There is no adequate data to support safe and effective use of ARIXTRA in pediatric patients with hepatic impairment.

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.

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.

In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, ARIXTRA 2.5 mg subcutaneously once daily was compared to enoxaparin sodium 40 mg subcutaneously 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 years 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. ARIXTRA 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 10 and demonstrate that under the conditions of the trial ARIXTRA 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 ARIXTRA and 2.3% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with ARIXTRA 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 ARIXTRA 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. Patients ranged in age from 23 years 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 11 and demonstrate that extended prophylaxis with ARIXTRA was associated with a VTE rate of 1.4% compared with a VTE rate of 35% 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 ARIXTRA occurred in 2.4% of patients receiving ARIXTRA and 0.6% of placebo-treated patients [see Adverse Reactions (6.1)].

In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, ARIXTRA 2.5 mg subcutaneously once daily was compared to either enoxaparin sodium 30 mg subcutaneously every 12 hours (Study 1) or to enoxaparin sodium 40 mg subcutaneously 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 years to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% black, less than 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 years 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, ARIXTRA was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 hours to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, ARIXTRA 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 hours 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 12. Under the conditions of Study 1, ARIXTRA 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% of patients receiving ARIXTRA and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

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), ARIXTRA 2.5 mg subcutaneously once daily was compared to enoxaparin sodium 30 mg subcutaneously every 12 hours. A total of 1,049 patients were randomized and 1,034 were treated. Patients ranged in age from 19 years to 94 years (mean age 68 years) with 41% men and 59% women. Patients were 88% Caucasian, 8% black, less 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. ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 hours 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 13 and demonstrate that under the conditions of the trial, ARIXTRA 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 ARIXTRA and 0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

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, ARIXTRA 2.5 mg subcutaneously once daily started postoperatively was compared to dalteparin sodium 5,000 IU subcutaneously once daily, with one 2,500 IU subcutaneously preoperative injection and a 2,500 IU subcutaneously first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 years 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 14 and demonstrate that prophylaxis with ARIXTRA was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium (P = NS).

In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, ARIXTRA 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) subcutaneously once daily (ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg subcutaneously 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 years 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 15.

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%).

In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, ARIXTRA 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) subcutaneously once daily (ARIXTRA 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 ARIXTRA therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from 18 years 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 16.

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%).

The efficacy of ARIXTRA for the treatment of VTE in pediatric patients aged 1 year and older is based on an open-label, single-arm retrospective clinical study (FDPX-IJS-7001) in 366 pediatric patients aged 0.3 years to 17 years with VTE who were treated with fondaparinux sodium injection, including ARIXTRA, at a single center in a tertiary care pediatric hospital. Out of these 366 patients, 325 patients with diagnosis of VTE were included in the efficacy analysis set. Of the 325 total patients, 30 patients were less than 2 years, 65 patients were 2 years to less than 6 years, 78 patients were 6 years to less than 12 years, and 152 patients were 12 years to less than18 years. Patients were started on fondaparinux sodium injection 0.1 mg/kg once daily with doses rounded to the nearest prefilled syringe (2.5 mg, 5 mg, or 7.5 mg) for patients weighing over 20 kg. For patients weighing 10 kg to 20 kg, dosing was based on body weight without rounding to the nearest prefilled syringe. Fondaparinux levels were monitored after the second or third dose until therapeutic levels were achieved. Fondaparinux levels were then monitored weekly while patients were admitted within the hospital and, after approximately every 1 month to 3 months while outpatient for the duration of treatment. Dosing adjustments were made to achieve peak fondaparinux blood concentration within the therapeutic target of 0.5 mg/L to 1 mg/L.

Patients received an initial median dose of approximately 0.1 mg/kg body weight of fondaparinux sodium injection, which translates into a median dose of 1.37 mg in the less than 20 kg weight group, 2.5 mg in the 20 kg to less than 40 kg weight group, 5 mg in the 40 kg to less than 60 kg, and 7.5 mg in the greater than or equal to 60 kg weight group. Based on median values, it took approximately 3 days (range 1 day to 929 days) to achieve therapeutic levels across all age groups.

The efficacy of ARIXTRA was based on measuring the proportion of pediatric patients with complete clot resolution up to 3 months (±15 days). Among the 325 pediatric patients in the efficacy analysis set, 146 (44.9%; 95% CI: 39.6, 50.4) experienced complete resolution of at least one clot, while 143 (44%; 95% CI: 38.7, 49.4) had complete resolution of all clots. Summaries of complete clot resolution of patients’ main VTEs at month 3 are provided by age group (see Table 17) and weight group (see Table 18).

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

The use of aspirin and other NSAIDS may enhance the risk of hemorrhage. Advise patients to discontinue use prior to ARIXTRA 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 ARIXTRA or if administered by a caregiver, (e.g., if ARIXTRA is used at home), advise patients of the following:

• Advise patients that ARIXTRA should be given by subcutaneous injection. Instruct patients in the proper technique for administration.
• Instruct patients that if they miss a dose of ARIXTRA, to inject the dose as soon as they remember. Advise patients not to inject two doses at the same time.
• The most important risk with ARIXTRA administration is bleeding. Counsel patients on signs and symptoms of possible bleeding.
• Advise patients that it may take them longer than usual to stop bleeding.
• Advise patients that they may bruise and/or bleed more easily when they are treated with ARIXTRA.
• Advise patients to 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 (5.2, 5.5)].
• Advise patients to tell their physicians and dentists they are taking ARIXTRA 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 (5.2)].
• Advise patients 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)].

Manufactured for:
Mylan Institutional LLC
Morgantown, WV 26505 U.S.A.

Manufactured by:
Aspen Notre Dame de Bondeville
Notre Dame de Bondeville, France

MI:ARXTIJ:R7p