Data Sheet

ARIXTRA® Injection

Fondaparinux sodium, (INN)

Presentation

MW = 1728 C₃₁H₄₃N₃Na₁₀O₄₉S₈

CAS No. 114870-03-0

Fondaparinux sodium is a white to almost white powder which is highly soluble in water and in dilute alkali solution, but insoluble in ethanol.

Each pre-filled syringe contains 2.5 mg of fondaparinux sodium in 0.5 mL, of an isotonic solution of sodium chloride and Water for Injections.

Uses

Actions

Fondaparinux is a synthetic and specific inhibitor of activated Factor X (Xa) with no animal sourced components. The anti-thrombotic 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 neutralisation of Factor Xa by antithrombin. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development.

Fondaparinux does not inactivate thrombin (activated Factor II) and has no effects on platelet aggregation. It does not cross-react with sera from patients with heparin-induced thrombocytopenia. At the recommended dose, it does not affect fibrinolytic activity or bleeding time.

At equivalent anti-thrombotic doses, an experimental bleeding model in rats demonstrates that fondaparinux induces less bleeding than unfractionated heparin.

Pharmacokinetics

Absorption: after subcutaneous dosing, fondaparinux is completely and rapidly absorbed, the absolute bioavailability being 100%. Following a single subcutaneous injection of 2.5 mg of fondaparinux, peak plasma concentration (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.

Mean (SD) pharmacokinetic parameters of fondaparinux following a single subcutaneous injection of Arixtra 2.5 mg in young healthy subjects are provided below :

Table 1: Mean (SD) Pharmacokinetic Parameters

The pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. At steady state, mean plasma concentration 2 hours post-dosing ranged between 0.32 and 0.47 mg/L in patients undergoing orthopaedic surgeries receiving fondaparinux 2.5 mg.

Distribution: the distribution volume of fondaparinux is limited (7-11 litres) and is consistent with blood volume. Fondaparinux is highly (at least 97.0%) and specifically bound to ATIII protein and does not bind significantly to other plasma proteins, including platelet factor 4 (PF4).

Metabolism/Elimination: There is no evidence that fondaparinux is metabolised. Fondaparinux is almost completely excreted by the kidney as unchanged compound. The elimination half-life (t_1/2) is about 17 hours in healthy young subjects and about 20 hours in healthy elderly subjects.

Special populations

• Paediatric patients: Fondaparinux has not been investigated in this population.
• Elderly patients: in patients over 75 years, the estimated plasma clearance was 1.2 to 1.4 times lower than in patients less than 65 years.
• Renally impaired patients: 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).
• 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.

Clinical Trials

The fondaparinux clinical program was designed to demonstrate the superior efficacy of fondaparinux versus enoxaparin for the prevention of venous thromboembolic events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, knee or hip replacement.

Over 12,000 patients (age 17 to 101 years; bodyweight 30 to 226 kg) have been studied in controlled Phase II and III clinical studies.

In a double blind dose-response clinical study of fondaparinux (0.75 to 8 mg once daily) in patients undergoing hip replacement surgery, a statistically significant dose response (p = 0.003) for prevention of VTE was demonstrated. This dose effect relationship was confirmed in a second dose-response study performed in patients undergoing knee replacement. Based on these studies, a 2.5 mg once daily dose of fondaparinux was selected for the Phase III clinical development program.

The efficacy of fondaparinux 2.5 mg in preventing VTE was confirmed in four Phase III studies in patients undergoing major orthopaedic surgery of the lower limbs: PENTHIFRA (hip fracture), PENTAMAKS (knee replacement), PENTATHLON 2000 (hip replacement) and EPHESUS (hip replacement).

Fondaparinux 2.5 mg once daily was compared with enoxaparin. The overall risk reduction of adjudicated venous thromboembolic events [mandatory venogram positive for Deep Vein thrombosis (DVT), symptomatic DVT and/or non-fatal Pulmonary Embolism (PE), and fatal PE] in these four studies was more than 50 % (see figure below).

