Anticoagulants

Fondaparinux Sodium

Each pre-filled syringe contains 5 mg, 7.5 mg or 10 mg of fondaparinux sodium in 0.4 ml, 0.6 ml or 10ml solution for injection. Excipient(s): Contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

Solution for injection. The solution is a clear and colourless to slightly yellow liquid.

Treatment of acute Deep Vein Thrombosis (DVT) and treatment of acute Pulmonary Embolism (PE), except in haemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy.

The recommended dose of fondaparinux is 7.5 mg (patients with body weight 50, 100kg) once daily administered by subcutaneous injection. For patients with body weight < 50 kg, the recommended dose is 5 mg. For patients with body weight > 100 kg, the recommended dose is 10 mg.

Treatment should be continued for at least 5 days and until adequate oral anticoagulation is established (International Normalised Ratio 2 to 3). Concomitant oral anticoagulation treatment should be initiated as soon as possible and usually within 72 hours. The average duration of administration in clinical trials was 7 days and the clinical experience from treatment beyond 10 days is limited.

Special populations

Elderly patients - No dosing adjustment is necessary.In patients 75 years, fondaparinux should be used with care, as renal function decreases with age.

Renal impairment - Fondaparinux should be used with caution in patients with moderate renal impairment.

There is no experience in the subgroup of patients with both high body weight (>100 kg) and moderate renal impairment (creatinine clearance 30-50 ml/min). In this subgroup, after an initial 10 mg daily dose, a reduction of the daily dose to 7.5 mg may be considered, based on pharmacokinetic modelling.

Fondaparinux should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).

Hepatic impairment - No dosing adjustment is necessary in patients with either mild or moderate hepatic impairment. In patients with severe hepatic impairment, fondaparinux should be used with care as this patient group has not been studied.

Paediatric population - Fondaparinux is not recommended for use in children below 17 years of age due to a lack of data on safety and efficacy.

Method of administration

Fondaparinux is administered by deep subcutaneous injection while the patient is lying down. Sites of administration should alternate between the left and the right anterolateral and left and right posterolateral abdominal wall. To avoid the loss of medicinal product when using the pre-filled syringe do not expel the air bubble from the syringe before the injection. The whole length of the needle should be inserted perpendicularly into a skin fold held between the thumb and the forefinger; the skin fold should be held throughout the injection.

Paediatric population: The safety and efficacy of Arixtra in patients under the age of 17 has not been studied.

Elderly patients: No dosing adjustment is necessary. In patients 75 years, Arixtra should be used with care, as renal function decreases with age. (See Special Precautions).

- hypersensitivity to the active substance or to any of the excipients

- active clinically significant bleeding

- acute bacterial endocarditis

- severe renal impairment defined by creatinine clearance < 30 ml/min.

Fondaparinux is intended for subcutaneous use only. Do not administer intramuscularly.

There is limited experience from treatment with fondaparinux in haemodynamically unstable patients and no experience in patients requiring thrombolysis, embolectomy or insertion of a vena cava filter.

Haemorrhage

Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage, such as those with congenital or acquired bleeding disorders (e.g. platelet count <50,000/mm³), active ulcerative gastrointestinal disease and recent intracranial haemorrhage or shortly after brain, spinal or ophthalmic surgery and in special patient groups as outlined below.

As for other anticoagulants, fondaparinux should be used with caution in patients who have undergone recent surgery (<3 days) and only once surgical haemostasis has been established.

Agents that may enhance the risk of haemorrhage should not be administered concomitantly with fondaparinux. These agents include desirudin, fibrinolytic agents, GP IIb/IIIa receptor antagonists, heparin, heparinoids, or Low Molecular Weight Heparin (LMWH). Other antiplatelet medicinal products (acetylsalicylic acid, dipyridamole, sulfinpyrazone, ticlopidine or clopidogrel), and NSAIDs should be used with caution. If co-administration is essential, close monitoring is necessary.

Spinal / Epidural anaesthesia

In patients receiving fondaparinux for treatment of VTE rather than prophylaxis, spinal/epidural anaesthesia in case of surgical procedures should not be used.

