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Quixidar (fondaparinux sodium) – Summary of product characteristics - B01AX05

Updated on site: 09-Oct-2017

Medication nameQuixidar
ATC CodeB01AX05
Substancefondaparinux sodium
ManufacturerGlaxo Group Ltd.
Solution for injection.
The solution is a clear and colourless liquid.
For a full list of excipients, see section 6.1.

1. NAME OF THE MEDICINAL PRODUCT

Quixidar 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): Contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

authorised

3.PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic

surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery.

 

longer

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing abdominal surgery who

no

 

are judged to be at high risk of thromboembolic complications, such as patients undergoing abdominal

cancer surgery (see sectionProduct5.1).

Prevention of Venous Thromboembolic Events (VTE) in 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.

4.2 Posology and method of administration

Patients undergoing major orthopaedic or abdominal surgery

MedicinalThe 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).

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 - 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).

Hepatic impairment - No dosing adjustment is necessary. In patients with severe hepatic impairment, fondaparinux should be used with care (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.

Method of administration

 

Fondaparinux is administered by deep subcutaneous injection while the patientauthorisedis 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

 

longer

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.

4.3Contraindications

-

Product

no

hypersensitivity to the active substance or to any of the excipients

-

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.

MedicinalHaemorrhage

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.

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.

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).

Severe hepatic impairmentauthorised

Low body weight

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).

Renal impairment

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.

Dosing adjustment of fondaparinux is not necessary. However, the use of fondaparinux should be

considered with caution because of an increased risk of bleedinglongerdue to a deficiency of coagulation factors in patients with severe hepatic impairment (see section 4.2).

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

 

no

been formally studied in patients with HIT type II.

4.5 Interaction with other medicinal products and other forms of interaction

Product

 

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.

MedicinalFollow-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 Pregnancy and lactation

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.

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.

4.7Effects on ability to drive and use machines

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

4.8Undesirable effects

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, 1407 patients undergoingauthorisedabdominal 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

 

Undesirable effects in patients

Undesirable effects in medical

 

MedDRA

 

undergoing major orthopaedic

patients

 

 

surgery of lower limbs and/or

 

 

 

 

 

 

 

 

abdominal surgery

 

 

 

 

 

 

 

 

 

Infections and

 

Rare: post-operative wound

longer

 

infestations

 

infection

 

 

 

 

 

 

 

Blood and lymphatic

 

Common: post-operative

 

Common: bleeding

 

system disorders

 

haemorrhage, anaemia

 

(haematoma, haematuria,

 

 

 

Uncommon: bleeding (epistaxis,

haemoptysis, gingival bleeding)

 

 

 

 

no

 

Uncommon: anaemia

 

 

 

gastrointestinal, haemoptysis,

 

 

 

haematuria, haematoma)

 

 

 

 

 

thrombocytopenia, purpura,

 

 

 

 

 

thrombocythaemia, platelet

 

 

 

 

 

abnormal, coagulation disorder

 

 

 

 

 

 

 

Immune system disorders

Rare: allergic reaction

 

 

 

 

Product

 

 

 

 

Metabolism and nutrition

Rare: hypokalaemia

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

Nervous system disorders

Rare: anxiety, somnolence,

 

 

 

 

 

vertigo, dizziness, headache,

 

 

 

 

 

confusion

 

 

 

 

 

 

 

 

 

 

 

Vascular disorders

 

Rare: hypotension

 

 

 

 

Medicinal

 

 

 

 

 

 

Respiratory, thoracic and

Rare: dyspnoea, coughing

 

Uncommon: dyspnoea

 

mediastinal disorders

 

 

 

 

 

Gastrointestinal

Uncommon: nausea, vomiting

 

 

 

disorders

Rare: abdominal pain, dyspepsia,

 

 

 

 

gastritis, constipation, diarrhoea

 

 

 

 

 

 

 

 

Hepatobiliary disorders

Uncommon: hepatic enzymes

 

 

 

 

increased, hepatic function

 

 

 

 

 

abnormal

 

 

authorised

 

Rare: bilirubinaemia

 

 

 

 

 

 

 

 

 

 

 

 

Skin and subcutaneous

Uncommon: rash, pruritus

 

Uncommon: rash, pruritus

tissue disorders

 

 

 

 

 

 

 

 

 

General disorders and

Uncommon: oedema, oedema

Uncommon: chest pain

administration site

peripheral, fever, wound

 

 

 

 

conditions

secretion

 

 

 

 

 

Rare: chest pain, fatigue, hot

 

 

 

 

flushes, leg pain, oedema genital,

 

 

 

 

flushing, syncope

longer

 

 

 

 

 

 

 

 

 

 

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

4.9Overdose

 

 

 

no

Fondaparinux doses above the recommended regimen may lead to an increased risk of bleeding. There

is no known antidote to fondaparinux.

 

 

 

Product

 

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 PROPERTIES

5.1

Pharmacodynamic properties

 

Medicinal

 

 

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.

Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.

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

but the incidence of proximal DVT was also significantly reduced. The incidenceauthorisedof symptomatic VTE, including PE was not significantly different between treatment groups.

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,

In a randomised double-blind clinical trial, 737 patients werelongertreated 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.

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

Fondaparinux provided a significant reduction in the overall rate of VTE compared with placebo [3

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.

patients (1.4%) vs 77 patients (35%), respectively]. The majority (70/80) of the recorded VTE events

 

no

were venographically detected non-symptomatic cases of DVT. Fondaparinux also provided a

Product

 

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 Medicinalabdominal cancer surgery

In a double-blind clinical study, 2927 patients were randomized to receive fondaparinux 2.5mg once daily or dalteparin 5000 IU once daily, with one 2500 IU preoperative injection and a first 2500 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% (47/1027) with fondaparinux, versus 6.1%: (62/1021) 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.

5.2 Pharmacokinetic properties

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.

Absorptionauthorised

Mean (CV%) steady state pharmacokinetic parameters estimateslongerof fondaparinux in patients

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.

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

 

 

no

increased age, fondaparinux steady state plasma concentrations are: Cmax (mg/l) - 0.50 (32%),

Cmin (mg/l) - 0.19 (58%).

 

Distribution

Product

 

 

 

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.

MedicinalMetabolism

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.

Excretion/Elimination

The elimination half-life (t½) 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.

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 timesauthorisedlower 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 - Fondaparinux pharmacokinetics has not been evaluated in hepatic impairment.

5.3Preclinical 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.

 

 

 

 

longer

6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

no

 

 

 

Sodium chloride

 

 

 

Water for injections

 

 

 

Hydrochloric acid

 

 

 

Sodium hydroxide

 

 

 

6.2

Incompatibilities

 

 

Medicinal

Product

 

 

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

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not freeze.

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

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.

Quixidar is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes with a yellow automatic safety system. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

administration.