Figure 1. Overall Efficacy: Relative Risk Reduction for VTE with Fondaparinux

Table 2: VTE Rate (%) in Clinical Studies

* Enoxaparin 40 mg once daily
NS = not significant
^t Enoxaparin 30 mg bid

The efficacy of fondaparinux 2.5 mg for extended prevention of VTE was confirmed in the PENTHIFRA PLUS study (Extended prophylaxis in hip fracture surgery).

The efficacy of fondaparinux 2.5 mg in preventing VTE in patients undergoing abdominal surgery was confirmed in the PEGASUS study.

The efficacy of fondaparinux 2.5 mg in preventing VTE in medical patients immobilised during acute illness was confirmed in the ARTEMIS study.

Prevention of Venous Thromboembolic Events in Hip Fracture Surgery - PENTHIFRA

A randomised, double-blind clinical trial compared the efficacy of a subcutaneous once daily injection of fondaparinux 2.5 mg to enoxaparin 40 mg during 7±2 days in patients undergoing hip fracture surgery. The efficacy data are provided in Table 3.

Table 3: Efficacy of Fondaparinux Injection in hip fracture surgery

^a Fondaparinux randomised patients were to receive the first 2.5 mg injection 12 hours before the operation when surgery was delayed by more than 24 hours after admission except in case of spinal anaesthesia

^b Enoxaparin randomised patients were to receive the first 40 mg injection 12 hours before the operation except in case of spinal anaesthesia (at the discretion of the investigator) or surgery performed within less than 12 hours after admission

Extended Prevention of Venous Thromboembolic Events following Hip Fracture Surgery - PENTHIFRA PLUS

A randomised double blind clinical trial involving 737 patients examined the additional effect of extending prophylaxis for VTE from 7 days to 28-31 days. After 7±1 days of treatment with Arixtra 2.5mg once daily following hip fracture surgery, patients were randomised to receive Arixtra 2.5mg once daily (n=327) or placebo (n=329) for an additional 21±2 days. After 28 days of treatment, fondaparinux provided a statistically significant reduction ( p < 0.001) of 96% in the rate of VTE compared to placebo. Fondaparinux also provided a statistically significant 89% reduction in the rate of symptomatic VTE, which was defined as DVT, fatal and non-fatal PE.

Table 4: Efficacy of ARIXTRA Injection In the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

Major bleeding, all at surgical sites, was observed in 8 patients (2.4%) treated with Arixtra 2.5 mg compared to 2 (0.6%) with placebo (p=0.063). Permanent premature treatment cessation was observed in 2 of these patients in the Arixtra group and in 1 patient in the placebo group. In each group, two of these major bleeding episodes (0.6%) led to surgical re-intervention Death occurred in 5 randomised patients (1.5%) treated with Arixtra 2.5 mg compared to 7 (2.1%) with placebo. The 2 excess death with placebo were due to PE.

Prevention of Venous Thromboembolic Events in Major Knee Surgery - PENTAMAKS

A randomised, double-blind clinical trial compared the efficacy of a subcutaneous once daily injection of fondaparinux 2.5 mg to enoxaparin 30 mg b.i.d. during 7±2 days in patients undergoing major knee surgery. The efficacy data are provided in Table 5.

Table 5: Efficacy of fondaparinux Injection in major knee surgery

^a first injection was to be given post-operatively.

Prevention of Venous Thromboembolic Events in Hip Replacement - PENTATHLON 2000 and EPHESUS

In two randomised, double-blind, controlled clinical trials, the efficacy of a subcutaneous once daily injection of fondaparinux 2.5 mg was compared to either 30 mg b.i.d. or to 40 mg once daily subcutaneous injection of enoxaparin, during 7±2 days, in patients undergoing hip replacement surgery, respectively. The efficacy data are provided in Table 6.

Table 6: Efficacy of Fondaparinux Injection in hip replacement surgery

^a first injection was to be given post-operatively.
^b first injection was to be given 12 hours before operation except in case of spinal anaesthesia (at the discretion of the investigator).

