ARIXTRA 7.5mg / 0.6ml injection solution in pre-filled syringe medication leaflet

Arixtra 7.5 mg/0.6 ml solution for injection, pre-filled syringe.

Each pre-filled syringe contains 7.5 mg of fondaparinux sodium in 0.6 ml solution for injection.

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

For the full list of excipients, see section 6.1.

Solution for injection.

The solution is a clear and colourless to slightly yellow liquid.

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 orpulmonary embolectomy.

The recommended dose of fondaparinux is 7.5 mg (patients with body weight  50,  100kg) oncedaily administered by subcutaneous injection. For patients with body weight < 50 kg, therecommended 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 initiatedas soon as possible and usually within 72 hours. The average duration of administration in clinicaltrials was 7 days and the clinical experience from treatment beyond 10 days is limited.

Elderly patients - No dosing adjustment is necessary. In patients 75 years, fondaparinux should beused with care, as renal function decreases with age (see section 4.4).

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

There is no experience in the subgroup of patients with both high body weight (>100 kg) and moderaterenal impairment (creatinine clearance 30-50 ml/min). In this subgroup, after an initial 10 mg dailydose, 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 < 30ml/min) (see section 4.3).

Hepatic impairment - No dosing adjustment is necessary in patients with either mild or moderatehepatic impairment. In patients with severe hepatic impairment, fondaparinux should be used withcare 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 agedue to a lack of data on safety and efficacy (see sections 5.1 and 5.2).

Fondaparinux is administered by deep subcutaneous injection while the patient is lying down. Sites ofadministration should alternate between the left and the right anterolateral and left and rightposterolateral abdominal wall. To avoid the loss of medicinal product when using the pre-filledsyringe do not expel the air bubble from the syringe before the injection. The whole length of theneedle 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 < 30 ml/min.

Fondaparinux is intended for subcutaneous use only. Do not administer intramuscularly.

There is limited experience from treatment with fondaparinux in haemodynamically unstable patientsand no experience in patients requiring thrombolysis, embolectomy or insertion of a vena cava filter.

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), activeulcerative gastrointestinal disease and recent intracranial haemorrhage or shortly after brain, spinal orophthalmic surgery and in special patient groups as outlined below.

As for other anticoagulants, fondaparinux should be used with caution in patients who have undergonerecent surgery (<3 days) and only once surgical haemostasis has been established.

Agents that may enhance the risk of haemorrhage should not be administered concomitantly withfondaparinux. 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 theinformation 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/epiduralanaesthesia in case of surgical procedures should not be used.

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 section5.2). 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. Thecorresponding incidences in patients receiving the recommended regimen of enoxaparin in thetreatment of DVT were 2.5%, 3.6% and 8.3% respectively, while the incidences in patients receivingthe 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 withcaution at a daily dose of 5 mg in this population (see sections 4.2 and 5.2).

The risk of bleeding increases with increasing renal impairment. Fondaparinux is known to beexcreted mainly by the kidney. Incidences of bleeding events in patients receiving the recommendedregimen in the treatment of DVT or PE with normal renal function, mild renal impairment, moderaterenal impairment and severe renal impairment were 3.0 % (34/1,132), pct. 4.4 % (32/733), 6.6% (21/318),and 14.5 % (8/55) respectively. The corresponding incidences in patients receiving the recommendedregimen of enoxaparin in the treatment of DVT were 2.3% (13/559), pct. 4.6% (17/368), 9.7% (14/145)and 11.1% (2/18) respectively, and in patients receiving the recommended regimen of unfractionatedheparin 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) andshould be used with caution in patients with moderate renal impairment (creatinine clearance 30-50ml/min). The duration of treatment should not exceed that evaluated during clinical trial (mean 7 days)(see sections 4.2, pct. 4.3 and 5.2).

