Arixtra - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Arixtra 1.5 mg/0.3 ml solution for injection, pre-filled syringe.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe (0.3 ml) contains 1.5 mg of fondaparinux sodium.

Excipient(s) with known effect: Contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

The solution is a clear and colourless liquid.

4. CLINICAL PARTICULARS4.1 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 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 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.

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 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 postoperative 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.

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.

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.

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, in 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week, 1,407 patients undergoing abdominal surgery treated up to 9 days, and in 425 medical patients who are at risk for thromboembolic complications treated up to 14 days.

The adverse reactions reported by the investigator as at least possibly related to fondaparinux are presented within each frequency grouping (very common > 1/10; common: >1/100 to < 1/10; uncommon: > 1/1,000 to < 1/100; rare: > 1/10,000 to <1/1,000; very rare <1/10,000) and system organ class by decreasing order of seriousness; these adverse reactions should be interpreted within the surgical and medical context.

System organ class MedDRA	Adverse reactions in patients undergoing major orthopaedic surgery of lower limbs and/or abdominal surgery	Adverse reactions in medical patients
Infections and infestations	Rare: post-operative wound infection
Blood and lymphatic system disorders	Common: post-operative haemorrhage, anaemia Uncommon: bleeding (epistaxis, gastrointestinal, haemoptysis, haematuria, haematoma) thrombocytopenia, purpura, thrombocythaemia, platelet abnormal, coagulation disorder	Common: bleeding (haematoma, haematuria, haemoptysis, gingival bleeding) Uncommon: anaemia
Immune system disorders	Rare: allergic reaction (including very rare reports of angioedema, anaphylactoid/a­naphylactic reaction)	Rare: allergic reaction (including very rare reports of angioedema, anaphylactoid/a­naphylactic reaction)
Metabolism and nutrition disorders	Rare: hypokalaemia
Nervous system disorders	Rare: anxiety, somnolence, vertigo, dizziness, headache, confusion
Vascular disorders	Rare: hypotension
Respiratory, thoracic and mediastinal disorders	Rare: dyspnoea, coughing	Uncommon: dyspnoea
Gastrointestinal disorders	Uncommon: nausea, vomiting Rare: abdominal pain, dyspepsia, gastritis, constipation, diarrhoea

Hepatobiliary disorders	Uncommon: hepatic enzymes increased, hepatic function abnormal Rare: bilirubinaemia
Skin and subcutaneous tissue disorders	Uncommon: rash, pruritus	Uncommon : rash, pruritus
General disorders and administration site conditions	Uncommon: oedema, oedema peripheral, fever, wound secretion Rare: chest pain, fatigue, hot flushes, leg pain, oedema genital, flushing, syncope	Uncommon : chest pain

In other studies or in post-marketing experience, rare cases of intracranial / intracerebral and retroperitoneal bleedings have been reported.

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.

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic 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.

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing hip fracture surgery treated for up to 24 days following an initial prophylaxis of 1 week

In a randomised double-blind clinical trial, 737 patients were treated with fondaparinux 2.5 mg once daily for 7 +/- 1 days following hip fracture surgery. At the end of this period, 656 patients were randomised to receive fondaparinux 2.5 mg once daily or placebo for an additional 21 +/- 2 days. Fondaparinux provided a significant reduction in the overall rate of VTE compared with placebo [3 patients (1.4%) vs 77 patients (35%), respectively]. The majority (70/80) of the recorded VTE events were venographically detected non-symptomatic cases of DVT. Fondaparinux also provided a significant reduction in the rate of symptomatic VTE (DVT, and / or PE) [1 (0.3%) vs 9 (2.7%) patients, respectively] including two fatal PE reported in the placebo group. Major bleedings, all at surgical site and none fatal, were observed in 8 patients (2.4%) treated with fondaparinux 2.5 mg compared to 2 (0.6%) with placebo.