Prevention of Venous Thromboembolic Events in patients undergoing abdominal surgery at risk of thromboembolic complications

In a randomised, double-blind clinical trial in patients undergoing abdominal surgery, fondaparinux 2.5mg SC once daily started postoperatively was compared to dalteparin sodium 5000 IU SC once daily, with one 2500 IU SC preoperative injection and a 2500 IU SC first postoperative injection. A total of 2927 patients were randomised and 2858 were treated. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 7 below and demonstrate that prophylaxis with fondaparinux was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium for a relative risk reduction of 24.6% (95% CI=[-9.0; 47.9]). The difference in the rate of VTE observed between patients taking fondaparinux and those taking dalteparin was not statistically significant. The incidence of VTE was assessed in all patients with a valid VTE assessment (70% of all randomised patients). Patients were excluded from this efficacy analysis if they did not have a valid VTE assessment performed (20.3%) or if the VTE assessment was non-evaluable (9.8%). In patients undergoing cancer surgery, representing the major subgroup of the clinical study (69% of the population), the VTE rate was 4.7% in the fondaparinux 2.5mg group versus 7.7% in the dalteparin sodium group.

Fewer deaths were reported in the fondaparinux sodium group compared with dalteparin sodium: 15 (1.0%) versus 20 (1.4%) during the treatment period and 40 (2.8%) versus 55 (3.9%) during the whole study period.

Table 7: Efficacy of fondaparinux in abdominal surgery patients

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

In a randomised, double-blind clinical trial, 839 patients were treated with Arixtra 2.5mg 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 hospitalised for congestive heart failure NYHA class III/IV and/or acute respiratory illness and/or acute infectious or inflammatory disease. Arixtra significantly reduced the overall rate of VTE compared to placebo [18 patients (5.6%) vs 34 patients (10.5%) respectively]. The incidence of VTE was assessed in all patients with a valid VTE assessment (76% of all randomised patients). Patients were excluded from this efficacy analysis if they did not have a valid VTE assessment performed (17.0%) or if the VTE assessment was non-evaluable (7.2%). Arixtra also significantly reduced the rate of fatal PE [0 patients (0.0%) vs 5 patients (1.2%), respectively. Major bleedings were observed in 1 patient (0.2%) of each group. The efficacy data are provided in Table 8 below.

Table 8: Efficacy of fondaparinux in medical patients

Indications

Arixtra is indicated for the prevention of Venous Thromboembolic Events (VTE):

in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee or hip replacement surgery.

in medical patients who are at risk of thromboembolic complications due to restricted mobility during acute illness.

in patients undergoing abdominal surgery who are at risk of thromboembolic complications.

Dosage and Administration

Adults

Patients undergoing major orthopaedic surgery and abdominal surgery

The recommended dose of Arixtra 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 for at least 7 ± 2 days. For orthopaedic surgery cases where the risk of VTE persists, treatment can be extended for as long as indicated up to a maximum of 31 days of therapy.

Medical patients who are at risk of thromboembolic complications

The recommended dose of Arixtra is 2.5 mg once daily administered by subcutaneous injection. Treatment should be continued until the risk of venous thromboembolism has diminished, with a minimum duration of 6 days.

Special Populations

Orthopaedic surgery and abdominal surgery patients

Timing of the first Arixtra dose requires strict adherence in patients ≥ 75 years (elderly patients may show reduced elimination of fondaparinux), and/or with body weight < 50kg and /or with moderate renal impairment (creatinine clearance 30 - 50mL/min).

The first Arixtra dose should be given not earlier than 6 hours following surgical closure. The injection should not be given unless haemostasis has been established (see PRECAUTIONS). No dosage adjustment is necessary.

Use in Patients with Severe Renal Impairment

Arixtra should not be used in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see CONTRAINDICATIONS).

Use in Patients with Hepatic Impairment

No dosing adjustment is necessary since there is no evidence that fondaparinux is metabolised or eliminated in bile. In patients with severe hepatic impairment, Arixtra should be used with care (see PRECAUTIONS).