There is no experience in the subgroup of patients with both high body weight (>100 kg) and moderaterenal impairment (creatinine clearance 30-50 ml/min). Fondaparinux should be used with care in thesepatients. 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).

The use of fondaparinux should be considered with caution because of an increased risk of bleedingdue 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 offondaparinux have not been formally studied in patients with HIT type II. Fondaparinux does not bindto 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 withfondaparinux have been received.

Latex Allergy

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

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

In clinical studies performed with fondaparinux, oral anticoagulants (warfarin) did not interact withthe pharmacokinetics of fondaparinux; at the 10 mg dose used in the interaction studies, fondaparinuxdid not influence the anticoagulation monitoring (INR) activity of warfarin.

Platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not interact with thepharmacokinetics of fondaparinux. At the 10 mg dose used in the interaction studies, fondaparinux didnot influence the bleeding time under acetylsalicylic acid or piroxicam treatment, nor thepharmacokinetics of digoxin at steady state.

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

Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in humanmilk. Breast-feeding is not recommended during treatment with fondaparinux. Oral absorption by thechild is however unlikely.

There are no data available on the effect of fondaparinux on human fertility. Animal studies do notshow any effect on fertility.

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

The most commonly reported serious adverse reactions reported with fondaparinux are bleedingcomplications (various sites including rare cases of intracranial/ intracerebral and retroperitonealbleedings). Fondaparinux should be used with caution in patients who have an increased risk ofhaemorrhage (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 prophylaxisof 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 anaverage 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 reactionsidentified 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 common uncommon rare

MedDRA (≥ 1/100, <1/10) (≥ 1/1,000, <1/100) (≥ 1/10,000, <1/1,000)

Infections and post-operative woundinfestations infections

Blood and lymphatic anaemia, post-operative thrombocytopenia, retroperitoneal bleeding*,system disorders haemorrhage, utero- thrombocythaemia, hepatic, intracranial/vaginal haemorrhage*, platelet abnormal, intracerebral bleeding*haemoptysis, haematuria, coagulation disorderhaematoma, gingivalbleeding, purpura,epistaxis, gastrointestinalbleeding, hemarthrosis*,ocular bleeding*, bruise*

Immune system allergic reactiondisorders (including very rarereports of angioedema,anaphylactoid/anaphylactic reaction)

Metabolism and hypokalaemia, non-nutrition disorders protein-nitrogen (Npn)increased1*

Nervous system headache anxiety, confusion,disorders dizziness, somnolence,vertigo

Vascular disorders hypotension

Respiratory, thoracic dyspnoea coughingand mediastinaldisorders

Gastrointestinal nausea, vomiting abdominal pain,disorders dyspepsia, gastritis,constipation, diarrhoea

Hepatobiliary disorders abnormal liver function bilirubinaemiatests, hepatic enzymesincreased

Skin and subcutaneous rash erythematous,tissue disorders pruritus

General disorders and oedema, oedema reaction at injection site,administration site peripheral, pain, fever, leg pain, fatigue, flushing,conditions chest pain, wound syncope, hot flushes,secretion 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 searchfor the primary cause. Initiation of appropriate therapy such as surgical haemostasis, bloodreplacements, fresh plasma transfusion, plasmapheresis should be considered.

Pharmacotherapeutic group: antithrombotic agents.

ATC code: B01AX05

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithromboticactivity of fondaparinux is the result of antithrombin III (antithrombin) mediated selective inhibitionof Factor Xa. By binding selectively to antithrombin, fondaparinux potentiates (about 300 times) theinnate neutralization of Factor Xa by antithrombin. Neutralisation of Factor Xa interrupts the bloodcoagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinuxdoes 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 routinecoagulation 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 orfibrinolytic activity. However, rare spontaneous reports of aPTT prolongation have been received. Athigher 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-inducedthrombocytopaenia (HIT). However, rare spontaneous reports of HIT in patients treated withfondaparinux have been received.