The subcutaneous injection is administered in the same way as with a classicalauthorisedsyringe. Parenteral solutions should be inspected visually for particulate matter and discoloration prior to

The needle protection system of the Quixidar pre-filled syringe has been designed with an automatic safety system to protect from needle stick injuries following injection.

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

7.

MARKETING AUTHORISATION HOLDER

Glaxo Group Ltd

 

 

longer

 

 

 

Greenford

 

no

 

Middlesex

 

 

 

 

 

UB6 0NN

 

 

 

United Kingdom

Product

 

 

8.

 

 

 

MARKETING AUTHORISATION NUMBERS

EU/1/02/207/005-008

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Medicinal

 

 

 

Date of first authorisation: 21 March 2002

 

 

Date of latest renewal: 21 March 2007

 

 

10.

DATE OF REVISION OF THE TEXT

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu

Solution for injection.
The solution is a clear and colourless liquid.
For a full list of excipients, see section 6.1.
1. NAME OF THE MEDICINAL PRODUCT
Quixidar 2.5 mg/0.5 ml solution for injection, pre-filled syringe.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pre-filled syringe (0.5 ml) contains 2.5 mg of fondaparinux sodium.

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

authorised

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic

surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery.

 

longer

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing abdominal surgery who

no

 

are judged to be at high risk of thromboembolic complications, such as patients undergoing abdominal

cancer surgery (see sectionProduct5.1).

Prevention of Venous Thromboembolic Events (VTE) in medical patients who are judged to be at high risk for VTE and who are immobilised due to acute illness such as cardiac insufficiency and/or acute respiratory disorders, and/or acute infectious or inflammatory disease.

Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) in patients for whom urgent (< 120 mins) invasive management (PCI) is not indicated (see sections 4.4 and 5.1).

MedicinalTreatment of ST segment elevation myocardial infarction (STEMI) in patients who are managed with thrombolytics or who initially are to receive no other form of reperfusion therapy.

4.2 Posology and method of administration

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).

Special populations

Medical patients who are at high risk for thromboembolic complications based on an individual risk assessment

The recommended dose of fondaparinux is 2.5 mg once daily administered by subcutaneous injection. A treatment duration of 6-14 days has been clinically studied in medical patients (see section 5.1).

Treatment of unstable angina/non- ST segment elevation myocardial infarction (UA/NSTEMI)

The recommended dose of fondaparinux is 2.5 mg once daily, administered by subcutaneous injection.

Treatment of ST segment elevation myocardial infarction (STEMI) authorised

Treatment should be initiated as soon as possible following diagnosis and continued for up to a maximum of 8 days or until hospital discharge if that occurs earlier.

If a patient is to undergo percutaneous coronary intervention (PCI), unfractionated heparin (UFH) as

per local practice should be administered during PCI, taking into account the patient’s potential risk of

bleeding, including the time since the last dose of fondaparinux (see section 4.4). The timing of

restarting subcutaneous fondaparinux after sheath removal should be based on clinical judgment. In the pivotal UA/NSTEMI clinical trial, treatment with fondaparinux was restarted no earlier than 2 hours after sheath removal.

The recommended dose of fondaparinux is 2.5 mg once daily. The first dose of fondaparinux is administered intravenously and subsequent doses are administered by subcutaneous injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to a maximum of 8 days or until hospital discharge if that occurs earlier.

fondaparinux after sheath removal should be based on clinicallongerjudgment. In the pivotal STEMI clinical trial, treatment with fondaparinux was restarted no earlier than 3 hours after sheath removal.

If a patient is to undergo non-primary PCI, unfractionated heparin (UFH) as per local practice should

be administered during PCI, taking into account the patient’s potential risk of bleeding, including the time since the last dose of fondaparinux (see section 4.4). The timing of restarting subcutaneous

Prevention of VTE following Surgery

In STEMI or UA/NSTEMI patients who are to undergo coronary artery bypass graft (CABG) surgery,

 

no

fondaparinux where possible, should not be given during the 24 hours before surgery and may be

restarted 48 hours post-operatively.

 

Product

 

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

Medicinalclearance ranging between 20 to 50 ml/min.

The first fondaparinux administration should be given not earlier than 6 hours following surgical closure. The injection should not be given unless haemostasis has been established (see section 4.4).

Renal impairment

Prophylaxis of VTE - Fondaparinux should not be used in patients with creatinine clearance <20 ml/min (see section 4.3). The dose should be reduced to 1.5 mg once daily in patients with creatinine clearance in the range of 20 to 50 ml/min (see sections 4.4 and 5.2).

No dosage reduction is required for patients with mild renal impairment (creatinine clearance >50 ml/min).

Treatment of UA/NSTEMI and STEMI - fondaparinux should not be used in patients with creatinine clearance < 20 ml/min (see section 4.3). No dosage reduction is required for patients with creatinine clearance > 20 ml/min.

Hepatic impairment - No dosing adjustment is necessary. In patients with severe hepatic impairment, fondaparinux should be used with care (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.

Method of administration

 

 

 

Subcutaneous 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.

 

Intravenous administration (first dose in patients with STEMI only)

 

 

Intravenous administration should be through an existing intravenous line either directly or using a

 

small volume (25 or 50ml) 0.9% saline minibag. To avoid the loss of medicinal product when

 

using the pre-filled syringe do not expel the air bubble from the syringe before the injection. The

 

intravenous tubing should be well flushed with saline after injection to ensure that all of the

 

medicinal product is administered. If administered via a minibag, the infusion should be given

 

over 1 to 2 minutes.

 

 

authorised

 

 

 

 

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

 

-

active clinically significant bleeding

 

longer

 

-

acute bacterial endocarditis

 

 

-

 

 

 

severe renal impairment defined by creatinine clearance < 20 ml/min.

4.4 Special warnings and precautions for use

 

 

 

 

no

 

 

Fondaparinux must not be administered intramuscularly.

 

 

Product

 

 

 

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.

MedicinalFor prevention of VTE, agents that may enhance the risk of haemorrhage should not be administered concomitantly with fondaparinux. These agents include desirudin, fibrinolytic agents, GP IIb/IIIa

receptor antagonists, heparin, heparinoids, or Low Molecular Weight Heparin (LMWH). When required, concomitant therapy with vitamin K antagonist should be administered in accordance with the information of section 4.5. Other antiplatelet medicinal products (acetylsalicylic acid, dipyridamole, sulfinpyrazone, ticlopidine or clopidogrel), and NSAIDs should be used with caution. If co-administration is essential, close monitoring is necessary.

For treatment of UA/NSTEMI and STEMI, fondaparinux should be used with caution in patients who are being treated concomitantly with other agents that increase the risk of haemorrhage (such as GPIIb/IIIa inhibitors or thrombolytics).

