4.1. Therapeutic 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 (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 adults for 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).

4.2. Posology and method of administration

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 proceduresIn 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 administrationFondaparinux 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.

4.3. Contraindications

- 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.

4.4. Special warnings and precautions for use

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.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

Breastfeeding

Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding 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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 2.5 mg has been evaluated in:

- 3,595 patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 days (Fondaparinux 1.5 mg/0.3 ml and Fondaparinux 2.5 mg/0.5 ml)

- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week (Fondaparinux 1.5 mg/0.3 ml and Fondaparinux 2.5 mg/0.5 ml)

- 1,407 patients undergoing abdominal surgery treated up to 9 days (Fondaparinux 1.5 mg/0.3 ml and Fondaparinux 2.5 mg/0.5 ml)

- 425 medical patients who are at risk for thromboembolic complications treated up to 14 days (Fondaparinux 1.5 mg/0.3 ml and Fondaparinux 2.5 mg/0.5 ml)

- 10,057 patients undergoing treatment of UA or NSTEMI ACS (Fondaparinux 2.5 mg/0.5 ml)

- 6,036 patients undergoing treatment of STEMI ACS (Fondaparinux 2.5 mg/0.5 ml)

- 2,517 patients treated for Venous Thrombo-Embolism and treated with fondaparinux for an average of 7 days (Fondaparinux 5 mg/0.4 ml, Fondaparinux 7.5 mg/0.6 ml and Fondaparinux 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, uterovaginal 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, nonprotein-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

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.