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

In a double-blind clinical study, 2,927 patients were randomised to receive fondaparinux 2.5mg once daily or dalteparin 5,000 IU once daily, with one 2,500 IU preoperative injection and a first 2,500 IU post-operative injection, for 7+2 days. The main sites of surgery were colonic/rectal, gastric, hepatic, cholecystectomy or other biliary. Sixty-nine percent of the patients underwent surgery for cancer. Patients under-going urological (other than kidney) or gynaecological surgery, laparoscopic surgery or vascular surgery were not included in the study.

In this study, the incidence of total VTE was 4.6% (47/1,027) with fondaparinux, versus 6.1%: (62/1,021) with dalteparin: odds ratio reduction [95%CI] = –25.8% [-49.7%, 9.5%]. The difference in total VTE rates between the treatment groups, which was not statistically significant, was mainly due to a reduction of asymptomatic distal DVT. The incidence of symptomatic DVT was similar between treatment groups: 6 patients (0.4%) in the fondaparinux group vs 5 patients (0.3%) in the dalteparin group. In the large subgroup of patients undergoing cancer surgery (69% of the patient population), the VTE rate was 4.7% in the fondaparinux group, versus 7.7% in the dalteparin group.

Major bleeding was observed in 3.4% of the patients in the fondaparinux group and in 2.4% of the dalteparin group.

Prevention of Venous Thromboembolic Events (VTE) in medical patients who are at high risk for thromboembolic complications due to restricted mobility during acute illness

In a randomised double-blind clinical trial, 839 patients were treated with fondaparinux 2.5 mg once daily or placebo for 6 to 14 days. This study included acutely ill medical patients, aged > 60 years, expected to require bed rest for at least four days, and hospitalized for congestive heart failure NYHA class III/IV and/or acute respiratory illness and/or acute infectious or inflammatory disease.

Fondaparinux significantly reduced the overall rate of VTE compared to placebo [18 patients (5.6%) vs 34 patients (10.5%), respectively]. The majority of events were asymptomatic distal DVT.

Fondaparinux also significantly reduced the rate of adjudicated fatal PE [0 patients (0.0%) vs 5 patients (1.2%), respectively]. Major bleedings were observed in 1 patient (0.2%) of each group.

Treatment of patients with acute symptomatic spontaneous superficial-vein thrombosis without concomitant Deep-Vein Thrombosis (DVT)

A randomised, double blind, clinical trial (CALISTO) included 3002 patients with acute symptomatic isolated, spontaneous superficial-vein thrombosis of the lower limbs, at least 5 cm long, confirmed by compression ultrasonography. Patients were not included if they had concomitant DVT or superficial-vein thrombosis within 3 cm of the sapheno-femoral junction. Patients were excluded if they had severe hepatic impairment, severe renal impairment (creatinine clearance <30ml/min), low body weight (<50kg), active cancer, symptomatic PE or a recent history of DVT/PE (<6 months) or superficial-vein thrombosis (<90 days), or superficial-vein thrombosis associated with sclerotherapy or a complication of an IV line, or they were at high risk of bleeding.

Patients were randomised to receive fondaparinux 2.5 mg once daily or placebo for 45 days in addition to elastic stockings, analgesic and/or topical NSAIDS anti-inflammatory drugs. Follow-up continued up to Day 77. The study population was 64% female, with a median age of 58 years, 4.4% had a creatinine clearance <50ml/min.

The primary efficacy outcome, a composite of symptomatic PE, symptomatic DVT, symptomatic superficial-vein thrombosis extension, symptomatic superficial-vein thrombosis reoccurrence, or Death up to Day 47, was significantly reduced from 5.9% in placebo patients to 0.9% in those receiving fondaparinux 2.5 mg (relative risk reduction: 85.2%; 95% CIs, 73.7% to 91.7% [p<0.001]). The incidence of each thromboembolic component of the primary outcome was also significantly reduced in fondaparinux patients as follows: symptomatic PE [0 (0%) vs 5 (0.3%) (p=0.031)], symptomatic DVT [3 (0.2%) vs 18 (1.2%); relative risk reduction 83.4% (p<0.001)], symptomatic superficial-vein thrombosis extension [4 (0.3%) vs 51 (3.4%); relative risk reduction 92.2% (p<0.001)], symptomatic superficial-vein thrombosis reoccurrence [5 (0.3%) vs 24 (1.6%); relative risk reduction 79.2% (p<0.001)].

