Sign Out
Pharmacology: Pharmacodynamics: Mechanism of Action: 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 known effect on platelet function.
Pharmacodynamic Effects: At the 2.5 mg dose, fondaparinux does not have a clinically relevant affect on routine coagulation tests, such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma, nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of evelated aPTT have been received at the 2.5mg dose.
Fondaparinux does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT) type II.
Anti-Xa activity: The pharmacodynamics/pharmacokinetics of fondaparinux 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 low molecular weight heparin (LMWH) are not appropriate for this use. As a result, the concentration of fondaparinux is expressed as milligrams of the fondaparinux calibrator/litre.
Clinical Studies: 2.5 mg/0.5 mL: Prevention of venous thromboembolic events (VTE) in patient undergoing major orthopaedic surgery of the lower limbs treated up to 9 days: The clinical program included patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery. ARIXTRA 2.5mg once daily started 6 to 8 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours before surgery, or 30 mg twice daily started 12 to 24 hours after surgery. Both treatments were administered for 7 ± 2 days.
In a pooled analysis of these studies, ARIXTRA was associated with a significant decrease in VTE compared to enoxaparin (6.8% versus 13.7%, respectively), irrespective of the type of surgery performed. The majority of endpoint events consisted mainly of distal DVT, but the incidence of proximal DVT was also significantly reduced. The incidence of symptomatic VTE, including PE was not significantly different between treatment groups.
In studies versus enoxaparin 40 mg once daily started 12 hours before surgery, major bleeding was observed in 3.3% of ARIXTRA patients treated with the recommended dose, compared to 2.6% with enoxaparin. In patients treated with ARIXTRA according to the recommended regimen (6 hours after surgery), the rate of major bleeding was 2.8 %. In studies versus enoxaparin 30 mg twice daily started 12 to 24 hours after surgery, major bleeding was observed in 1.9% of ARIXTRA patients treated with the recommended dose, compared to 1.1% with enoxaparin.
Extended prophylaxis: 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: Following treatment with 2.5 mg ARIXTRA for 7 ± 1 day, hip fracture surgery patients were randomised to receive ARIXTRA 2.5 mg once daily or placebo for an additional 21 ± 2 days.
Extended prophylaxis with ARIXTRA provided a significant reduction in the overall rate of VTE compared with placebo (1.4% versus 35%, respectively). ARIXTRA also provided a significant reduction in the rate of symptomatic VTE (0.3% versus 2.7%, respectively). Major bleeding, all at surgical site and none fatal, was observed in 2.4% ARIXTRA patients compared to 0.6% with placebo.
Prevention of VTE in patients undergoing abdominal surgery at risk of thromboembolic events: Patients were randomised to receive either ARIXTRA 2.5 mg 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 following abdominal surgery.
ARIXTRA was non-inferior to dalteparin (VTE rates 4.6% versus 6.1%, respectively).
The incidence of symptomatic VTE was similar between treatment groups (0.4 % on ARIXTRA versus 0.3% on dalteparin).
In patients undergoing cancer surgery, representing the major subgroup of the clinical study (69% of the population) the VTE rate was 4.7 % in the ARIXTRA group versus 7.7% in the dalteparin group.
Major bleeding was observed in 3.4% of the patients in the ARIXTRA group and in 2.4% of the dalteparin group. In patients treated with ARIXTRA according to the recommended regimen (6 hours after surgery), the rate of major bleeding was 2.8 %.
Prevention of VTE in medical patients: Acutely ill medical patients, aged 60 years or older and expected to require bed rest for at least four days were randomised to receive either ARIXTRA 2.5 mg once daily or placebo for 6 to 14 days. ARIXTRA significantly reduced the overall rate of VTE compared to placebo (5.6% versus 10.5%, respectively). The majority of events were asymptomatic distal DVT. ARIXTRA also significantly reduced the rate of adjudicated fatal PE (0.0% versus 1.2%, respectively). Major bleeding was observed in one patient (0.2%) in each group.
Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI): A double-blind, randomised, non-inferiority study (OASIS 5) assessed the safety and efficacy of ARIXTRA 2.5 mg subcutaneously once daily versus enoxaparin 1 mg/kg subcutaneously twice daily in approximately 20,000 patients with UA/NSTEMI. The median treatment duration was 6 days in the ARIXTRA treatment group and 5 days in the enoxaparin treatment group. The mean age of the patients was 67 years, and approximately 60% were aged at least 65 years. Approximately 40% and 17% of patients had mild (creatinine clearance 50 to less than 80 ml/min) or moderate (creatinine clearance 30 to less than 50 ml/min) renal impairment, respectively.