Method of administration

Arixtra is administered by subcutaneous injection. It contains no antimicrobial agent. Arixtra is for single use in one patient only. Discard any residue.

The different parts of Arixtra safety syringe are :

1. Rigid needle guard
2. Cap
3. Plunger
4. Finger-grip
5. Security sleeve

Syringe BEFORE USE

Syringe AFTER USE

To use the Arixtra syringes, remove the plunger cap by pulling it off.	Figure 1
Remove the needle guard, by first twisting it and then pulling it straight off (figure 2).	Figure 2
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. Administration should be made in fatty tissues alternating injection sites (e.g. alternating between the left and right anterolateral or the left and right posterolateral abdominal wall).
Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger during the entire injection (figure 3).	Figure 3
Insert the full length of the needle perpendicularly (at an angle of 90°) into the skin fold (figure 4).	Figure 4
Inject ALL of the content of the syringe by pressing down on the plunger as far as it goes (figure 5), and then release it: the needle will withdraw automatically from the skin into a security sleeve and then will be locked permanently (figure 6).	Figure 5
	Figure 6
Discard the used syringe in a safe manner. Do not put the needle guard back onto the syringe.

Contraindications

• Active major bleeding
• Known hypersensitivity to fondaparinux sodium
• Acute bacterial endocarditis.
• Severe renal impairment

Warnings and Precautions

Arixtra is indicated for subcutaneous use only. Do not administer intramuscularly.

Haemorrhage

Arixtra, like other anti-thrombotic medicinal products, should be used with caution in patients who have an increased risk of haemorrhage, such as those with congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, recent intracranial haemorrhage, shortly after brain, spinal or ophthalmic surgery, and in patients treated concomitantly with anti-platelet drugs. If co-administration is essential, close monitoring may be appropriate. In the pivotal orthopaedic surgery clinical studies, the percentages of patients with adjudicated bleeding events are shown in Table 9.

Table 9: Summary of bleeding results from peri-operative studies (first injection up to Day 11) and Extended prophylaxis study (randomisation to Day 24) - (%) of Patients

^a Comparator was Enoxaparin 30 mg bid..

^b Major bleeding was defined as clinically overt bleeding that was (1)fatal, (2) at a critical site (eg intracranial, retroperitoneal, intra-ocular, pericardial, spinal or into adrenal gland), (3) associated with re-operation or (4), Bleeding Index ≥ 2 i.e. BI = drop in Hb pre-bleed minus post-bleed + number of units transfused. There were no fatal bleeds in the fondaparinux group, and one fatal bleed in the enoxaparin group.

^c Minor bleeding was clinically overt bleeding that was not major.

^d p value versus Enoxaparin is 0.0061.

^e Comparator was Enoxaparin 40 mg once daily.

^f During non-comparative, unblinded peri-operative prophylaxis, major bleeding was reported in 22/737 (3.0%) patients. Fifteen (15) of these 22 patients continued to receive ARIXTRA in extended prophylaxis. After randomisation, 4/327 (1.2%) patients experienced major bleeding for the first time.

The rates of bleeding events reported during the abdominal surgery clinical trial with Arixtra 2.5 mg injection are provided in Table 10 below.

Table 10: Summary of bleeding results from the Abdominal Surgery Study

1. Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (eg. Intracranial, retroperitoneal, intraocular, pericardial, spinal or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) >2. (BI calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) - (post-bleeding)] haemoglobin (g/dL) values].)
2. Minor bleeding was defined as clinically overt bleeding that was not major.

A separate analysis of major bleeding according to the time of the first injection of Arixtra after surgical closure was performed. In this analysis the incidences of major bleeding were as follows: 3.4% (9/263) if the first injection was given < 6 hours after closure, and 2.8% (32/1139) if the first injection was given > 6 hours after closure.

