fondaparinux sodium: prescribing information – dosing, contraindications, interactions, side effects

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 (see section 5.1).

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 adults with acute symptomatic spontaneous superficial-vein thrombosis of the lower limbs without concomitant deep-vein thrombosis (see sections 4.2 and 5.1).

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 (see section 5.1).

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 adultsfor whom urgent (< 120 mins) invasive management (PCI) is not indicated (see sections 4.4 and 5.1).

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 (see sections 4.2 and 5.1).

Treatment of adults with 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.

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 (see section 5.1).

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 (see section 5.1).

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 (see sections 4.4 and 5.1). 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
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 (see section 4.4).

Renal impairment
 Prevention of VTE - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). 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 (see sections 4.4 and 5.2). No dosage reduction is required for patients with mild renal impairment (creatinine clearance >50 ml/min).


Treatment of superficial-vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). 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 (see sections 4.4 and 5.2). 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 (see section 4.4.)

Hepatic impairment

Prevention of VTE - 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 (see sections 4.4 and 5.2).


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 (see section 4.4).

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 - 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 (see section 4.4).


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 (see section 4.4).

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.

For additional instructions for use and handling and disposal see section 6.6.

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 (see section 5.1).

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 (see section 5.1).

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 (see section 4.4). 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 (see section 4.4). 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 (see sections 4.4 and 5.1). 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 (see section 4.4).

Renal impairment

Prophylaxis of VTE - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). 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 (see sections 4.4 and 5.2). 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 (see section 4.3). 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 (see section 4.3). 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 (see sections 4.4 and 5.2). 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 (see section 4.4.)

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 (see sections 4.4 and 5.2).


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 (see section 4.4).

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 (see section 4.4).


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 (see section 4.4).

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.

For additional instructions for use and handling and disposal see section 6.6.

Posology
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 (see section 4.4).

Renal impairment - Fondaparinux should be used with caution in patients with moderate renal impairment (see section 4.4).

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 (see section 4.4).

Fondaparinux should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3).

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 (see sections 4.4 and 5.2).

Paediatric population - Fondaparinux is not recommended for use in children below 17 years of age due to limited data on safety and efficacy (see sections 5.1 and 5.2).

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.

For additional instructions for use and handling and disposal see section 6.6.

Posology
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 (see section 4.4).

Renal impairment - Fondaparinux should be used with caution in patients with moderate renal impairment (see section 4.4).

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 (see section 4.4).

Fondaparinux should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min) (See section 4.3).

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 (see sections 4.4 and 5.2).

Paediatric population - Fondaparinux is not recommended for use in children below 17 years of age due to limited data on safety and efficacy (see sections 5.1 and 5.2).

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.

For additional instructions for use and handling and disposal see section 6.6.

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• active clinically significant bleeding
• acute bacterial endocarditis
• severe renal impairment defined by creatinine clearance < 20 ml/min.

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• active clinically significant bleeding
• acute bacterial endocarditis
• severe renal impairment defined by creatinine clearance < 30 ml/min.

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 (see section 4.4).

The safety of fondaparinux has been evaluated in:
- 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 1,407 patients undergoing abdominal surgery treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)

• 425 medical patients who are at risk for thromboembolic complications treated up to 14 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
• 10,057 patients undergoing treatment of UA or NSTEMI ACS (Arixtra 2.5 mg/0.5 ml)
• 6,036 patients undergoing treatment of STEMI ACS (Arixtra 2.5 mg/0.5 ml)
• 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days (Arixtra 5 mg/0.4 ml, Arixtra 7.5 mg/0.6 ml and Arixtra 10 mg/0.8 ml).

These adverse reactions should be interpreted within the surgical or medical context of the indications.
The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000).