PCI and risk of guiding catheter thrombus

In STEMI patients undergoing primary PCI, the use of fondaparinux prior to and during PCI is not recommended. Similarly, in UA/NSTEMI patients with life threatening conditions that require urgent revascularisation, the use of fondaparinux prior to and during PCI is not recommended. These are

patients with refractory or recurrent angina associated with dynamic ST deviation, heart failure, life- threatening arrhythmias or haemodynamic instability.

In UA/NSTEMI and STEMI patients undergoing non-primary PCI, the use of fondaparinux as the sole anticoagulant during PCI is not recommended, therefore UFH should be used according to local practice (see section 4.2).

There are limited data on the use of UFH during non-primary PCI in patients treated with fondaparinux (see section 5.1). In those patients who underwent non-primary PCI 6-24 hours after the last dose of fondaparinux, the median dose of UFH was 8000 IU and the incidence of major bleeding was 2% (2/98). In those patients who underwent non-primary PCI <6 hours after the last dose of fondaparinux, the median dose of UFH was 5000 IU and the incidence of major bleeding was 4.1% (2/49).

Clinical trials have shown a low but increased risk of guiding catheter thrombus in patients treated with fondaparinux for anticoagulation during PCI compared to control. Incidences in non-primary PCI

in UA/NSTEMI were 1.0% vs 0.3% (fondaparinux vs. enoxaparin) and in primary PCI in STEMI were 1.2% vs 0% (fondaparinux vs. control).

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.

Spinal / Epidural anaesthesia

 

In patients undergoing major orthopaedic surgery, epidural or spinal haematomasauthorisedthat may result in

long-term or permanent paralysis cannot be excluded with the concurrent use of fondaparinux and

 

longer

Elderly patients

no

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

Product

 

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).

Renal impairment

Fondaparinux is known to be mainly excreted by the kidney.

Prophylaxis of VTE - Patients with creatinine clearance <50 ml/min are at increased risk of

Medicinalbleeding and VTE and should be treated with caution (see sections 4.2, 4.3 and 5.2). There are limited clinical data available from patients with creatinine clearance less than 30 ml/min.

Treatment of UA/NSTEMI and STEMI - For the treatment of UA/NSTEMI and STEMI, there are limited clinical data available on the use of fondaparinux 2.5mg once daily in patients with creatinine clearance between 20 and 30 ml/min. Therefore the physician should determine if the benefit of treatment outweighs the risk (see sections 4.2 and 4.3).

Severe hepatic impairment

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).

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.

4.5Interaction 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 bleedingauthorisedtime 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 Pregnancy and lactation

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.

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

4.8 Undesirable effects

child is however unlikely.

 

longer

 

 

4.7 Effects on ability to drive and use machines

 

 

no

 

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

Product

 

 

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

- 327 patients undergoing hip fracture surgery treated for 3 weeks following an initial prophylaxis of 1 week

Medicinal- 1407 patients undergoing abdominal surgery treated up to 9 days

- 425 medical patients who are at risk for thromboembolic complications treated up to 14 days - 10,057 patients undergoing treatment of UA or NSTEMI ACS

- 6,036 patients undergoing treatment of STEMI ACS.

For the prevention of VTE, 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

 

Undesirable effects in patients

Undesirable effects in medical

 

 

MedDRA

 

undergoing major orthopaedic

patients

 

 

 

 

surgery of lower limbs and/or

 

 

 

 

 

 

 

 

 

 

 

 

abdominal surgery

 

 

 

 

 

 

 

 

 

 

 

 

Infections and

 

Rare: post-operative wound

 

 

 

 

infestations

 

infection

 

 

 

 

 

 

 

 

 

 

 

 

 

Blood and lymphatic

 

Common: post-operative

 

Common: bleeding

 

 

system disorders

 

haemorrhage, anaemia

 

(haematoma, haematuria,

 

 

 

 

Uncommon: bleeding (epistaxis,

haemoptysis, gingival bleeding)

 

 

 

 

gastrointestinal, haemoptysis,

Uncommon: anaemia

 

 

 

 

haematuria, haematoma)

longer

authorised

 

 

 

thrombocytopenia, purpura,

 

 

 

 

 

 

 

thrombocythaemia, platelet

 

 

 

 

 

 

 

abnormal, coagulation disorder

 

 

 

 

 

 

 

 

 

 

 

Immune system disorders

Rare: allergic reaction

 

 

 

 

 

Metabolism and nutrition

 

no

 

 

 

 

 

Rare: hypokalaemia

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nervous system disorders

Product

 

 

 

 

 

 

Rare: anxiety, somnolence,

 

 

 

 

 

 

 

vertigo, dizziness, headache,

 

 

 

 

 

 

 

confusion

 

 

 

 

 

 

Vascular disorders

 

Rare: hypotension

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Medicinal

 

Rare: dyspnoea, coughing

 

Uncommon: dyspnoea

 

Respiratory, thoracic and

 

 

mediastinal disorders

 

 

 

 

 

 

 

 

Gastrointestinal

 

Uncommon: nausea, vomiting

 

 

 

 

disorders

 

Rare: abdominal pain, dyspepsia,

 

 

 

 

 

 

gastritis, constipation, diarrhoea

 

 

 

 

Hepatobiliary disorders

 

Uncommon: hepatic enzymes

 

 

 

 

 

 

increased, hepatic function

 

 

 

 

 

 

 

abnormal

 

 

 

 

 

 

 

 

Rare: bilirubinaemia

 

 

 

 

 

 

 

 

 

 

 

 

 

Skin and subcutaneous

Uncommon: rash, pruritus

Uncommon: rash, pruritus

tissue disorders

 

 

 

 

 

General disorders and

Uncommon: oedema, oedema

Uncommon: chest pain

administration site

peripheral, fever, wound

 

conditions

secretion

 

 

Rare: chest pain, fatigue, hot

 

 

flushes, leg pain, oedema genital,

 

 

flushing, syncope

 

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

The adverse event profile reported in the ACS program is consistent with the adverse drug reactions identified for VTE prophylaxis.

Bleeding was a commonly reported event in patients with UA/NSTEMI and STEMI. The incidence of

adjudicated major bleeding was 2.1% (fondaparinux) vs. 4.1% (enoxaparin) up to and including Day 9 longer

in the Phase III UA/NSTEMI study, and the incidence of adjudicated severe hemorrhage by modified

TIMI criteria was 1.1% (fondaparinux) vs. 1.4% (control [UFH/placebo]) up to and including Day 9 in the Phase III STEMI study.

In the Phase III UA/NSTEMI study, the most commonly reported non-bleeding adverse events (reported in at least 1% of subjects on fondaparinux) were headache, chest pain and atrial fibrillation.

In the Phase III study in STEMI patients, the mostnocommonly reported non-bleeding adverse events (reported in at least 1% of subjects on fondaparinux) were atrial fibrillation, pyrexia, chest pain, headache, ventricular tachycardia, vomiting, and hypotension.

4.9Overdose

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.