In the medical patients study, bleeding events are shown in the following table:

Table 11: Summary of bleeding events in Medical Patients

^a Associated or not with minor bleeding

Spinal/Epidural anaesthesia

As with other anti-thrombotic medicinal products, epidural or spinal haematomas may occur with concurrent use of Arixtra and spinal/epidural anaesthesia or spinal puncture. Such complications can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting haemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. There is no clinical experience with the use of Arixtra in patients requiring an indwelling catheter for spinal anaesthesia for periods greater than six hours.

If the patient is given anticoagulation in the context of epidural/spinal anaesthesia extreme vigilance and frequent monitoring is required to detect any signs and symptoms of spinal haematoma such as midline back pain, sensory and motor deficits (numbness, weakness, or paralysis in the lower limbs, bowel and/or bladder dysfunction). If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment should be initiated. Patients should be instructed to inform their doctor immediately if they experience any of the above signs or symptoms.

Impaired hepatic function

Since there is no evidence of metabolism or elimination by the liver, dosing adjustment of Arixtra is not necessary. However, as for other medicinal products which interfere with blood coagulation, the use of Arixtra 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 DOSAGE and ADMINISTRATION).

Impaired renal function

Arixtra should be used with caution in patients with moderate (creatinine clearance 30 - 50 mL/min) renal insufficiency as these patients may show delayed elimination of fondaparinux and are at increased risk of bleeding. (see DOSAGE and ADMINISTRATION and CONTRAINDICATIONS).

Use in Elderly

Age is a recognised risk factor for venous thromboembolic events (VTE); the VTE rate was uniformly lower in patients treated with Arixtra than with enoxaparin sodium across all age categories. The rate of bleeding appeared to be related to age, but was comparable with enoxaparin across all age categories. Fondaparinux is known to be substantially excreted by the kidney. As renal function generally decreases with age, elderly patients may show reduced elimination and increased exposure of fondaparinux. (See Pharmacokinetics). Arixtra should be used with caution in elderly patients. (see DOSAGE and ADMINISTRATION).

Low Body Weight

Patients with body weight <50kg are at increased risk of bleeding. Elimination of fondaparinux decreases with decreasing body weight. Fondaparinux should be used with caution in these patients (see DOSAGE and ADMINISTRATION).

Patients with Heparin Induced Thrombocytopenia

Fondaparinux does not bind to platelet factor 4 and does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT) type II. The efficacy and safety of fondaparinux have not been formally studied in patients with HIT type II.

Use in Children

The safety and efficacy of Arixtra in paediatric populations has not been studied.

Carcinogenicity and Mutagenicity/Fertility

Fondaparinux has not been tested for its carcinogenic potential in long-term animal studies.

Fondaparinux was not mutagenic in bacterial reverse mutation and mouse lymphoma cell forward mutation assays in vitro. It did not induce chromosomal aberrations in human lymphocytes in vitro or in bone marrow cells of rats in vivo.

There are no human data on the effects of fondaparinux on male or female fertility.

Fondaparinux did not affect the fertility and reproductive performance of male and female rats at SC doses of up to 10 mg/kg/day, corresponding to approximately 5 times the human clinical exposure based on AUC.

Use in Pregnancy

Pregnancy Category C

Anticoagulant and thrombolytic agents can produce placental haemorrhage and subsequent prematurity and foetal loss. Fondaparinux crossed the placenta of rats and rabbits. Administration of fondaparinux during the period of organogenesis did not affect embryofetal development of rats and rabbits at SC doses up to 10 mg/kg/day, with respective systemic exposures (plasma AUC) approximately 5 and 13 times the human clinical exposure. There are no adequate and well controlled studies of fondaparinux in pregnant women². Fondaparinux should be used during pregnancy only if clearly indicated.

Use in Lactation

Fondaparinux was excreted in rat milk. No effects on pup survival and development were observed at doses up to 10 mg/kg/day administered to lactating rats, associated with maternal systemic exposure (plasma AUC) 5 times the human clinical exposure.