The mortality rates were low and similar between the treatments groups with 2 (0.1%) deaths in the fondaparinux group versus 1 (0.1%) death in the placebo group.

Efficacy was maintained up to Day 77 and was consistent across all predefined subgroups including patients with varicose veins and patients with superficial-vein thrombosis located below the knee.

Major bleeding during treatment occurred in 1 (0.1%) fondaparinux patient and in 1 (0.1%) placebo patient. Clinically relevant non major bleeding occurred in 5 (0.3%) fondaparinux patients and 8 (0.5%) placebo patients.

5.2 Pharmacokinetic properties

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.

Fondaparinux does not inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4) in vitro. Thus, fondaparinux is not expected to interact with other medicinal products in vivo by inhibition of CYP-mediated metabolism.

Elimination

The elimination half-life (t % ) is about 17 hours in healthy young subjects and about 21 hours in healthy elderly subjects. Fondaparinux is excreted to 64 – 77 % by the kidney as unchanged compound.

Special populations

Paediatric patients – Fondaparinux has not been investigated in this population for the prevention of VTE or for the treatment of superficial vein thrombosis.

Elderly patients – Renal function may decrease with age and thus, the elimination capacity for fondaparinux may be reduced in elderly. In patients >75 years undergoing orthopaedic surgery, the estimated plasma clearance was 1.2 to 1.4 times lower than in patients <65 years.

Renal impairment – Compared with patients with normal renal function (creatinine clearance > 80 ml/min), plasma clearance is 1.2 to 1.4 times lower in patients with mild renal impairment (creatinine clearance 50 to 80 ml/min) and on average 2 times lower in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min). In severe renal impairment (creatinine clearance < 30 ml/min), plasma clearance is approximately 5 times lower than in normal renal function. Associated terminal half-life values were 29 h in moderate and 72 h in patients with severe renal impairment.

Gender – No gender differences were observed after adjustment for body weight.

Race – Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopaedic surgery.

Body weight – Plasma clearance of fondaparinux increases with body weight (9% increase per 10 kg).

Hepatic impairment - Following a single, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), total (i.e., bound and unbound) Cmax and AUC were decreased by 22% and 39%, respectively, as compared to subjects with normal liver function. The lower plasma concentrations of fondaparinux were attributed to reduced binding to ATIII secondary to the lower ATIII plasma concentrations in subjects with hepatic impairment thereby resulting in increased renal clearance of fondaparinux. Consequently, unbound concentrations of fondaparinux are expected to be unchanged in patients with mild to moderate hepatic impairment, and therefore, no dose adjustment is necessary based on pharmacokinetics.

The pharmacokinetics of fondaparinux has not been studied in patients with severe hepatic impairment (see sections 4.2 and 4.4).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Animal studies are insufficient with respect to effects on toxicity to reproduction because of limited exposure.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium chloride

Water for injections

Hydrochloric acid Sodium hydroxide

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C. Do not freeze.

6.5 Nature and contents of container

Type I glass barrel (1 ml) affixed with a 27 gauge x 12.7 mm needle and stoppered with a bromobutyl or chlorobutyl elastomer plunger stopper.

• Arixtra is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes. There are two types of syringes: • syringe with a yellow plunger and an automatic safety system
• • syringe with yellow plunger and a manual safety system.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The subcutaneous injection is administered in the same way as with a classical syringe.

Parenteral solutions should be inspected visually for particulate matter and discoloration prior to administration.

Instruction for self-administration is mentioned in the Package Leaflet.

The needle protection system of the Arixtra pre-filled syringes have been designed with a safety system to protect from needle stick injuries following injection.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36 Grange Parade

Baldoyle Industrial Estate

Dublin 13,

Ireland

8. MARKETING AUTHORISATION NUMBERS

EU/1/02/206/005–008

EU/1/02/206/024

EU/1/02/206/025

EU/1/02/206/026

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007