 

 

Product

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Medicinal

 

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.

Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.

Clinical studies

 

authorised

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

 

 

no

observed in 2.8% of fondaparinux patients treated with thelongerrecommended dose, compared to 2.6%

with enoxaparin.

Product

 

 

 

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%) Medicinalpatients, 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, 2927 patients were randomized to receive fondaparinux 2.5mg once daily or dalteparin 5000 IU once daily, with one 2500 IU preoperative injection and a first 2500 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% (47/1027) with fondaparinux, versus 6.1%: (62/1021) 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

Treatment of unstable angina or non-ST segment elevation myocardialauthorisedinfarction (UA/NSTEMI)

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.

OASIS 5 was a double-blind, randomised, non-inferiority study with fondaparinux 2.5 mg subcutaneously once daily versus enoxaparin 1 mg/kg subcutaneously twice daily in approximately

20,000 patients with UA/NSTEMI. All patients received standard medical treatment for UA/NSTEMI, with 34% of patients undergoing PCI and 9% undergoing CABG. The mean treatment duration was 5.5 days in the fondaparinux group and 5.2 days in the enoxaparin group. If PCI was performed, patients received either intravenous fondaparinux (fondaparinux patients) or weight adjusted intravenous UFH (enoxaparin patients) as adjunctive therapy, dependent on the timing of the last subcutaneous dose and planned use of GP IIb/IIIa inhibitor. The mean age of the patients was 67

years, and approximately 60% were at least 65 years old. Approximately 40% and 17% of patients had

 

 

longer

mild (creatinine clearance ≥50 to <80 ml/min) or moderate (creatinine clearance ≥30 to <50 ml/min)

renal impairment, respectively.

no

 

 

 

The primary adjudicated endpoint was a composite of death, myocardial infarction (MI) and refractory

Product

 

 

ischaemia (RI) within 9 days of randomisation. Of the patients in the fondaparinux group, 5.8% experienced an event by Day 9 compared to 5.7% for enoxaparin-treated patients (hazard ratio 1.01, 95% CI, 0.90, 1.13, one-sided non-inferiority p value = 0.003).

By Day 30, the incidence of all cause mortality was significantly reduced from 3.5% on enoxaparin to 2.9% on fondaparinux (hazard ratio 0.83, 95% CI, 0.71;0.97, p = 0.02). The effects on the incidence of MI and RI were not statistically different between the fondaparinux and enoxaparin treatment groups.

MedicinalAt Day 9 the incidence of major bleeding on fondaparinux and enoxaparin was 2.1% and 4.1%, respectively (hazard ratio 0.52, 95% CI, 0.44;0.61, p < 0.001).

The efficacy findings and results on major bleeding were consistent across prespecified subgroups such as elderly, renally impaired patients, type of concomitant platelet aggregation inhibitors (aspirin, thienopyridines or GP IIb/IIIa inhibitors).

In the subgroup of patients treated with fondaparinux or enoxaparin who underwent PCI, 8.8% and 8.2% of patients respectively, experience death/MI/RI within 9 days of randomisation (hazard ratio 1.08, 95% CI, 0.92;1.27). In this subgroup, the incidence of major bleeding on fondaparinux and enoxaparin at Day 9 was 2.2% and 5.0% respectively (hazard ratio 0.43, 95% CI, 0.33;0.57).

Treatment of ST segment elevation myocardial infarction (STEMI)

OASIS 6 was a double blind, randomised study assessing the safety and efficacy of fondaparinux 2.5 mg once daily, versus usual care (placebo (47%) or UFH (53%)) in approximately 12000 patients with STEMI. All patients received standard treatments for STEMI, including primary PCI (31%), thrombolytics (45%) or no reperfusion (24%). Of the patients treated with a thrombolytic, 84% were

treated with a non-fibrin specific agent (primarily streptokinase). The mean treatment duration was 6.2 days on fondaparinux. The mean age of the patients was 61 years, and approximately 40% were at least 65 years old. Approximately 40% and 14% of patients had mild (creatinine clearance ≥50 to <80 ml/min) or moderate (creatinine clearance ≥30 to <50 ml/min) renal impairment, respectively.

The primary adjudicated endpoint was a composite of death and recurrent MI (re-MI) within 30 days of randomisation. The incidence of death/re-MI at Day 30 was significantly reduced from 11.1% for

the incidence of death/re-MI at Day 30 was significantly reduced from 14.0% on placebo to 11.3% (hazard ratio 0.80, 95% CI, 0.69, 0.93, p = 0.003). In the predefined stratum comparing fondaparinux to UFH (patients treated with primary PCI (58.5%), fibrin-specific lytics (13%), non-fibrin-specific lytics (2.6%) and no reperfusion (25.9%)), the effects of fondaparinux and UFH on the incidence of death/re-MI at Day 30 were not statistically different: respectively, 8.3% vs 8.7% (hazard ratio 0.94, 95% CI, 0.79, 1.11 p = 0.460). However, in this stratum, in the subgroup of indicated population undergoing thrombolysis or no reperfusion (i.e patients not undergoing primary PCI), the incidence of death/re-MI at Day 30 was significantly reduced from 14.3% on UFH to 11.5% with fondaparinux (hazard ratio 0.79, 95% CI, 0.64, 0.98, p = 0.03).

the control group to 9.7% for the fondaparinux group (hazard ratio 0.86, 95% CI, 0.77, 0.96, p = 0.008). In the predefined stratum comparing fondaparinux to placebo (i.e patientsauthorisedtreated with non- fibrin specific lytics (77.3%), no reperfusion (22%), fibrin-specific lytics (0.3%), primary PCI (0.4%)),

The incidence of all cause mortality at Day 30 was also significantly reduced from 8.9% for the

control group to 7.8% in the fondaparinux group (hazardlongerratio 0.87, 95% CI, 0.77;0.98, p = 0.02). The difference in mortality was statistically significant in stratum 1 (placebo comparator) but not in

stratum 2 (UFH comparator). The mortality benefit shown in the fondaparinux group was maintained until the end of follow-up at Day 180.

In patients who were revascularised with a thrombolytic, fondaparinux significantly reduced the incidence of death/re-MI at Day 30 from 13.6%nofor the control group to 10.9% (hazard ratio 0.79,

95%CI, 0.68;0.93, p = 0.003). Among patients initially not reperfused, the incidence of death/re-MI at Day 30 was significantly reduced from 15% for the control group to 12.1% for the fondaparinux group

(hazard ratio 0.79, 95% CI,Product0.65;0.97, p = 0.023). In patients treated with primary PCI, the incidence

of death/re-MI at Day 30 was not statistically different between the two groups [6.0% in fondaparinux group vs 4.8% in the control group; hazard ratio 1.26, 95% CI, 0.96, 1.66)].