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Infections and infestations

post-operative wound infections
Blood and lymphatic system disorders anaemia, post- operative haemorrhage, utero-vaginal haemorrhage*, haemoptysis, haematuria, haematoma, gingival bleeding, purpura, epistaxis, gastrointestinal bleeding, hemarthrosis*, ocular bleeding*, bruise* thrombocytopenia, thrombocythaemia, platelet abnormal, coagulation disorder retroperitoneal bleeding*, hepatic, intracranial/ intracerebral bleeding* Immune system disorders

allergic reaction (including very rare reports of angioedema, anaphylactoid/ anaphylactic reaction)

Metabolism and nutrition disorders

hypokalaemia, non-protein-nitrogen
(Npn) increased1*
Nervous system disorders

headache

anxiety, confusion, dizziness, somnolence, vertigo

Vascular disorders

hypotension
Respiratory, thoracic and mediastinal disorders

dyspnoea coughing
Gastrointestinal disorders

nausea, vomiting

abdominal pain, dyspepsia, gastritis, constipation, diarrhoea

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Hepatobiliary disorders

abnormal liver function tests, hepatic enzymes increased

bilirubinaemia

Skin and subcutaneous tissue disorders

rash erythematous, pruritus

General disorders and administration site conditions

oedema, oedema peripheral, pain, fever, chest pain, wound secretion reaction at injection site, leg pain, fatigue, flushing, syncope, hot flushes, oedema genital (1) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.
* ADRs occurred at higher doses 5 mg/0.4 ml, 7.5 mg/0.6 ml and 10 mg/0.8 ml.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 (see section 4.4).

The safety of fondaparinux has been evaluated in:
- 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 1,407 patients undergoing abdominal surgery treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 425 medical patients who are at risk for thromboembolic complications treated up to 14 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 10,057 patients undergoing treatment of UA or NSTEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 6,036 patients undergoing treatment of STEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days (Arixtra 5 mg/0.4 ml, Arixtra 7.5 mg/0.6 ml and Arixtra 10 mg/0.8 ml).

These adverse reactions should be interpreted within the surgical or medical context of the indications.
The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000).

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Infections and infestations

post-operative wound infections
Blood and lymphatic system disorders

anaemia, post-operative haemorrhage, utero- vaginal haemorrhage*, haemoptysis, haematuria, haematoma, gingival bleeding, purpura, epistaxis, gastrointestinal bleeding, hemarthrosis*, ocular bleeding*, bruise* thrombocytopenia, thrombocythaemia, platelet abnormal, coagulation disorder

retroperitoneal bleeding*, hepatic, intracranial/ intracerebral bleeding*

Immune system disorders

allergic reaction
(including very rare reports of angioedema, anaphylactoid/ anaphylactic reaction) Metabolism and nutrition disorders

hypokalaemia, non- protein-nitrogen (Npn) increased1*

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Nervous system disorders

headache

anxiety, confusion, dizziness, somnolence, vertigo
Vascular disorders

hypotension
Respiratory, thoracic and mediastinal disorders

dyspnoea coughing
Gastrointestinal disorders

nausea, vomiting

abdominal pain, dyspepsia, gastritis, constipation, diarrhoea
Hepatobiliary disorders abnormal liver function tests, hepatic enzymes increased bilirubinaemia

Skin and subcutaneous tissue disorders

rash erythematous, pruritus

General disorders and administration site conditions

oedema, oedema peripheral, pain, fever, chest pain, wound secretion reaction at injection site, leg pain, fatigue, flushing, syncope, hot flushes, oedema genital (1) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.
* ADRs occurred at higher doses 5 mg/0.4 ml, 7.5 mg/0.6 ml and 10 mg/0.8 ml.

Arixtra 2.5 mg/0.5 ml
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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

The most commonly reported serious adverse reactions reported with fondaparinux are bleeding complications (various sites including rare cases of intracranial/ intracerebral and retroperitoneal bleedings). Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage (see section 4.4).

The safety of fondaparinux has been evaluated in:
- 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 1,407 patients undergoing abdominal surgery treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 425 medical patients who are at risk for thromboembolic complications treated up to 14 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 10,057 patients undergoing treatment of UA or NSTEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 6,036 patients undergoing treatment of STEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days (Arixtra 5 mg/0.4 ml, Arixtra 7.5 mg/0.6 ml and Arixtra 10 mg/0.8 ml).

These adverse reactions should be interpreted within the surgical or medical context of the indications.
The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000).