Clinical studies

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

Treatment of Deep Venous Thrombosis

In a randomised, double-blind, clinical trial in patients with a confirmed diagnosis of acutesymptomatic DVT, fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight  50 kg,  100kg) or 10 mg (body weight >100 kg) SC once daily was compared to enoxaparin sodium 1 mg/kg SCtwice daily. A total of 2,192 patients were treated; for both groups, patients were treated for at least 5days and up to 26 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapyusually initiated within 72 hours after the first study drug administration and continued for 90 ± 7days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was thecomposite 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% and4.1%, 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

A randomised, open-label, clinical trial was conducted in patients with acute symptomatic PE. Thediagnosis was confirmed by objective testing (lung scan, pulmonary angiography or spiral CT scan).

Patients who required thrombolysis or embolectomy or vena cava filter were excluded. Randomisedpatients could have been pre-treated with UFH during the screening phase but patients treated formore than 24 hours with therapeutic dose of anticoagulant or with uncontrolled hypertension wereexcluded. Fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight  50kg,  100 kg) or 10mg (body weight >100 kg) SC once daily was compared to unfractionated heparin IV bolus (5,000 IU)followed by a continuous IV infusion adjusted to maintain 1.5-2.5 times aPTT control value. A totalof 2,184 patients were treated; for both groups, patients were treated for at least 5 days and up to 22days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiatedwithin 72 hours after the first study drug administration and continued for 90 ± 7 days, with regulardose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite ofconfirmed symptomatic recurrent non-fatal VTE and fatal VTE reported up to Day 97. Treatment withfondaparinux was demonstrated to be non-inferior to unfractionated heparin (VTE rates 3.8% and5.0%, respectively).

Major bleeding during the initial treatment period was observed in 1.3% of fondaparinux patients,compared to 1.1% with unfractionated heparin.

A pilot dose-finding and pharmacokinetic study of fondaparinux in children with deep veinthrombosis

In an open-label study, 24 paediatric patients (n=10, age 1 to ≤ 5 years weight range 8-20 kg; n=7, age6 to ≤ 12 years weight range 17-47 kg and n=7 age 13 to ≤ 18 years weight range 47-130 kg)diagnosed with venous thrombosis at study entry were administered fondaparinux. The majority ofpatients were Hispanic (67%) and 58% were male. Fondaparinux was administered at an initial dose of0.1 mg/kg subcutaneously once daily and dosing was adjusted to achieve peak fondaparinux sodiumconcentrations of 0.5 to 1 mg/L after 4 hours. The median duration of treatment in this study was 3.5days. The majority of patients (88%) achieved target fondaparinux concentrations at 4 hours after thefirst dose of fondaparinux. Two patients had reports of bleeding during the study. One experiencedhypertensive encephalopathy accompanied by intracranial bleeding on day 5 of therapy resulting infondaparinux discontinuation. Minor gastrointestinal bleeding was reported in another patient on day 5of therapy which resulted in temporary discontinuation of fondaparinux. No conclusion can be drawnwith regard to clinical efficacy in this uncontrolled study.

The pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrationsquantified via anti factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay (theinternational standards of heparin or LMWH are not appropriate for this use). As a result, theconcentration of fondaparinux is expressed as milligrams (mg).

After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability100%). 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. Plasmaconcentrations 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 bysubcutaneous route. Following once daily dosing, steady state of plasma levels is obtained after 3 to 4days with a 1.3-fold increase in Cmax and AUC.

Mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patientsundergoing 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 theirincreased age, fondaparinux steady state plasma concentrations are: Cmax (mg/l) - 0.50 (32%), Cmin(mg/l) - 0.19 (58%).