By Day 9, 1.1% of patients treated with fondaparinux and 1.4% of control patients experienced a severe haemorrhage. In patients given a thrombolytic, severe haemorrhage occurred in 1.3% of the fondaparinux patients and in 2.0% of controls. In patients initially not reperfused, the incidence of severe haemorrhage was 1.2% for fondaparinux vs 1.5% for controls. For patients receiving primary PCI, the incidence of severe haemorrhage was 1.0% for fondaparinux and 0.4% for controls.

MedicinalThe efficacy findings and results on severe haemorrhage were consistent across prespecified subgroups such as elderly, renally impaired patients, type of concomitant platelet aggregation

inhibitors (aspirin, thienopyridines).

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 subcutaneous 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

significantly to other plasma proteins, including platelet factor 4 (PF4).

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 concentrationauthorisedbinding (98.6% to 97.0% in the concentration range from 0.5 to 2 mg/l). Fondaparinux does not bind

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

Metabolism

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.

Excretion/Elimination

The elimination half-life (t½) 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

 

 

longer

 

 

 

Paediatric patients - Fondaparinux has not been investigated in this population.

 

 

no

 

Elderly patients - Renal function may decrease with age and thus, the elimination capacity for

 

Product

 

 

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

Medicinal(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 - Fondaparinux pharmacokinetics has not been evaluated in hepatic impairment.

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 PARTICULARS

6.3

Shelf life

authorised

6.1

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.

2 years.

If fondaparinux sodium is added to a 0.9% saline minibag it should ideally be infused immediately,

but can be stored at room temperature for up to 24 hours.

6.4

Special precautions for storage

longer

no

Do not freeze.

6.5

Nature and contents of container

 

Product

 

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.

Quixidar is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes with a blue automatic safety system. Not all pack sizes may be marketed.

Medicinal6.6 Special precautions for disposal and other handling

The subcutaneous injection is administered in the same way as with a classical syringe. Intravenous administration should be through an existing intravenous line either directly or using a small volume (25 or 50ml) 0.9% saline minibag.

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

Instruction on self-administration by subcutaneous injection is included in the Package Leaflet.

The needle protection system of the Quixidar pre-filled syringe has been designed with an automatic safety system to protect from needle stick injuries following injection.

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

7.MARKETING AUTHORISATION HOLDER

Glaxo Group Ltd

Greenford

Middlesex

UB6 0NN

United Kingdom

8.

MARKETING AUTHORISATION NUMBERS

 

EU/1/02/207/001-004

 

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2002

 

 

authorised

Date of latest renewal: 21 March 2007

 

 

10.

DATE OF REVISION OF THE TEXT

longer

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

Agency (EMEA) http://www.emea.europa.eu

 

 

 

 

 

Product

no

 

 

Medicinal

 

 

 

 

 

 

 

Solution for injection.
The solution is a clear and colourless to slightly yellow liquid.
For a full list of excipients, see section 6.1.

1. NAME OF THE MEDICINAL PRODUCT

Quixidar 5 mg/0.4 ml solution for injection, pre-filled syringe.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 5 mg of fondaparinux sodium in 0.4 ml solution for injection. Excipient(s): Contains less than 1 mmol of sodium (23 mg) per dose, and thereforeauthorisedis essentially sodium free.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of acute Deep Vein Thrombosis (DVT) and treatmentlongerof acute Pulmonary Embolism (PE),

except in haemodynamically unstable patients or patients who require thrombolysis or pulmonary

embolectomy.

 

no

 

 

 

 

4.2 Posology and method of administration

 

 

Product

 

100kg) once

The recommended dose of fondaparinux is 7.5 mg (patients with body weight 50,

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.

MedicinalSpecial 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 severe hepatic impairment, fondaparinux should be used with care (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.

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 andauthorisedleft 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 - 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

 

 

 

longer

and no experience in patients requiring thrombolysis, embolectomy or insertion of a vena cava filter.

Haemorrhage

 

no

 

 

 

 

Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage,

 

Product

 

 

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.

MedicinalAgents 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).

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 % (34/1132), 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.

Renal impairmentauthorised

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

longer

patients. After an initial 10 mg daily dose, a reduction of the daily dose to 7.5 mg may be considered,

 

no

based on pharmacokinetic modelling (see section 4.2).

Severe hepatic impairment

 

Product

 

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 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.

4.5 Interaction with other medicinal products and other forms of interaction

MedicinalBleeding 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 Pregnancy and lactation

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.

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.

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

reactions were bleeding complications (see section 4.4).

The safety of fondaparinux has been evaluated in 2,517 patients treated for authorisedVenous Thrombo- Embolism and treated with fondaparinux for an average of 7 days. The most common adverse

 

 

no

longer

 

Product

 

Medicinal

 

 

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.

(1) Isolated AEs have not been considered except if they were medically relevant.

(2) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.

4.9 Overdose

System organ class

Undesirable effects in patients treated for VTE1

 

MedDRA

 

 

 

 

 

 

 

 

 

Blood and lymphatic

Common: bleeding (gastrointestinal, haematuria,

 

system disorders

haematoma, epistaxis, haemoptysis, utero-vaginal

 

 

 

haemorrhage, haemarthrosis, ocular, purpura,

 

 

 

bruise)

 

 

 

 

 

 

Uncommon: anaemia, thrombocytopaenia

 

 

 

Rare: other bleeding (hepatic, retroperitoneal,

 

 

 

intracranial/intracerebral), thrombocythaemia

 

 

 

 

 

 

Immune system

 

Rare: allergic reaction

 

 

disorders

 

 

 

 

 

 

 

 

 

Metabolism and

Rare: non-protein-nitrogen (Npn) 2 increased

 

nutrition disorders

 

 

 

authorised

 

 

Nervous system

Uncommon: headache

 

 

disorders

 

Rare: dizziness

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Uncommon: nausea, vomiting

 

 

disorders

 

 

 

 

 

 

 

 

 

 

Hepatobiliary disorders

Uncommon: abnormal liver function

 

 

 

 

 

 

longer

 

 

Skin and subcutaneous

Rare: rash erythematous

 

 

tissue disorders

 

no

 

 

 

 

 

 

 

 

 

General disorders and

Uncommon: pain, oedema,

 

 

administration site

Rare: reaction at injection site

 

 

conditions

 

 

 

Product

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MedicinalFondaparinux 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 PROPERTIES

5.1 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 (antithrombin) mediated selective inhibition of Factor Xa. By binding selectively to antithrombin, fondaparinux potentiates (about 300 times) the innate neutralization 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 platelets.

or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. At higher 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.

At the doses used for treatment, fondaparinux does not, to a clinically relevantauthorisedextent, affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT)

Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.

Clinical studies

The fondaparinux clinical program in treatment of Venous Thromboembolism was designed to demonstrate the efficacy of fondaparinux for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Over 4874 patients were studied in controlled Phase II and III clinical studies.