The primary adjudicated endpoint was a composite of death, myocardial infarction (MI) and refractory ischaemia (RI) within 9 days of randomisation. ARIXTRA was as effective as enoxaparin on the primary endpoint. Of the patients treated with ARIXTRA or enoxaparin, 5.8% and 5.7% of patients, respectively experienced an event by Day 9 (hazard ratio 1.01, 95% CI, 0.90, 1.13, one-sided non-inferiority p value = 0.003).
There was a 17% reduction in the risk of all-cause mortality in favour of ARIXTRA by Day 30 (ARIXTRA, 2.9%, enoxaparin, 3.5%, hazard ratio 0.83, 95% CI, 0.71, 0.97, p = 0.02) that was apparent by Day 14 (ARIXTRA, 2.1%, enoxaparin, 2.4%, hazard ratio 0.86, 95% CI, 0.72, 1.04, p = 0.14) and sustained to Day 180 (ARIXTRA, 5.7%, enoxaparin, 6.4%, hazard ratio 0.89, 95% CI, 0.80, 1.00, p = 0.05). The effects of ARIXTRA and enoxaparin on the incidence of MI and RI were similar at all time points. The efficacy findings were consistent across demographic subgroups, including elderly and renally impaired patients, and across the range of concomitant medications and interventions.
Treatment with ARIXTRA was associated with a statistically and clinically significant reduction in the incidence of major bleeding compared to enoxaparin. At Day 9 the incidence of major bleeding on ARIXTRA and enoxaparin was 2.1% and 4.1%, respectively (hazard ratio 0.52, 95% CI, 0.44, 0.61, p < 0.001). The lower incidence of major bleeding on ARIXTRA compared to enoxaparin was also observed consistently across demographic subgroups, including elderly and renally impaired patients, and when ARIXTRA was used concomitantly with aspirin, thienopyridines or GPIIb/IIIa inhibitors.
In patients undergoing CABG surgery, the incidence of major bleeding at Day 9 was similar on ARIXTRA and enoxaparin (9.7% and 9.8% respectively).
Treatment of unstable angina (UA) or non-ST segment elevation myocardial infarction (NSTEMI) in patients who underwent subsequent PCI with adjunctive UFH: In a study of 3235 high-risk UA/NSTEMI patients scheduled for angiography and treated with open-label fondaparinux (OASIS 8/FUTURA), the 2026 patients indicated for PCI were randomised to receive one of two double-blind dose regimens of adjunctive UFH. All enrolled patients received fondaparinux 2.5 mg subcutaneously, once daily for up to 8 days, or until hospital discharge. Randomised patients received either "low dose" UFH regimen (50 U/kg irrespective of planned GPIIb/IIIa use; non ACT guided) or “standard dose” UFH regimen (no GPIIb/IIIa use: 85 U/kg, ACT guided; planned GPIIb/IIIa use: 60 U/kg, ACT guided) immediately prior to the start of the PCI.
The baseline characteristics and duration of fondaparinux treatment were comparable in both UFH groups.
The primary outcome was a composite of peri-PCI (defined as time of randomisation up to 48 hours post-PCI) adjudicated major or minor bleeding, or major vascular access site complications. (See table.)
Click on icon to see table/diagram/imageThe incidences of catheter thrombus were 0.1% (1/1002) and 0.5% (5/1024), in patients randomised to "standard dose" and "low dose" UFH respectively during PCI.
Four (0.3%) non-randomized patients experienced thrombus in the diagnostic catheter during coronary angiography. Twelve (0.37%) enrolled patients experienced thrombus in the arterial sheath, of these 7 were reported during angiography and 5 were reported during PCI.
Treatment of ST segment elevation myocardial infarction (STEMI): A double blind, randomised study (OASIS 6) assessed the safety and efficacy of ARIXTRA 2.5 mg once daily up to 8 days, or until hospital discharge, versus usual care (placebo or UFH) in approximately 12000 patients with STEMI. All patients received standard treatments for STEMI at the investigators discretion, including reperfusion with primary PCI (31%), thrombolytics (45%) or no reperfusion (24%). The mean age of the patients was 61 years, and approximately 40% were aged at least 65 years. Approximately 40% and 14% of patients had mild (creatinine clearance 50 to less than 80 ml/min) or moderate (creatinine clearance 30 to less than 50 ml/min) renal impairment, respectively.