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Infections and infestations

post-operative wound infections
Blood and lymphatic system disorders anaemia, post-operative haemorrhage, utero- vaginal haemorrhage*, haemoptysis, haematuria, haematoma, gingival bleeding, purpura, epistaxis, gastrointestinal bleeding, hemarthrosis*, ocular bleeding*, bruise* thrombocytopenia, thrombocythaemia, platelet abnormal, coagulation disorder

retroperitoneal bleeding*, hepatic, intracranial/ intracerebral bleeding*

Immune system disorders

allergic reaction
(including very rare reports of angioedema, anaphylactoid/ anaphylactic reaction) Metabolism and nutrition disorders

hypokalaemia, non- protein-nitrogen (Npn) increased1*
Nervous system disorders

headache

anxiety, confusion, dizziness, somnolence, vertigo
Vascular disorders

hypotension
Respiratory, thoracic and mediastinal disorders

dyspnoea coughing
Gastrointestinal disorders

nausea, vomiting abdominal pain, dyspepsia, gastritis, constipation, diarrhoea
Hepatobiliary disorders abnormal liver function tests, hepatic enzymes increased bilirubinaemia Skin and subcutaneous tissue disorders

rash erythematous, pruritus

General disorders and administration site conditions

oedema, oedema peripheral, pain, fever, chest pain, wound secretion reaction at injection site, leg pain, fatigue, flushing, syncope, hot flushes, oedema genital (1) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.
* ADRs occurred at higher doses 5 mg/0.4 ml, 7.5 mg/0.6 ml and 10 mg/0.8 ml.

Paediatric population
The safety of fondaparinux in paediatric patients has not been established. In an open-label, single-arm retrospective, non-randomized, single-centre clinical study with 366 paediatric VTE patients treated with fondaparinux, the safety profile was as follows:
Major bleeding events as per ISTH definition (n=7; 1.9%): 1 patient (0.3%) had clinically overt bleeding, 3 patients (0.8%) had major bleeding, and 3 patients (0.8%) had major bleeding that required surgical intervention. Major bleeding events resulted in the interruption of fondaparinux treatment for 4 patients and the discontinuation of fondaparinux for 3 patients.

In addition, 8 patients (2.2%) had overt bleeding for which a blood product was administered, and which was not directly attributable to the patient’s underlying medical condition and 4 patients (1.1%) had bleeding that required medical or surgical intervention. All these events warranted either interruption or withdrawal of fondaparinux treatment except for 1 patient for whom the action taken with fondaparinux was not reported.
An additional 65 patients (17.8%) reported other overt bleeding events or menstrual bleeding resulting in a medical consultation and/or intervention.

The following adverse events of special interest were noted (n=189, 51.6%): anaemia (27%), thrombocytopenia (18%), allergic reactions (1%) and hypokalaemia (14%).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

The most commonly reported serious adverse reactions reported with fondaparinux are bleeding complications (various sites including rare cases of intracranial/ intracerebral and retroperitoneal bleedings). Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage (see section 4.4).

The safety of fondaparinux has been evaluated in:
- 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 1,407 patients undergoing abdominal surgery treated up to 9 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 425 medical patients who are at risk for thromboembolic complications treated up to 14 days (Arixtra 1.5 mg/0.3 ml and Arixtra 2.5 mg/0.5 ml)
- 10,057 patients undergoing treatment of UA or NSTEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 6,036 patients undergoing treatment of STEMI ACS (Arixtra 2.5 mg/0.5 ml)
- 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days (Arixtra 5 mg/0.4 ml, Arixtra 7.5 mg/0.6 ml and Arixtra 10 mg/0.8 ml)

These adverse reactions should be interpreted within the surgical or medical context of the indications.
The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000).

System organ class
MedDRA common
(≥ 1/100, <1/10) uncommon
(≥ 1/1,000, <1/100) rare
(≥ 1/10,000, <1/1,000)
Infections and infestations

post-operative wound infections
Blood and lymphatic system disorders anaemia, post-operative haemorrhage, utero- vaginal haemorrhage*, haemoptysis, haematuria, haematoma, gingival bleeding, purpura, epistaxis, gastrointestinal bleeding, hemarthrosis*, ocular bleeding*, bruise* thrombocytopenia, thrombocythaemia, platelet abnormal, coagulation disorder