Treatment of Deep Venous Thrombosis

longer

In a randomised, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT, fondaparinux 5 mg (body weightno< 50 kg), 7.5 mg (body weight 50 kg, 100

kg) or 10 mg (body weight >100 kg) SC once daily was compared to enoxaparin sodium 1 mg/kg SC twice daily. A total of 2192 patients were treated; for both groups, patients were treated for at least 5

days and up to 26 days (meanProduct7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7

days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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% and 4.1%, respectively).

Major bleeding during the initial treatment period was observed in 1.1% of fondaparinux patients,

compared to 1.2% with enoxaparin.

MedicinalTreatment of Pulmonary Embolism

A randomised, open-label, clinical trial was conducted in patients with acute symptomatic PE. The diagnosis 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. Randomised patients could have been pre-treated with UFH during the screening phase but patients treated for more than 24 hours with therapeutic dose of anticoagulant or with uncontrolled hypertension were excluded. Fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight 50kg, 100 kg) or 10 mg (body weight >100 kg) SC once daily was compared to unfractionated heparin IV bolus (5000 IU) followed by a continuous IV infusion adjusted to maintain 1.5–2.5 times aPTT control value.. A total of 2184 patients were treated; for both groups, patients were treated for at least 5 days and up to 22 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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 unfractionated heparin (VTE rates 3.8% and 5.0%, respectively).

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

5.2 Pharmacokinetic properties

The pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations

quantified via anti factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay (the international standards of heparin or LMWH are not appropriate for this use). As a result, the concentration of fondaparinux is expressed as milligrams (mg).

subcutaneous route. Following once daily dosing, steady state of plasma levelsauthorisedis obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC.

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 is linear in the range of 2 to 8 mg by

weight 50-100 kg inclusive) and 10 mg (body weight >100longerkg) once daily, the body weight-adjusted doses provide similar exposure across all body weight categories. The mean (CV%) steady state

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%).

In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight <50 kg), 7.5 mg (body

pharmacokinetic parameters estimates of fondaparinux in patients with VTE receiving the

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).

fondaparinux proposed dose regimen once daily are: Cmax (mg/l) - 1.41 (23 %), Tmax (h) – 2.4 (8%) and

 

no

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).

 

Product

 

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

Metabolism

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.

Excretion/Elimination

The elimination half-life (t½) 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.

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 and receiving fondaparinux 2.5 mg once daily, the estimated plasma clearance was 1.2 to 1.4 times lower

> 80 ml/min) undergoing orthopaedic surgery and receiving fondaparinux 2.5 mg once daily, 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. A similar pattern is observed in DVT and PE treatment patients.

than in patients <65 years. A similar pattern is observed in DVT and PE treatment patients. Renal impairment - Compared with patients with normal renal function (creatinineauthorisedclearance

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

Gender - No gender differences were observed after adjustmentlongerfor 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.

Hepatic impairment - Fondaparinux pharmacokinetics has not been evaluated in hepatic impairment.

5.3 Preclinical safety data

no

Product

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology and genotoxicity. The repeated dose and reproduction toxicity studies did not reveal any special risk but did not provide adequate documentation of safety margins due to limited exposure in the animal species.

6. PHARMACEUTICAL PARTICULARS

Medicinal6.1 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

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 chlorobutyl elastomer plunger stopper.

Quixidar 5 mg/0.4 ml is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes with an orange automatic safety system. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

 

authorised

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.

 

longer

 

The Quixidar pre-filled syringe has been designed with an automatic needle protection system to prevent needle stick injuries following injection.

Any unused product or waste material should be disposed of in accordance with local requirements. This medicinal product is for single use only.

 

no

7. MARKETING AUTHORISATION HOLDER

Product

 

Glaxo Group Ltd

Greenford

Middlesex

UB6 0NN

United Kingdom

8.MARKETING AUTHORISATION NUMBERS

MedicinalEU/1/02/207/009-011, 018

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu

For a full list of excipients, see section 6.1.

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 7.5 mg of fondaparinux sodium in 0.6 ml solution for injection. Excipient(s): Contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

3.

PHARMACEUTICAL FORM

authorised

Solution for injection.

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

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

except in haemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy.

Treatment of acute Deep Vein Thrombosis (DVT) and treatmentlongerof acute Pulmonary Embolism (PE),

 

no

 

4.2 Posology and method of administration

 

Product

 

100kg) once

The recommended dose of fondaparinux is 7.5 mg (patients with body weight 50,

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.

MedicinalSpecial 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 severe hepatic impairment, fondaparinux should be used with care (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.

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

 

-

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

 

authorised

 

 

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

 

 

longer

 

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.

such as those with congenital or acquired bleedingnodisorders (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.

Haemorrhage

Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage,

fondaparinux. These agentsProductinclude 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,

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

Medicinalsulfinpyrazone, 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

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 % (34/1132), 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.

The risk of bleeding increases with increasing renal impairment. Fondaparinuxauthorisedis known to be excreted mainly by the kidney. Incidences of bleeding events in patients receiving the recommended

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

longer

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

no

 

The use of fondaparinux should be considered with caution because of an increased risk of bleeding due to a deficiency of coagulationProductfactors in patients with severe hepatic impairment (see section 4.2).

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.

4.5 Interaction with other medicinal products and other forms of interaction

MedicinalBleeding 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 Pregnancy and lactation

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.

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.

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 authorised

The safety of fondaparinux has been evaluated in 2,517 patients treated for Venous Thrombo- Embolism and treated with fondaparinux for an average of 7 days. The most common adverse reactions were bleeding complications (see section 4.4).

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.

 

System organ class

Undesirable effects in patients treated for VTE1

 

MedDRA

 

 

 

 

 

 

 

 

Blood and lymphatic

Common: bleeding (gastrointestinal, haematuria,

 

system disorders

haematoma, epistaxis, haemoptysis, utero-vaginal

 

 

 

haemorrhage, haemarthrosis, ocular, purpura,

 

 

 

bruise)

 

longer

 

 

 

 

 

 

 

 

Uncommon: anaemia, thrombocytopaenia

 

 

 

Rare: other bleeding (hepatic, retroperitoneal,

 

 

 

intracranial/intracerebral), thrombocythaemia

 

 

 

 

no

 

 

Immune system

 

Rare: allergic reaction

 

disorders

 

 

 

 

 

 

 

 

Metabolism and

Rare: non-protein-nitrogen (Npn) 2 increased

 

nutrition disorders

 

 

 

 

 

 

 

Nervous system

Uncommon: headache

 

disorders

 

Rare: dizziness

 

 

 

 

 

 

 

Product

 

 

 

Gastrointestinal

Uncommon: nausea, vomiting

 

disorders

 

 

 

 

 

 

 

 

Hepatobiliary disorders

Uncommon: abnormal liver function

 

 

 

 

Skin and subcutaneous

Rare: rash erythematous

 

tissue disorders

 

 

 

 

 

 

 

General disorders and

Uncommon: pain, oedema,

Medicinaladministration site

Rare: reaction at injection site

 

conditions

 

 

 

 

 

 

(1)Isolated AEs have not been considered except if they were medically relevant.

