4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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 a lack of 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.

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 < 30 ml/min.

4.4. Special warnings and precautions for use

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.

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).

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.

4.6. Fertility, pregnancy and lactation

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.

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). 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 (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*

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.

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.