retroperitoneal bleeding*, hepatic, intracranial/ intracerebral bleeding*

Immune system disorders

allergic reaction
(including very rare reports of angioedema, anaphylactoid/ anaphylactic reaction) Metabolism and nutrition disorders

hypokalaemia, non- protein-nitrogen (Npn) increased1*
Nervous system disorders

headache

anxiety, confusion, dizziness, somnolence, vertigo
Vascular disorders

hypotension
Respiratory, thoracic and mediastinal disorders

dyspnoea coughing
Gastrointestinal disorders

nausea, vomiting

abdominal pain, dyspepsia, gastritis, constipation, diarrhoea
Hepatobiliary disorders abnormal liver function tests, hepatic enzymes increased bilirubinaemia

Skin and subcutaneous tissue disorders

rash erythematous, pruritus

General disorders and administration site conditions

oedema, oedema peripheral, pain, fever, chest pain, wound secretion reaction at injection site, leg pain, fatigue, flushing, syncope, hot flushes, oedema genital (1) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.
* ADRs occurred at higher doses 5 mg/0.4 ml, 7.5 mg/0.6 ml and 10 mg/0.8 ml.

Paediatric population
The safety of fondaparinux in paediatric patients has not been established. In an open-label, single-arm retrospective, non-randomized, single-centre clinical study with 366 paediatric VTE patients treated with fondaparinux, the safety profile was as follows:
Major bleeding events as per ISTH definition (n=7; 1.9%): 1 patient (0.3%) had clinically overt bleeding, 3 patients (0.8%) had major bleeding, and 3 patients (0.8%) had major bleeding that required surgical intervention. Major bleeding events resulted in the interruption of fondaparinux treatment for 4 patients and the discontinuation of fondaparinux for 3 patients.

In addition, 8 patients (2.2%) had overt bleeding for which a blood product was administered, and which was not directly attributable to the patient’s underlying medical condition and 4 patients (1.1%) had bleeding that required medical or surgical intervention. All these events warranted either interruption or withdrawal of fondaparinux treatment except for 1 patient for whom the action taken with fondaparinux was not reported.
An additional 65 patients (17.8%) reported other overt bleeding events or menstrual bleeding resulting in a medical consultation and/or intervention.

The following adverse events of special interest were noted (n=189, 51.6%): anaemia (27%), thrombocytopenia (18%), allergic reactions (1%) and hypokalaemia (14%).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Fondaparinux is intended for subcutaneous use only. Do not administer 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 of Section 4.5. 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 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.

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 with 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 (see section 4.2 and 5.1).

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 (see section 4.2 and 5.1).

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 (see section 5.2). Fondaparinux should be used with caution in elderly patients (see section 4.2).

Low body weight

Prevention of VTE - 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 (see section 4.2).


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 (see section 4.2).

Renal impairment

Prevention of VTE - Fondaparinux is known to be mainly excreted by the kidney. Patients with creatinine clearance <50 ml/min are at increased risk of bleeding and VTE and should be treated with caution (see sections 4.2, 4.3 and 5.2). There are limited clinical data available from patients with creatinine clearance less than 30 ml/min.


Treatment of superficial-vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). 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 (see sections 4.2 and 5.2). The safety and efficacy of 1.5 mg has not been studied.

Severe hepatic impairment

Prevention of VTE - 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 (see section 4.2).


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 (see section 4.2).

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 usually 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.

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

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 of section 4.5. 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 (see clinical studies section 5.1). Therefore adjunctive UFH should be used during non-primary PCI according to standard practice (see posology in section 4.2).

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 (see section 4.2 and 5.1).

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 (see section 4.2 and 5.1).

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 (see section 5.2). Fondaparinux should be used with caution in elderly patients (see section 4.2).

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 (see section 4.2).


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 (see section 4.2).

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 (see sections 4.2, 4.3 and 5.2). 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 (see sections 4.2 and 4.3).


Treatment of superficial-vein thrombosis - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). 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 (see sections 4.2 and 5.2). 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 (see section 4.2).


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 (see section 4.2).

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 usually 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.

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.

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). During treatment of VTE, concomitant therapy with vitamin K antagonist should be administered in accordance with the information of Section 4.5. 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 (see section 5.2). 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 (see section 4.2).