(2)Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.

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 PROPERTIES

5.1Pharmacodynamic properties

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa)authorised. The antithrombotic activity of fondaparinux is the result of antithrombin III (antithrombin) mediated selective inhibition

Pharmacotherapeutic group: antithrombotic agents.

ATC code: B01AX05

Pharmacodynamic effects

coagulation tests such as activated partial thromboplastinlongertime (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or

of Factor Xa. By binding selectively to antithrombin, fondaparinux potentiates (about 300 times) the

innate neutralization 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 platelets.

At the doses used for treatment, fondaparinux does not, to a clinically relevant extent, affect routine

fibrinolytic activity. At higher 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.

no

 

Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.

Clinical studies

Product

 

The fondaparinux clinical program in treatment of Venous Thromboembolism was designed to demonstrate the efficacy of fondaparinux for the treatment of deep vein thrombosis (DVT) and

Medicinalpulmonary embolism (PE). Over 4874 patients were studied in controlled Phase II and III clinical studies.

Treatment of Deep Venous Thrombosis

In a randomised, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT, fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight 50 kg, 100 kg) or 10 mg (body weight >100 kg) SC once daily was compared to enoxaparin sodium 1 mg/kg SC twice daily. A total of 2192 patients were treated; for both groups, patients were treated for at least 5 days and up to 26 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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% and 4.1%, 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. The diagnosis 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. Randomised patients could have been pre-treated with UFH during the screening phase but patients treated for more than 24 hours with therapeutic dose of anticoagulant or with uncontrolled hypertension were excluded. Fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight 50kg, 100 kg) or 10

mg (body weight >100 kg) SC once daily was compared to unfractionated heparin IV bolus (5000 IU) followed by a continuous IV infusion adjusted to maintain 1.5–2.5 times aPTTauthorisedcontrol value.. A total

of 2184 patients were treated; for both groups, patients were treated for at least 5 days and up to 22 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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 unfractionated heparin (VTE rates 3.8% and 5.0%, respectively).

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

5.2 Pharmacokinetic properties

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

100%). Following a single subcutaneous injectionnoof fondaparinux 2.5 mg to young healthy subjects,

Absorption

longer

 

After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability

peak plasma concentrationProduct(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 is 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

Medicinal(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%).

In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg inclusive) and 10 mg (body weight >100 kg) once daily, the body weight-adjusted doses provide similar exposure across all body weight categories. The mean (CV%) steady state pharmacokinetic parameters estimates of fondaparinux in patients with VTE receiving the fondaparinux 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).

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 antithrombin, no interaction with other medicinal products by protein binding displacement are expected.

Metabolism

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,

Elderly patients - Renal function may decrease with age and thus, the eliminationauthorisedcapacity for fondaparinux may be reduced in elderly. In patients >75 years undergoing orthopaedic surgery and

CYP2E1 or CYP3A4) in vitro. Thus, fondaparinux is not expected to interact with other medicinal products in vivo by inhibition of CYP-mediated metabolism.

Excretion/Elimination

The elimination half-life (t½) 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.

80 ml/min) and on average 2 times lower in patients withlongermoderate renal impairment (creatinine clearance 30 to 50 ml/min). In severe renal impairment (creatinine clearance <30 ml/min), plasma

receiving fondaparinux 2.5 mg once daily, the estimated plasma clearance was 1.2 to 1.4 times lower than 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

> 80 ml/min) undergoing orthopaedic surgery and receiving fondaparinux 2.5 mg once daily, plasma

clearance is 1.2 to 1.4 times lower in patients with mild renal impairment (creatinine clearance 50 to

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. A similar pattern is

observed in DVT and PE treatment patients.

no

Product

 

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, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile

Medicinalcompared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopaedic surgery.

Hepatic impairment - Fondaparinux pharmacokinetics has not been evaluated in hepatic impairment.

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS
6.1 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

authorised

3 years

6.4

Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

 

 

 

 

longer

Type I glass barrel (1 ml) affixed with a 27 gauge x 12.7 mm needle and stoppered with a chlorobutyl

elastomer plunger stopper.

no

 

Quixidar 7.5 mg/0.6 ml is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes with a magenta

automatic safety system. Not all pack sizes may be marketed.

 

 

Product

 

 

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.

Medicinal

 

 

 

The Quixidar pre-filled syringe has been designed with an automatic needle protection system to

prevent needle stick injuries following injection.

 

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

This medicinal product is for single use only.

 

 

7.

MARKETING AUTHORISATION HOLDER

 

Glaxo Group Ltd

Greenford

Middlesex

UB6 0NN

United Kingdom

8.MARKETING AUTHORISATION NUMBERS

EU/1/02/207/012-014, 019

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007

10. DATE OF REVISION OF THE TEXT

 

 

 

 

authorised

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

Agency (EMEA) http://www.emea.europa.eu

 

 

 

 

 

no

longer

 

 

Product

 

 

Medicinal

 

 

 

 

 

 

 

Solution for injection.
The solution is a clear and colourless to slightly yellow liquid.
For a full list of excipients, see section 6.1.

1. NAME OF THE MEDICINAL PRODUCT

Quixidar 10 mg/0.8 ml solution for injection, pre-filled syringe.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 10 mg of fondaparinux sodium in 0.8 ml solution for injection. Excipient(s): Contains less than 1 mmol of sodium (23 mg) per dose, and thereforeauthorisedis essentially sodium free.

3. PHARMACEUTICAL FORM

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of acute Deep Vein Thrombosis (DVT) and treatmentlongerof acute Pulmonary Embolism (PE),

except in haemodynamically unstable patients or patients who require thrombolysis or pulmonary

embolectomy.

 

no

 

 

 

 

4.2 Posology and method of administration

 

 

Product

 

100kg) once

The recommended dose of fondaparinux is 7.5 mg (patients with body weight 50,

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.

MedicinalSpecial 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 severe hepatic impairment, fondaparinux should be used with care (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

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 andauthorisedleft 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 - 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

 

 

 

longer

and no experience in patients requiring thrombolysis, embolectomy or insertion of a vena cava filter.

Haemorrhage

 

no

 

 

 

 

Fondaparinux should be used with caution in patients who have an increased risk of haemorrhage,

 

Product

 

 

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.

MedicinalAgents 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).

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 % (34/1132), 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.

Renal impairmentauthorised

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

longer

patients. After an initial 10 mg daily dose, a reduction of the daily dose to 7.5 mg may be considered,

 

no

based on pharmacokinetic modelling (see section 4.2).

Severe hepatic impairment

 

Product

 

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 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.

4.5 Interaction with other medicinal products and other forms of interaction

MedicinalBleeding 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 Pregnancy and lactation

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.

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.

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

reactions were bleeding complications (see section 4.4).

The safety of fondaparinux has been evaluated in 2,517 patients treated for authorisedVenous Thrombo- Embolism and treated with fondaparinux for an average of 7 days. The most common adverse

 

 

no

longer

 

Product

 

Medicinal

 

 

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.

(1) Isolated AEs have not been considered except if they were medically relevant.

(2) Npn stands for non-protein-nitrogen such as urea, uric acid, amino acid, etc.

4.9 Overdose

System organ class

Undesirable effects in patients treated for VTE1

 

MedDRA

 

 

 

 

 

 

 

 

 

Blood and lymphatic

Common: bleeding (gastrointestinal, haematuria,

 

system disorders

haematoma, epistaxis, haemoptysis, utero-vaginal

 

 

 

haemorrhage, haemarthrosis, ocular, purpura,

 

 

 

bruise)

 

 

 

 

 

 

Uncommon: anaemia, thrombocytopaenia

 

 

 

Rare: other bleeding (hepatic, retroperitoneal,

 

 

 

intracranial/intracerebral), thrombocythaemia

 

 

 

 

 

 

Immune system

 

Rare: allergic reaction

 

 

disorders

 

 

 

 

 

 

 

 

 

Metabolism and

Rare: non-protein-nitrogen (Npn) 2 increased

 

nutrition disorders

 

 

 

authorised

 

 

Nervous system

Uncommon: headache

 

 

disorders

 

Rare: dizziness

 

 

 

 

 

 

 

 

 

 

 

 

Gastrointestinal

Uncommon: nausea, vomiting

 

 

disorders

 

 

 

 

 

 

 

 

 

 

Hepatobiliary disorders

Uncommon: abnormal liver function

 

 

 

 

 

 

longer

 

 

Skin and subcutaneous

Rare: rash erythematous

 

 

tissue disorders

 

no

 

 

 

 

 

 

 

 

 

General disorders and

Uncommon: pain, oedema,

 

 

administration site

Rare: reaction at injection site

 

 

conditions

 

 

 

Product

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MedicinalFondaparinux 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 PROPERTIES

5.1 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 (antithrombin) mediated selective inhibition of Factor Xa. By binding selectively to antithrombin, fondaparinux potentiates (about 300 times) the innate neutralization 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 platelets.

or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. At higher 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.

At the doses used for treatment, fondaparinux does not, to a clinically relevantauthorisedextent, affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT)

Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.

Clinical studies

The fondaparinux clinical program in treatment of Venous Thromboembolism was designed to demonstrate the efficacy of fondaparinux for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Over 4874 patients were studied in controlled Phase II and III clinical studies.

Treatment of Deep Venous Thrombosis

longer

In a randomised, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT, fondaparinux 5 mg (body weightno< 50 kg), 7.5 mg (body weight 50 kg, 100

kg) or 10 mg (body weight >100 kg) SC once daily was compared to enoxaparin sodium 1 mg/kg SC twice daily. A total of 2192 patients were treated; for both groups, patients were treated for at least 5

days and up to 26 days (meanProduct7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7

days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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% and 4.1%, respectively).

Major bleeding during the initial treatment period was observed in 1.1% of fondaparinux patients,

compared to 1.2% with enoxaparin.

MedicinalTreatment of Pulmonary Embolism

A randomised, open-label, clinical trial was conducted in patients with acute symptomatic PE. The diagnosis 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. Randomised patients could have been pre-treated with UFH during the screening phase but patients treated for more than 24 hours with therapeutic dose of anticoagulant or with uncontrolled hypertension were excluded. Fondaparinux 5 mg (body weight < 50 kg), 7.5 mg (body weight 50kg, 100 kg) or 10 mg (body weight >100 kg) SC once daily was compared to unfractionated heparin IV bolus (5000 IU) followed by a continuous IV infusion adjusted to maintain 1.5–2.5 times aPTT control value.. A total of 2184 patients were treated; for both groups, patients were treated for at least 5 days and up to 22 days (mean 7 days). Both treatment groups received Vitamin K antagonist therapy usually initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was the composite 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 unfractionated heparin (VTE rates 3.8% and 5.0%, respectively).

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

5.2 Pharmacokinetic properties

The pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations

quantified via anti factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay (the international standards of heparin or LMWH are not appropriate for this use). As a result, the concentration of fondaparinux is expressed as milligrams (mg).

subcutaneous route. Following once daily dosing, steady state of plasma levelsauthorisedis obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC.

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 is linear in the range of 2 to 8 mg by

weight 50-100 kg inclusive) and 10 mg (body weight >100longerkg) once daily, the body weight-adjusted doses provide similar exposure across all body weight categories. The mean (CV%) steady state

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%).

In DVT and PE treatment, patients receiving fondaparinux 5 mg (body weight <50 kg), 7.5 mg (body

pharmacokinetic parameters estimates of fondaparinux in patients with VTE receiving the

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).

fondaparinux proposed dose regimen once daily are: Cmax (mg/l) - 1.41 (23 %), Tmax (h) – 2.4 (8%) and

 

no

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).

 

Product

 

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

Metabolism

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.

Excretion/Elimination

The elimination half-life (t½) 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.

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 and receiving fondaparinux 2.5 mg once daily, the estimated plasma clearance was 1.2 to 1.4 times lower

> 80 ml/min) undergoing orthopaedic surgery and receiving fondaparinux 2.5 mg once daily, 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. A similar pattern is observed in DVT and PE treatment patients.

than in patients <65 years. A similar pattern is observed in DVT and PE treatment patients. Renal impairment - Compared with patients with normal renal function (creatinineauthorisedclearance

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

Gender - No gender differences were observed after adjustmentlongerfor 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.

Hepatic impairment - Fondaparinux pharmacokinetics has not been evaluated in hepatic impairment.

5.3 Preclinical safety data

no

Product

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology and genotoxicity. The repeated dose and reproduction toxicity studies did not reveal any special risk but did not provide adequate documentation of safety margins due to limited exposure in the animal species.

6. PHARMACEUTICAL PARTICULARS

Medicinal6.1 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

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 chlorobutyl elastomer plunger stopper.

Quixidar 10 mg/0.8 ml is available in pack sizes of 2, 7, 10 and 20 pre-filled syringes with a violet automatic safety system. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

 

authorised

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.

 

longer

 

The Quixidar pre-filled syringe has been designed with an automatic needle protection system to prevent needle stick injuries following injection.

Any unused product or waste material should be disposed of in accordance with local requirements. This medicinal product is for single use only.

 

no

7. MARKETING AUTHORISATION HOLDER

Product

 

Glaxo Group Ltd

Greenford

Middlesex

UB6 0NN

United Kingdom

8.MARKETING AUTHORISATION NUMBERS

MedicinalEU/1/02/207/015-017, 020

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu

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