Elderly patients

The elderly population is at increased risk of bleeding. As renal function generally decreases with age, elderly patients may show reduced elimination and increased exposure of fondaparinux. Incidences of bleeding events in patients receiving the recommended regimen in the treatment of DVT or PE and aged <65 years, 65-75 and >75 years were 3.0 %, 4.5 % and 6.5 %, respectively. The corresponding incidences in patients receiving the recommended regimen of enoxaparin in the treatment of DVT were 2.5%, 3.6% and 8.3% respectively, while the incidences in patients receiving the recommended regimen of UFH in the treatment of PE were 5.5%, 6.6% and 7.4%, respectively. Fondaparinux should be used with caution in elderly patients.

Low body weight

Clinical experience is limited in patients with body weight <50 kg. Fondaparinux should be used with caution at a daily dose of 5 mg in this population.

Renal impairment

The risk of bleeding increases with increasing renal impairment. Fondaparinux is known to be excreted mainly by the kidney. Incidences of bleeding events in patients receiving the recommended regimen in the treatment of DVT or PE with normal renal function, mild renal impairment, moderate renal impairment and severe renal impairment were 3.0 % (34/1,132), 4.4 % (32/733), 6.6% (21/318), and 14.5 % (8/55) respectively. The corresponding incidences in patients receiving the recommended regimen of enoxaparin in the treatment of DVT were 2.3% (13/559), 4.6% (17/368), 9.7% (14/145) and 11.1% (2/18) respectively, and in patients receiving the recommended regimen of unfractionated heparin in the treatment of PE were 6.9% (36/523), 3.1% (11/352), 11.1% (18/162) and 10.7% (3/28), respectively.

Fondaparinux is contra-indicated in severe renal impairment (creatinine clearance <30 ml/min) and should be used with caution in patients with moderate renal impairment (creatinine clearance 30-50 ml/min). The duration of treatment should not exceed that evaluated during clinical trial (mean 7 days).

There is no experience in the subgroup of patients with both high body weight (>100 kg) and moderate renal impairment (creatinine clearance 30-50 ml/min). Fondaparinux should be used with care in these patients. After an initial 10 mg daily dose, a reduction of the daily dose to 7.5 mg may be considered, based on pharmacokinetic modelling.

Severe hepatic impairment

The use of fondaparinux should be considered with caution because of an increased risk of bleeding due to a deficiency of coagulation factors in patients with severe hepatic impairment.

Patients with Heparin Induced Thrombocytopenia

Fondaparinux should be used with caution in patients with a history of HIT. The efficacy and safety of fondaparinux have not been formally studied in patients with HIT type II. Fondaparinux does not bind to platelet factor 4 and does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT) type II. However, rare spontaneous reports of HIT in patients treated with fondaparinux have been received. To date a causal association between treatment with fondaparinux and the occurrence of HIT has not been established.

Bleeding risk is increased with concomitant administration of fondaparinux and agents that may enhance the risk of haemorrhage.

In clinical studies performed with fondaparinux, oral anticoagulants (warfarin) did not interact with the pharmacokinetics of fondaparinux; at the 10 mg dose used in the interaction studies, fondaparinux did not influence the anticoagulation monitoring (INR) activity of warfarin.

Platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with the pharmacokinetics of fondaparinux. At the 10 mg dose used in the interaction studies, fondaparinux did not influence the bleeding time under acetylsalicylic acid or piroxicam treatment, nor the pharmacokinetics of digoxin at steady state.

The safety of fondaparinux has been evaluated in 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days. The most common adverse reactions were bleeding complications.

The adverse reactions reported by the investigator as at least possibly related to fondaparinux are presented within each frequency grouping (very common 1/10; common: 1/100 to < 1/10; uncommon: 1/1,000 to < 1/100; rare: 1/10,000 to <1/1,000; very rare <1/10,000) and system organ class by decreasing order of seriousness.

(1) Isolated AEs have not been considered except if they were medically relevant.

(2) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.

GlaxoSmithKline(GSK)

(POM)

30 June 2009