Other Antithrombotic Agents

Fondaparinux soduim

Solution for injection, pre-filled syringes. The solution is a clear and colourless liquid.

Each pre-filled syringe (0.5 ml) contains 2.5 mg of fondaparinux sodium.

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery.

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing abdominal surgery who are judged to be at high risk of thromboembolic complications.

Prevention of Venous Thromboembolic Events (VTE) in medical patients who are judged to be at high risk for VTE and who are immobilised due to acute illness such as cardiac insufficiency and/or acute respiratory disorders, and/or acute infectious or inflammatory disease.

Patients undergoing major orthopaedic or abdominal surgery The recommended dose of Quixidar is 2.5 mg once daily administered post-operatively by subcutaneous injection.

The initial dose should be given 6 hours following surgical closure provided that haemostasis has been established. Treatment should be continued until the risk of venous thrombo-embolism has diminished, usually until the patient is ambulant, at least 5 to 9 days after surgery. Experience shows that in patients undergoing hip fracture surgery, the risk of VTE continues beyond 9 days after surgery. In these patients the use of prolonged prophylaxis with Quixidar should be considered for up to an additional 24 days. Medical patients who are at high risk for thromboembolic complications based on individual risk assessment. The recommended dose of Quixidar is 2.5 mg once daily administered by subcutaneous injection. A treatment duration of 6-14 days has been clinically studied in medical patients. Special populations In patients undergoing major orthopaedic surgery, timing of the first Quixidar injection requires strict adherence in patients =75 years, and/or with body weight <50 kg and/or with renal impairment with creatinine clearance ranging between 20 to 50 ml/min.

The first Quixidar administration should be given not earlier than 6 hours following surgical closure. The injection should not be given unless haemostasis has been established. (See Special Warnings). Renal impairment: Quixidar should not be used in patients with creatinine clearance < 20 ml/min. In patients with creatinine clearance in the range of 20 to 30 ml/min, the use of the Quixidar 1.5 mg dose is recommended. In patients with creatinine clearance in the range of 30 to 50 ml/min, the use of the Quixidar 1.5 mg dose may be considered for short- term prophylaxis based on pharmacokinetic modelling results. For long term prophylaxis, the 1.5 mg dose should be considered as an alternative to the 2.5 mg dose. (See Special Warnings). Hepatic impairment: no dosing adjustment is necessary. In patients with severe hepatic impairment, Quixidar should be used with care. (See Special Warnings).

Method of administration: Quixidar 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.

The safety and efficacy of Quixidar in patients under the age of 17 has not been studied.

See Adult Dosage

-known hypersensitivity to fondaparinux or to any of the excipients

-active clinically significant bleeding

-acute bacterial endocarditis

-severe renal impairment defined by creatinine clearance < 20 ml/min

Quixidar is intended for subcutaneous use only. Do not administer intramuscularly. Haemorrhage Quixidar should be used with caution in patients who have an increased risk of haemorrhage, such as those with congenital or acquired bleeding disorders (eg. 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. 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). When required, concomitant therapy with vitamin K antagonist should be administered in accordance with the information of Interactions Section. Other antiplatelet drugs (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 undergoing major orthopaedic surgery, epidural or spinal haematomas that may result in long-term or permanent paralysis cannot be excluded with the concurrent use of Quixidar and spinal/epidural anaesthesia or spinal puncture. The risk of these rare events may be higher with post operative use of indwelling epidural catheters or the concomitant use of other medicinal products affecting haemostasis.

Elderly patients: the elderly population is at increased risk of bleeding. As renal function is generally decreasing with age, elderly patients may show reduced elimination and increased exposure of fondaparinux. Quixidar should be used with caution in elderly patients. (See Adult Dosage). Low body weight: patients with body weight <50 kg are at increased risk of bleeding. Elimination of fondaparinux decreases with weight. Quixidar should be used with caution in these patients. (See Adult Dosage). Renal impairment: Fondaparinux is known to be mainly excreted by the kidney.

Patients with creatinine clearance <50 ml/min are at increased risk of bleeding and should be treated with caution. (See Adult Dosage and Contraindications). Severe hepatic impairment: dosing adjustment of Quixidar is not necessary. However, the use of Quixidar 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. (See Adult Dosage). Patients with Heparin Induced Thrombocytopenia Fondaparinux does not bind to platelet factor 4 and does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT) type II. The efficacy and safety of fondaparinux have not been formally studied in patients with HIT type II.

Bleeding risk is increased with concomitant administration of Quixidar and agents that may enhance the risk of hemorrhage (See Special Precautions). Oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with the pharmacokinetics of Quixidar.

The Quixidar dose (10 mg) in the interaction studies was higher than the dose recommended for the present indications. Quixidar neither influenced the INR activity of warfarin, nor the bleeding time under acetylsalicylic acid or piroxicam treatment, nor the pharmacokinetics of digoxin at steady state. Follow-up therapy with another anticoagulant medicinal product If follow-up treatment is to be initiated with heparin or LMWH, the first injection should, as a general rule, be given one day after the last Quixidar injection.

If follow up treatment with a Vitamin K antagonist is required, treatment with fondaparinux should be continued until the target INR value has been reached. Pregnancy and lactation There are no adequate data from the use of Quixidar in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryo/foetal development, parturition and postnatal development because of limited exposure. Quixidar should not be prescribed to pregnant women unless clearly necessary.

Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breast-feeding is not recommended during treatment with fondaparinux. Oral absorption by the child is however unlikely.

The safety of Quixidar 2.5 mg has been evaluated in 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days, in 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week, 1407 patients undergoing abdominal surgery treated up to 9 days, and in 425 medical patients who are at risk for thromboembolic complications treated up to 14 days. The undesirable effects reported by the investigator as at least possibly related to Quixidar are presented within each frequency grouping (common: = 1 % < 10 %; uncommon: = 0.1 % < 1 %; rare: = 0.01 % < 0.1 %) and system organ class by decreasing order of seriousness; these undesirable effects should be interpreted within the surgical and medical context.

System organ class MedDRA Undesirable effects in patients undergoing major orthopaedic surgery of lower limbs and/or abdominal surgery Undesirable effects in medical patients Infections and infestations Rare: post-operative wound infection Blood and lymphatic system disorders Common: post-operative haemorrhage, anaemia Uncommon: bleeding (epistaxis, gastrointestinal, haemoptysis, hematuria, haematoma) thrombocytopenia, purpura, thrombocythaemia, platelet abnormal, coagulation disorder Common: bleeding (haematoma, haematuria, haemoptysis, gingival bleeding) Uncommon: anaemia Immune system disorders Rare: allergic reaction Metabolism and nutrition disorders Rare: hypokalaemia Nervous system disorders Rare: anxiety, somnolence, vertigo, dizziness, headache, confusion Vascular disorders Rare: hypotension Respiratory, thoracic and mediastinal disorders Rare: dyspnoea, coughing Uncommon: dyspnoea Gastrointestinal disorders Uncommon: nausea, vomiting Rare: abdominal pain, dyspepsia, gastritis, constipation, diarrhoea Hepatobiliary disorders Uncommon: hepatic enzymes increased, hepatic function abnormal Rare: bilirubinaemia Skin and subcutaneous tissue disorders Uncommon: rash, pruritus Uncommon: rash, pruritus General disorders and administration site conditions Uncommon: oedema, oedema peripheral, fever, wound secretion Rare: chest pain, fatigue, hot flushes, leg pain, oedema genital, flushing, syncope Uncommon: chest pain In other studies or in post-marketing experience, rare cases of intracranial / intracerebral and retroperitoneal bleedings have been reported.

GlaxoSmithKline(GSK)

(POM)

18 June 2009