Fondaparinux Sodium

There is no known antidote for ARIXTRA. Overdose of ARIXTRA may lead to hemorrhagic complications. Discontinue treatment and initiate appropriate therapy if bleeding complications associated with overdosage occur.

Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of ARIXTRA can increase by 20% during hemodialysis.

You should not use this medication if you are allergic to fondaparinux, heparin, or pork products, or if you have:

• active or uncontrolled bleeding;
• severe kidney disease;
• an infection in the lining of your heart (also called bacterial endocarditis); or
• a low level of platelets in your blood after testing positive for a certain antibody while using fondaparinux.

You should not use fondaparinux to prevent blood clots after surgery if you weigh less than 110 pounds (50 kilograms).

Fondaparinux may cause you to bleed more easily, especially if you have:

• a bleeding disorder that is inherited or caused by disease;
• hemorrhagic stroke;
• eye problems caused by diabetes;
• uncontrolled high blood pressure;
• stomach or intestinal bleeding or ulcer;
• recent brain, spine, or eye surgery; or
• kidney disease (especially if you are an older adult).

Fondaparinux can cause a very serious blood clot around your brain or spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural). This type of blood clot could cause long-term paralysis, and may be more likely to occur if you have:

• a genetic spinal defect;
• a history of spinal surgery or repeated spinal taps; or
• if you are using other medications to treat or prevent blood clots.

FDA pregnancy category B. Fondaparinux is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether fondaparinux passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Your doctor or pharmacist can provide more information about fondaparinux.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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• Deep Vein Thrombosis (DVT, Blood Clot in the Legs)
• Pulmonary Embolism (Blood Clot in the Lung)

Contraindications

• Patients with severe renal impairment (Clcr <30 mL/minute or Scr ≥3).1 32

• Prophylactic use in patients undergoing hip-fracture, hip-replacement, knee-replacement, or abdominal surgery who weigh <50 kg.1

• Active major bleeding, bacterial endocarditis, or thrombocytopenia associated with a positive in vitro test for antiplatelet antibody (HIT) in the presence of the drug.1 3 4 10 16

• History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to fondaparinux.1

Warnings/Precautions

Warnings

Epidural or spinal hematoma reported with concurrent use of anticoagulants (e.g., LMWHs, heparinoids, fondaparinux) and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 16 Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.1 (See Boxed Warning.)

Optimal timing between administration of fondaparinux and neuraxial procedures not known.1 Frequently monitor for signs of neurologic impairment (e.g., midline back pain; numbness, tingling, or weakness in lower limbs; bowel or bladder dysfunction).1 Carefully consider potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis; some experts suggest avoidance of fondaparinux prophylaxis in patients receiving epidural analgesia.3 4

Use with extreme caution in patients with an increased risk of hemorrhage (e.g., congenital or acquired bleeding disorders; active ulceration and angiodysplastic GI disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; recent brain, spinal, or ophthalmic surgery).1 3 4 Use with caution in the treatment of DVT or PE in patients who weigh <50 kg.1 Use with caution in patients with moderate renal insufficiency (Clcr 30–50 mL/minute).1

Periodic routine blood counts, including platelet counts, and tests for occult blood in stool recommended.1

Avoid concomitant use of drugs that increase risk of bleeding unless essential for management of underlying condition (e.g., concomitant use of vitamin K antagonists for treatment of venous thromboembolism).1 Closely monitor for signs and symptoms of bleeding.1

Do not administer earlier than 6–8 hours after surgery because of increased risk of major bleeding.1

Moderate thrombocytopenia (platelet counts of 50,000–100,000/mm3) and severe thrombocytopenia (platelet counts <50,000/mm3) reported.1 Fondaparinux unlikely to cause HIT;2 11 12 13 however, isolated cases of thrombocytopenia with thrombosis resembling HIT reported during postmarketing experience.1 Manufacturer recommends monitoring thrombocytopenia of any degree closely and discontinuing fondaparinux if platelet counts fall below 100,000/mm3.1

Cases of valve thrombosis resulting in death and/or requiring surgical intervention reported with low molecular weight heparin (e.g., enoxaparin) therapy in patients with prosthetic heart valves; some cases included pregnant women, and maternal and/or fetal deaths have been reported.15 Manufacturer states that fondaparinux has not been studied in patients with prosthetic heart valves and that no information is available on safety of the drug in such patients.16

Sensitivity Reactions

Serious hypersensitivity reactions, including angioedema and anaphylactoid/anaphylactic reactions, reported.1 (See Contraindications.)

Some packaging components (e.g., needle covers) contain natural latex proteins in the form of dry natural rubber (latex), which may cause allergic-type reactions (including life-threatening hypersensitivity reactions) in susceptible individuals.1 24 30 31 The needle cover of the diluent syringe should not be handled by individuals sensitive to latex.1 24 30 31

Specific Populations

Category B.1

Distributed into milk in rats; not known whether distributed into human milk.1 Manufacturer states to use caution.1 ACCP suggests the use of alternative anticoagulants in nursing women.1012

Safety and efficacy not established in children <17 years of age.1 16

Use with caution.1 No substantial differences in efficacy relative to younger adults.1 16 Possible increased major bleeding or other serious adverse effects in patients ≥75 years of age compared with younger adults.1 16 Substantially eliminated by kidneys; assess renal function periodically since geriatric patients are more likely to have decreased renal function.1 Careful attention to dosage directions and concomitant therapy (particularly platelet-aggregation inhibitors) is advised.1

Following a single 7.5 mg dose in patients with moderate hepatic impairment, response (i.e., aPTT, PT/INR, and antithrombin III) similar to that in patients with normal hepatic function.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Increased risk of hemorrhage; closely monitor for signs and symptoms of bleeding.1 (See Hematologic Effects under Cautions.)

Use with caution in those with moderate renal impairment (Clcr 30–50 mL/minute); increased risk of hemorrhage.1 16 Contraindicated in patients with severe renal impairment (Clcr <30 mL/minute or Scr ≥3).1 16 32 Assess renal function periodically (e.g., serum creatinine determinations).1 Discontinue immediately in patients who develop severe renal impairment during therapy.1

Common Adverse Effects

Patients undergoing hip-fracture, hip- or knee-replacement surgery: Anemia, fever, nausea, edema, constipation, rash, vomiting, insomnia, increased wound drainage, hypokalemia, urinary tract infection, dizziness, purpura, hypotension, confusion, bullous eruption, urinary retention, hematoma, major bleeding, diarrhea, dyspepsia, postoperative hemorrhage, headache.1 16

Patients undergoing abdominal surgery: Postoperative wound infection, postoperative hemorrhage, fever, surgical site reaction, anemia, hypertension, pneumonia, vomiting.1

Venous thromboembolism: Constipation, headache, insomnia, fever, nausea, urinary tract infection, coughing.1

Storage

Parenteral

25°C (may be exposed to 15–30°C).1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not mix with other injections or infusions.1

• Anticoagulation results from rapid inhibition of factor Xa by antithrombin III bound to fondaparinux (about 300-fold greater than innate activity).1 2 4 10 Neutralization of coagulation factor Xa inhibits the conversion of prothrombin to thrombin and subsequent thrombus formation.1 2 4 10 Unable to lyse established thrombi.16

• Binds selectively to antithrombin III; unable to inactivate thrombin.1 2 4 16 At the recommended dosage, fibrinolytic activity not affected.1

• Platelet function or global clotting function tests (e.g., PT, bleeding time, aPTT) generally not affected when administered at the recommended dosage.1 10 16

In clinical studies performed with Fondaparinux Sodium, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of Fondaparinux Sodium. In addition, Fondaparinux Sodium neither influenced the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state.

Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with Fondaparinux Sodium unless these agents are essential. If co-administration is necessary, monitor patients closely for hemorrhage. [See Warnings and Precautions (5.2).]

In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200 micromolar i.e., 350 mg/L) was 17 to 28%. Inhibition of the other isozymes evaluated (CYPs 1A2, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0 to 16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro,Fondaparinux Sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes.

Since Fondaparinux Sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected.

 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.

 Pharmacodynamics

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.

 Pharmacokinetics

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, Cmax 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.

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.

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.

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.

Special Populations

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 (5.3).]

Following a single, subcutaneous dose of 7.5 mg of Fondaparinux Sodium in patients with moderate hepatic impairment (Child-Pugh Category B), Cmax 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).]

The pharmacokinetics of fondaparinux have not been investigated in pediatric patients. [See Contraindications (4), Warnings and Precautions (5.4), and Pediatric Use (8.4).]

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).]

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)].

The pharmacokinetic properties of Fondaparinux Sodium are not significantly affected by gender.

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.

Fondaparinux Sodium Injection, USP is available in the following strengths:

2.5 mg Fondaparinux Sodium 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 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 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 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 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.