It is not known whether fondaparinux is excreted in human milk. Because many medicinal products are excreted in human milk, caution should be exercised when fondaparinux is administered to breast-feeding women. Oral absorption by the child is however unlikely.

Effects On Ability To Drive And Use Machinery

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

Adverse Effects

In clinical trials, the safety of Arixtra 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 three weeks following an initial prophylaxis of 1 week, in 1407 patients undergoing abdominal surgery treated up to 9 days and in 425 medical patients who are at risk of thromboembolic complications, treated for up to 14 days.

During Arixtra 2.5 mg therapy in patients undergoing orthopaedic surgeries, as with other anti-thrombotics, bleeding was a common adverse reaction (see PRECAUTIONS - Haemorrhage).

Other adverse events that occurred during treatment with Arixtra or enoxaparin sodium in clinical trials with patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery and that occurred at a rate of at least 2% in either treatment group, are provided in Table 12 below.

Other adverse events that occurred during treatment with Arixtra or dalteparin in the clinical trial with patients undergoing abdominal surgery and that occurred at a rate of at least 2% in any treatment group are provided in Table 13 below.

Table 12: Adverse Events Occurring in ≥ 2% of Arixtra, Enoxaparin Sodium or Placebo Treated Patients Regardless of Relationship to Study Drug Across Randomised, Controlled, Hip Fracture Surgery, Hip Replacement Surgery or Knee Replacement Surgery Studies

1. Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
2. Localized blister coded as bullous eruption

Table 13: Adverse Events occurring in ≥ 2% of Arixtra or Dalteparin Sodium treated patients undergoing abdominal surgery, regardless of relationship to study drug.

In medical patients, adverse events reported as being possibly related to Arixtra are:

Haematological

Common: bleeding (haematoma, haematuria, haemoptysis, gingival bleeding)

Uncommon: anaemia

Respiratory Disorders

Uncommon: dyspnoea

Skin and Appendage

Uncommon: Rash, pruritus

Body as a whole

Uncommon: Chest pain

Post-Marketing

In clinical trials or in post-marketing experience, rare cases of intracranial/intracerebral or retroperitoneal bleeding have been reported.

Note
very common ≥ 1/10 (≥ 10%)
common ≥ 1/100 and < 1/10 ( ≥1% and <10%)
uncommon ≥ 1/1000 and < 1/100 ( ≥0.1% and <1.0%)
rare ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%)
very rare < 1/10,000 (< 0.01%)

Interactions

In clinical studies performed with Arixtra, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (aspirin), NSAIDs (piroxicam) and digoxin did not interact with the pharmacokinetics/pharmacodynamics of fondaparinux. In addition, fondaparinux neither influenced the pharmacodynamics of warfarin, aspirin, piroxicam and digoxin, nor the pharmacokinetics of digoxin at steady state.

Agents which may enhance the risk of haemorrhage should be discontinued prior to initiation of Arixtra therapy. If co-administration is essential, close monitoring may be appropriate.

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

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

Effect on Laboratory Tests

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 are not affected by the activity of 2.5 mg fondaparinux.

Overdosage

As with any anti-thrombotic agent, Arixtra doses above the recommended regimen, may lead to an increased risk of bleeding.

There is no antidote for Arixtra. Overdosage associated with bleeding complications should lead to treatment discontinuation, search for the primary cause and initiation of appropriate therapy.

Pharmaceutical Precautions

Storage

Store below 25°C.

Package Quantities

Arixtra 2.5 mg is available as pre-filled syringes with a blue automatic safety system..

Arixtra pre-filled single use syringes consist of a Type I glass barrel (1 mL) with a 27 gauge x 12.7 mm needle.

Name and Address

GlaxoSmithKline NZ Ltd
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
|NEW ZEALAND

Telephone (09) 367 2900

Facsimile (09) 367 2506

Date of Preparation

Date: 5 December 2005

Issue: 2

ARIXTRA® is a trade mark of the GlaxoSmithKline group of companies.

© This data sheet is copyrighted to GlaxoSmithKline and may be reproduced but not altered in any way.