Fondaparinux Sodium (Page 7 of 13)

8.5 Geriatric Use

In clinical trials the efficacy of fondaparinux sodium in the elderly (65 years or older) was similar to that seen in patients younger than 65 years; however, serious adverse events increased with age. When using fondaparinux sodium in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication) [see Warnings and Precautions (5.2)].

Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to fondaparinux sodium may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, assess renal function prior to fondaparinux sodium administration [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.4)].

In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving fondaparinux sodium 2.5 mg, serious adverse events increased with age for patients receiving fondaparinux sodium. The incidence of major bleeding in clinical trials of fondaparinux sodium by age is provided in Table 6.

Table 6. Incidence of Major Bleeding in Patients Treated With Fondaparinux Sodium by Age
*
Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis.

Age

<65 years

% (n/N)

65 to 74 years

% (n/N)

≥75 years

% (n/N)

Orthopedic surgery *

1.8% (23/1,253)

2.2% (24/1,111)

2.7% (33/1,277)

Extended prophylaxis

1.9% (1/52)

1.4% (1/71)

2.9% (6/204)

Abdominal surgery

3.0% (19/644)

3.2% (16/507)

5.0% (14/282)

DVT and PE treatment

0.6% (7/1,151)

1.6% (9/560)

2.1% (12/583)

8.6 Renal Impairment

Patients with impaired renal function are at increased risk of bleeding due to reduced clearance of fondaparinux sodium [see Contraindications (4) and Warnings and Precautions (5.3)]. Assess renal function periodically in patients receiving fondaparinux sodium. Discontinue fondaparinux sodium immediately in patients who develop severe renal impairment while on therapy. After discontinuation of fondaparinux sodium, its anticoagulant effects may persist for 2 to 4 days in patients with normal renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of fondaparinux sodium may persist even longer in patients with renal impairment [see Clinical Pharmacology (12.4)].

8.7 Hepatic Impairment

Following a single, subcutaneous dose of 7.5 mg of fondaparinux sodium in patients with moderate hepatic impairment (Child-Pugh Category B) compared to subjects with normal liver function, changes from baseline in aPTT, PT/INR, and antithrombin III were similar in the two groups. However, a higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects, especially mild hematomas at the blood sampling or injection site. The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.4)].

10 OVERDOSAGE

There is no known antidote for fondaparinux sodium. Overdose of fondaparinux sodium 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 fondaparinux sodium can increase by 20% during hemodialysis.

11 DESCRIPTION

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.

The molecular formula of fondaparinux sodium is C31 H43 N3 Na10 O49 S8 and its molecular weight is 1728. The structural formula is provided below:

Fondaparinux Sodium Structural Formula
(click image for full-size original)

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

Each single-dose, prefilled syringe of fondaparinux sodium injection, 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. May also contain sodium hydroxide and/or hydrochloric acid as pH adjusters. 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.

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