In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight <50 kg), 7.5 mg (bodyweight 50-100 kg inclusive) and 10 mg (body weight >100 kg) once daily, the body weight-adjusteddoses provide similar exposure across all body weight categories. The mean (CV%) steady statepharmacokinetic parameters estimates of fondaparinux in patients with VTE receiving thefondaparinux proposed dose regimen once daily are: Cmax (mg/l) - 1.41 (23 %), Tmax (h) - 2.4 (8%) and

Cmin (mg/l) -0.52 (45 %). The associated 5th and 95th percentiles are, respectively, 0.97 and 1.92 for

Cmax (mg/l), and 0.24 and 0.95 for Cmin (mg/l).

The distribution volume of fondaparinux is limited (7-11 litres). In vitro, fondaparinux is highly andspecifically 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 bindsignificantly to other plasma proteins, including platelet factor 4 (PF4).

Since fondaparinux does not bind significantly to plasma proteins other than antithrombin, nointeraction with other medicinal products by protein binding displacement are expected.

Although not fully evaluated, there is no evidence of fondaparinux metabolism and in particular noevidence 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 medicinalproducts in vivo by inhibition of CYP-mediated metabolism.

The elimination half-life (t½) is about 17 hours in healthy young subjects and about 21 hours in healthyelderly subjects. Fondaparinux is excreted to 64 - 77 % by the kidney as unchanged compound.

Paediatric patients - Limited data are available in paediatric patients (see section 5.1).

Elderly patients - Renal function may decrease with age and thus, the elimination capacity forfondaparinux may be reduced in elderly. In patients >75 years undergoing orthopaedic surgery andreceiving fondaparinux 2.5 mg once daily, the estimated plasma clearance was 1.2 to 1.4 times lowerthan in patients <65 years. A similar pattern is observed in DVT and PE treatment patients.

Renal impairment - Compared with patients with normal renal function (creatinine clearance > 80ml/min) undergoing orthopaedic surgery and receiving fondaparinux 2.5 mg once daily, plasmaclearance is 1.2 to 1.4 times lower in patients with mild renal impairment (creatinine clearance 50 to80 ml/min) and on average 2 times lower in patients with moderate renal impairment (creatinineclearance 30 to 50 ml/min). In severe renal impairment (creatinine clearance <30 ml/min), plasmaclearance is approximately 5 times lower than in normal renal function. Associated terminal half-lifevalues were 29 h in moderate and 72 h in patients with severe renal impairment. A similar pattern isobserved in DVT and PE treatment patients.

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

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

Race - Pharmacokinetic differences due to race have not been studied prospectively. However, studiesperformed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profilecompared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observedbetween black and Caucasian patients undergoing orthopaedic surgery.

Hepatic impairment - Following a single, subcutaneous dose of fondaparinux in subjects withmoderate hepatic impairment (Child-Pugh Category B), total (i.e., bound and unbound) Cmax and AUCwere 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 ATIIIsecondary to the lower ATIII plasma concentrations in subjects with hepatic impairment therebyresulting in increased renal clearance of fondaparinux. Consequently, unbound concentrations offondaparinux are expected to be unchanged in patients with mild to moderate hepatic impairment, andtherefore, 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).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and genotoxicity. The repeated dose and reproduction toxicity studies did not revealany special risk but did not provide adequate documentation of safety margins due to limited exposurein the animal species.

Sodium chloride

Water for injections

Hydrochloric acid

Sodium hydroxide

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

3 years

Store below 25°C. Do not freeze.

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

Arixtra 7.5 mg/0.6 ml is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes. There are twotypes of syringes:

* syringe with a magenta plunger and an automatic safety system

* syringe with magenta plunger and a manual safety system.

Not all pack sizes may be marketed.

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 toadministration.

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

The Arixtra pre-filled syringes have been designed with a needle protection system to prevent needlestick injuries following injection.

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

This medicinal product is for single use only.

Viatris Healthcare Limited

Damastown Industrial Park,

Mulhuddart

Dublin 15,

DUBLIN

Ireland

EU/1/02/206/012-014, 019

EU/1/02/206/029

EU/1/02/206/030

EU/1/02/206/034

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu