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Drug Details

Arixtra 2.5mg/0.5ml solution for injection, pre-filled syringe

• Drug Class Description
  Antithrombotic Agents
• Generic Name
  Fondaparinux Sodium
• Presentation
  Solution for injection. The solution is a clear and colourless liquid.
• Description
  Each pre-filled syringe (0.5 ml) contains 2.5 mg of fondaparinux sodium. Excipient(s): Contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.
• Indications
  

   

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

  Prevention of Venous Thromboembolic Events (VTE) in adult 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.

  Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) in adults for whom urgent (< 120 mins) invasive management (PCI) is not indicated.

  Treatment of ST segment elevation myocardial infarction (STEMI) in adults who are managed with thrombolytics or who initially are to receive no other form of reperfusion therapy.

  Treatment of adults with acute symptomatic spontaneous superficial-vein thrombosis of the lower limbs without concomitant deep-vein thrombosis.

   

• Adult Dosage
  

  Posology

  Patients undergoing major orthopaedic or abdominal surgery

  The recommended dose of fondaparinux 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 fondaparinux should be considered for up to an additional 24 days.

  Medical patients who are at high risk for thromboembolic complications based on an individual risk assessment

  The recommended dose of fondaparinux is 2.5 mg once daily administered by subcutaneous injection. A treatment duration of 6-14 days has been clinically studied in medical patients.

  Treatment of unstable angina/non- ST segment elevation myocardial infarction (UA/NSTEMI)

  The recommended dose of fondaparinux is 2.5 mg once daily, administered by subcutaneous injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to a maximum of 8 days or until hospital discharge if that occurs earlier.

  If a patient is to undergo percutaneous coronary intervention (PCI), unfractionated heparin (UFH) as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of fondaparinux. The timing of restarting subcutaneous fondaparinux after sheath removal should be based on clinical judgment. In the pivotal UA/NSTEMI clinical trial, treatment with fondaparinux was restarted no earlier than 2 hours after sheath removal.

  Treatment of ST segment elevation myocardial infarction (STEMI)

  The recommended dose of fondaparinux is 2.5 mg once daily. The first dose of fondaparinux is administered intravenously and subsequent doses are administered by subcutaneous injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to a maximum of 8 days or until hospital discharge if that occurs earlier.

  If a patient is to undergo non-primary PCI, unfractionated heparin (UFH) as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of fondaparinux. The timing of restarting subcutaneous fondaparinux after sheath removal should be based on clinical judgment. In the pivotal STEMI clinical trial, treatment with fondaparinux was restarted no earlier than 3 hours after sheath removal.

  • Patients who are to undergo coronary artery bypass graft (CABG) surgery

  In STEMI or UA/NSTEMI patients who are to undergo coronary artery bypass graft (CABG) surgery, fondaparinux where possible, should not be given during the 24 hours before surgery and may be restarted 48 hours post-operatively.

  Treatment of superficial-vein thrombosis

  The recommended dose of fondaparinux is 2.5 mg once daily, administered by subcutaneous injection. Patients eligible for fondaparinux 2.5 mg treatment should have acute, symptomatic, isolated, spontaneous superficial-vein thrombosis of the lower limbs, at least 5 cm long and documented by ultrasonographic investigation or other objective methods. Treatment should be initiated as soon as possible following diagnosis and after exclusion of concomitant DVT or superficial-vein thrombosis within 3 cm from the sapheno-femoral junction. Treatment should be continued for a minimum of 30 days and up to a maximum of 45 days in patients at high risk of thromboembolic complications. Patients could be recommended to self-inject the product when they are judged willing and able to do so. Physicians should provide clear instructions for self-injection.

  • Patients who are to undergo surgery or other invasive procedures

  In superficial vein thrombosis patients who are to undergo surgery or other invasive procedures, fondaparinux, where possible, should not be given during the 24 hours before surgery. Fondaparinux may be restarted at least 6 hours post-operatively provided haemostasis has been achieved.

  Special populations

  Prevention of VTE following Surgery

  In patients undergoing surgery, timing of the first fondaparinux 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 fondaparinux administration should be given not earlier than 6 hours following surgical closure. The injection should not be given unless haemostasis has been established.

  Renal impairment

  • Prophylaxis of VTE - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min. The dose should be reduced to 1.5 mg once daily in patients with creatinine clearance in the range of 20 to 50 ml/min. No dosage reduction is required for patients with mild renal impairment (creatinine clearance >50 ml/min).

  • Treatment of UA/NSTEMI and STEMI - Fondaparinux should not be used in patients with creatinine clearance < 20 ml/min. No dosage reduction is required for patients with creatinine clearance > 20 ml/min.

  • Treatment of superficial-vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min. The dose should be reduced to 1.5 mg once daily in patients with creatinine clearance in the range of 20 to 50 ml/min. No dosage reduction is required for patients with mild renal impairment (creatinine clearance >50 ml/min). The safety and efficacy of 1.5 mg has not been studied.

  Hepatic impairment

  • Prevention of VTE and Treatment of UA/NSTEMI and STEMI - 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.

  • Treatment of superficial-vein thrombosis - The safety and efficacy of fondaparinux in patients with severe hepatic impairment has not been studied, therefore fondaparinux is not recommended for use in these patients.

  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.

  Low body weight

  • Prevention of VTE and Treatment of UA/NSTEMI and STEMI - Patients with body weight <50 kg are at increased risk of bleeding. Elimination of fondaparinux decreases with weight. Fondaparinux should be used with caution in these patients.

  • Treatment of superficial-vein thrombosis - The safety and efficacy of fondaparinux in patients with body weight less than 50 kg has not been studied, therefore fondaparinux is not recommended for use in these patients.

  Method of administration

  • Subcutaneous 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.

  • Intravenous administration (first dose in patients with STEMI only)

  Intravenous administration should be through an existing intravenous line either directly or using a small volume (25 or 50ml) 0.9% saline minibag. 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 intravenous tubing should be well flushed with saline after injection to ensure that all of the medicinal product is administered. If administered via a minibag, the infusion should be given over 1 to 2 minutes.

• Child Dosage
  

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

• Elderly Dosage
  

  See Adult Dosage

• Contra Indications
  

  - 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 < 20 ml/min.

• Special Precautions
  

  Fondaparinux must not be administered intramuscularly.

  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.

  For prevention of VTE- 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 in the interactions section. 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.

  For treatment of UA/NSTEMI and STEMI-Fondaparinux should be used with caution in patients who are being treated concomitantly with other agents that increase the risk of haemorrhage (such as GPIIb/IIIa inhibitors or thrombolytics).

  For treatment of superficial-vein thrombosis - Fondaparinux should be used with caution in patients who are being treated concomitantly with other medicinal products that increase the risk of haemorrhage.

  PCI and risk of guiding catheter thrombus

  In STEMI patients undergoing primary PCI, the use of fondaparinux prior to and during PCI is not recommended. Similarly, in UA/NSTEMI patients with life threatening conditions that require urgent revascularisation, the use of fondaparinux prior to and during PCI is not recommended. These are patients with refractory or recurrent angina associated with dynamic ST deviation, heart failure, life-threatening arrhythmias or haemodynamic instability.

  In UA/NSTEMI and STEMI patients undergoing non-primary PCI, the use of fondaparinux as the sole anticoagulant during PCI is not recommended due to an increased risk of guiding catheter thrombus. Therefore adjunctive UFH should be used during non-primary PCI according to standard practice.

  Patients with superficial-vein thrombosis

  Presence of superficial-vein thrombosis greater than 3 cm from the sapheno-femoral junction should be confirmed and concomitant DVT should be excluded by compression ultrasound or objective methods prior to initiating treatment of fondaparinux. There are no data regarding the use of fondaparinux 2.5 mg in superficial-vein thrombosis patients with concomitant DVT or with superficial-vein thrombosis within 3 cm of the sapheno-femoral junction.

  The safety and efficacy of fondaparinux 2.5 mg has not been studied in the following groups: patients with superficial-vein thrombosis following sclerotherapy or resulting as a complication of an intravenous line, patients with history of superficial-vein thrombosis within the previous 3 months, patients with history of venous thromboembolic disease within the previous 6 months, or patients with active cancer.