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 (see sections 4.2 and 5.2).

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) (see sections 4.2, 4.3 and 5.2).

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 (see section 4.2).

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 (see section 4.2).

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 usually 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.

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

Bleeding risk is increased with concomitant administration of fondaparinux and agents that may enhance the risk of haemorrhage (see section 4.4).

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.

Bleeding risk is increased with concomitant administration of fondaparinux and agents that may enhance the risk of haemorrhage (see section 4.4).

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.

Pregnancy
There are no adequate data from the use of fondaparinux in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryo/foetal development, parturition and postnatal development because of limited exposure. Fondaparinux should not be prescribed to pregnant women unless clearly necessary.

Breast-feeding
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.

Fertility
There are no data available on the effect of fondaparinux on human fertility. Animal studies do not show any effect on fertility.

Pregnancy
No clinical data on exposed pregnancies are available. Animal studies are insufficient with respect to effects on pregnancy, embryo/foetal development, parturition and postnatal development because of limited exposure. Fondaparinux should not be prescribed to pregnant women unless clearly necessary.

Breast-feeding
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.

Fertility
There are no data available on the effect of fondaparinux on human fertility. Animal studies do not show any effect on fertility.

No studies on the effect on the ability to drive and to use machines have been performed.

Fondaparinux doses above the recommended regimen may lead to an increased risk of bleeding. There is no known antidote to fondaparinux.

Overdose associated with bleeding complications should lead to treatment discontinuation and search for the primary cause. Initiation of appropriate therapy such as surgical haemostasis, blood replacements, fresh plasma transfusion, plasmapheresis should be considered.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antithrombotic agents.
ATC code: B01AX05

Pharmacodynamic effects

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII) mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no effects on platelets.

At the 2.5 mg dose, fondaparinux does not affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of aPTT prolongation have been received.

Fondaparinux does not usually cross-react with sera from patients with heparin-induced thrombocytopaenia (HIT). However, rare spontaneous reports of HIT in patients treated with fondaparinux have been received.

Clinical studies

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days The fondaparinux clinical program was designed to demonstrate the efficacy of fondaparinux for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery. Over 8,000 patients (hip fracture – 1,711, hip replacement – 5,829, major knee surgery – 1,367) were studied in controlled Phase II and III clinical studies. Fondaparinux 2.5 mg once daily started 6-8 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours before surgery, or 30 mg twice daily started 12-24 hours after surgery.

In a pooled analysis of these studies, the recommended dose regimen of fondaparinux versus enoxaparin was associated with a significant decrease (54% [95% CI, 44 %; 63%]) in the rate of VTE evaluated up to day 11 after surgery, irrespective of the type of surgery performed. The majority of endpoint events were diagnosed by a prescheduled venography and consisted mainly of distal DVT, but the incidence of proximal DVT was also significantly reduced. The incidence of symptomatic VTE, including PE was not significantly different between treatment groups.

In studies versus enoxaparin 40 mg once daily started 12 hours before surgery, major bleeding was observed in 2.8% of fondaparinux patients treated with the recommended dose, compared to 2.6% with enoxaparin.

Pharmacotherapeutic group: antithrombotic agents.
ATC code: B01AX05

Pharmacodynamic effects

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithrombotic activity of fondaparinux is the result of antithrombin III (antithrombin) mediated selective inhibition of Factor Xa. By binding selectively to antithrombin, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by antithrombin. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no effects on platelets.

At the doses used for treatment, fondaparinux does not, to a clinically relevant extent, affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of aPTT prolongation have been received. At higher doses, moderate changes in aPTT can occur. At the 10 mg dose used in interaction studies, fondaparinux did not significantly influence the anticoagulation activity (INR) of warfarin.

Fondaparinux does not usually cross-react with sera from patients with heparin-induced thrombocytopaenia (HIT). However, rare spontaneous reports of HIT in patients treated with fondaparinux have been received.

Clinical studies

The fondaparinux clinical program in treatment of Venous Thromboembolism was designed to demonstrate the efficacy of fondaparinux for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Over 4,874 patients were studied in controlled Phase II and III clinical studies.

Treatment of Deep Venous Thrombosis
In a randomised, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT, fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight  50 kg,  100 kg) or 10 mg (body weight >100 kg) SC once daily was compared to enoxaparin sodium 1 mg/kg SC twice daily. A total of 2,192 patients were treated; for both groups, patients were treated for at least 5 days and up to 26 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite of confirmed symptomatic recurrent non-fatal VTE and fatal VTE reported up to Day 97.
Treatment with fondaparinux was demonstrated to be non-inferior to enoxaparin (VTE rates 3.9% and 4.1%, respectively).

Major bleeding during the initial treatment period was observed in 1.1% of fondaparinux patients, compared to 1.2% with enoxaparin.

Treatment of Pulmonary Embolism

Absorption
After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of fondaparinux 2.5 mg to young healthy subjects,

peak plasma concentration (mean Cmax = 0.34 mg/l) is obtained 2 hours post-dosing. Plasma concentrations of half the mean Cmax values are reached 25 minutes post-dosing.

In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC.

Mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients undergoing hip replacement surgery receiving fondaparinux 2.5 mg once daily are: Cmax (mg/l) - 0.39 (31%), Tmax (h) - 2.8 (18%) and Cmin (mg/l) -0.14 (56%). In hip fracture patients, associated with their increased age, fondaparinux steady state plasma concentrations are: Cmax (mg/l) - 0.50 (32%), Cmin (mg/l) - 0.19 (58%).

Distribution
The distribution volume of fondaparinux is limited (7-11 litres). In vitro, fondaparinux is highly and specifically bound to antithrombin protein with a dose-dependant plasma concentration binding (98.6% to 97.0% in the concentration range from 0.5 to 2 mg/l). Fondaparinux does not bind significantly to other plasma proteins, including platelet factor 4 (PF4).

Since fondaparinux does not bind significantly to plasma proteins other than ATIII, no interaction with other medicinal products by protein binding displacement are expected.

Biotransformation
Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular no evidence for the formation of active metabolites.

Absorption
After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of fondaparinux 2.5 mg to young healthy subjects, peak plasma concentration (mean Cmax = 0.34 mg/l) is obtained 2 hours post-dosing. Plasma concentrations of half the mean Cmax values are reached 25 minutes post-dosing.

In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily subcutaneous dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC.

Mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients undergoing hip replacement surgery receiving fondaparinux 2.5 mg once daily are: Cmax (mg/l) - 0.39 (31%), Tmax (h) - 2.8 (18%) and Cmin (mg/l) -0.14 (56%). In hip fracture patients, associated with their increased age, fondaparinux steady state plasma concentrations are: Cmax (mg/l) - 0.50 (32%), Cmin (mg/l) - 0.19 (58%).

Distribution
The distribution volume of fondaparinux is limited (7-11 litres). In vitro, fondaparinux is highly and specifically bound to antithrombin protein with a dose-dependant plasma concentration binding (98.6% to 97.0% in the concentration range from 0.5 to 2 mg/l). Fondaparinux does not bind significantly to other plasma proteins, including platelet factor 4 (PF4).

Since fondaparinux does not bind significantly to plasma proteins other than ATIII, no interaction with other medicinal products by protein binding displacement are expected.

Biotransformation
Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular no evidence for the formation of active metabolites.

The 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 concentration of fondaparinux is expressed as milligrams (mg).

Absorption
After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of fondaparinux 2.5 mg to young healthy subjects, peak plasma concentration (mean Cmax = 0.34 mg/l) is obtained 2 hours post-dosing. Plasma concentrations of half the mean Cmax values are reached 25 minutes post-dosing.

In elderly healthy subjects, pharmacokinetics of fondaparinux is linear in the range of 2 to 8 mg by subcutaneous route. Following once daily dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC.

Mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients undergoing hip replacement surgery receiving fondaparinux 2.5 mg once daily are: Cmax (mg/l) - 0.39 (31%), Tmax (h) - 2.8 (18%) and Cmin (mg/l) -0.14 (56%). In hip fracture patients, associated with their increased age, fondaparinux steady state plasma concentrations are: Cmax (mg/l) - 0.50 (32%), Cmin (mg/l) - 0.19 (58%).