  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 fondaparinux 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. Fondaparinux should be used with caution in elderly patients.

  Low body weight

  • Prevention of VTE and Treatment of UA/NSTEMI and STEMI - Patients with body weight <50 kg are at increased risk of bleeding. Elimination of fondaparinux decreases with weight. Fondaparinux should be used with caution in these patients.

  • Treatment of superficial-vein thrombosis - There are no clinical data available for the use of fondaparinux for the treatment of superficial-vein thrombosis in patients with body weight less than 50kg. Therefore, fondaparinux is not recommended for treatment of superficial-vein thrombosis in these patients.

  Renal impairment

  Fondaparinux is known to be mainly excreted by the kidney.

  • Prophylaxis of VTE - Patients with creatinine clearance <50 ml/min are at increased risk of bleeding and VTE and should be treated with caution. There are limited clinical data available from patients with creatinine clearance less than 30 ml/min.

  • Treatment of UA/NSTEMI and STEMI - For the treatment of UA/NSTEMI and STEMI, there are limited clinical data available on the use of fondaparinux 2.5mg once daily in patients with creatinine clearance between 20 and 30 ml/min. Therefore the physician should determine if the benefit of treatment outweighs the risk.

  • Treatment of superficial-vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min. The dose should be reduced to 1.5 mg once daily in patients with creatinine clearance in the range of 20 to 50 ml/min. The safety and efficacy of 1.5 mg has not been studied.

  Severe hepatic impairment

  • Prevention of VTE and Treatment of UA/NSTEMI and STEMI - Dosing adjustment of fondaparinux is not necessary. However, 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.

  • Treatment of superficial-vein thrombosis - There are no clinical data available for the use of fondaparinux for the treatment of superficial-vein thrombosis in patients with severe hepatic impairment. Therefore, fondaparinux is not recommended for the treatment of superficial-vein thrombosis in these patients.

  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.

  Latex Allergy

  The needle shield of the pre-filled syringe may contain dry natural latex rubber that has the potential to cause allergic reactions in latex sensitive individuals.

• Interactions
  

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

  Oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with the pharmacokinetics of fondaparinux. The fondaparinux dose (10 mg) in the interaction studies was higher than the dose recommended for the present indications. Fondaparinux 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 fondaparinux 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.

• Adverse Drug Reactions
  

  The most commonly reported serious adverse reactions reported with fondaparinux are bleeding complications (various sites including rare cases of intracranial/ intracerebral and retroperitoneal bleedings) and anaemia. Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage.

  The safety of fondaparinux 2.5 mg has been evaluated in:

  - 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days

  - 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week

  - 1,407 patients undergoing abdominal surgery treated up to 9 days

  - 425 medical patients who are at risk for thromboembolic complications treated up to 14 days

  - 10,057 patients undergoing treatment of UA or NSTEMI ACS

  - 6,036 patients undergoing treatment of STEMI ACS.

  For the prevention of VTE, 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; these adverse reactions should be interpreted within the surgical and medical context.

  System organ class MedDRA	Adverse reactions in patients undergoing major orthopaedic surgery of lower limbs and/or abdominal surgery	Adverse reactions 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, haematuria, 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.

  The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.

  Bleeding was a commonly reported event in patients with UA/NSTEMI and STEMI. The incidence of adjudicated major bleeding was 2.1% (fondaparinux) vs. 4.1% (enoxaparin) up to and including Day 9 in the Phase III UA/NSTEMI study, and the incidence of adjudicated severe haemorrhage by modified TIMI criteria was 1.1% (fondaparinux) vs. 1.4% (control [UFH/placebo]) up to and including Day 9 in the Phase III STEMI study.

  In the Phase III UA/NSTEMI study, the most commonly reported non-bleeding adverse events (reported in at least 1% of subjects on fondaparinux) were headache, chest pain and atrial fibrillation.

  In the Phase III study in STEMI patients, the most commonly reported non-bleeding adverse events (reported in at least 1% of subjects on fondaparinux) were atrial fibrillation, pyrexia, chest pain, headache, ventricular tachycardia, vomiting, and hypotension.