The primary adjudicated endpoint was a composite of death and recurrent myocardial infarction (re-MI) within 30 days of randomisation. ARIXTRA was superior to control on the primary endpoint. Of the patients treated with ARIXTRA or control, 9.7% and 11.1% respectively experienced an event by Day 30 (hazard ratio 0.86, 95% CI, 0.77, 0.96, p = 0.008). This statistically significant benefit was observed as early as Day 9 and was maintained through Day 180.
There was a 13% reduction in the risk of all-cause mortality in favour of ARIXTRA at Day 30 (ARIXTRA, 7.8%, control, 8.9%, hazard ratio 0.87, 95% CI, 0.77, 0.98, p = 0.02) that was apparent by Day 9 (ARIXTRA, 6.1%, control, 7.0%, hazard ratio 0.86, 95% CI, 0.75, 0.99, p = 0.04) and sustained to Day 180 (ARIXTRA, 9.9%, control, 11.1%, hazard ratio 0.88, 95% CI, 0.79, 0.99, p = 0.03).
In patients for whom a thrombolytic was chosen as the reperfusion strategy, ARIXTRA reduced the risk of death and re-MI at Day 30. Of the patients receiving thrombolytics treated with ARIXTRA or control, 10.9% and 13.6%, respectively experienced an event by Day 30 (hazard ratio 0.79, 95% CI, 0.68, 0.93, p = 0.003).
In patients for whom primary PCI was chosen as the reperfusion strategy, there was no efficacy benefit with ARIXTRA. The incidence of death and re-MI at Day 30 in patients treated with ARIXTRA and control were 6.0% and 4.8%, respectively (hazard ratio 1.26, 95% CI, 0.96, 1.66, p = 0.1).
In patients who were treated without primary PCI or thrombolytic, ARIXTRA reduced the risk of death and re-MI at Day 30. Of the patients treated with ARIXTRA or control, 12.1% and 15.0% respectively experienced an event by Day 30 (hazard ratio 0.79, 95% CI, 0.65, 0.97, p = 0.023). The efficacy findings were consistent across demographic subgroups, including elderly and renally impaired patients, and across the range of concomitant medications.
Treatment with ARIXTRA was not associated with an increased risk of bleeding in the overall population or in demographic subgroups, including the elderly and renally impaired, and when used concomitantly with aspirin and thienopyridines. Overall, 1.1% of patients treated with ARIXTRA and 1.4% of control patients experienced a severe haemorrhage, defined according to modified thrombolysis in myocardial infarction criteria (TIMI), by Day 9.
In patients for whom a thrombolytic was chosen as the reperfusion strategy, the incidence of severe haemorrhage at Day 9 was 1.3% on ARIXTRA and 2.0% on control. In patients for whom primary PCI was chosen as the reperfusion strategy, the incidence of severe haemorrhage at Day 9 was 1.0% on ARIXTRA and 0.4% on control. In patients who were treated without primary PCI or thrombolytic, the incidence of severe haemorrhage at Day 9 was 1.2% on ARIXTRA and 1.5% on control.
In patients (n=234) undergoing non-primary PCI, where it was recorded that they received adjunct UFH for anticoagulation during the procedure (238 procedures), the incidence of severe haemorrhage occurring post-PCI was low and similar for ARIXTRA (1.7%; 4 cases) and control (1.3%;3 cases) at Day 9.
In ARIXTRA-treated STEMI patients undergoing non-primary PCI [n=311 (318 procedures)], in whom UFH was recommended for anticoagulation during the procedure, one event of guiding catheter thrombus was reported. However, this patient received UFH as treatment for the event of catheter thrombus rather than pre-PCI.
Approximately 1% of patients underwent CABG surgery. In these patients the incidence of severe haemorrhage at Day 9 was 6.9% on ARIXTRA and 17.1% on control.
7.5 mg/0.6 mL: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE): DVT: In patients with a confirmed diagnosis of acute symptomatic DVT, ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 kg to 100 kg) or 10 mg (body weight greater than 100 kg) once daily, was compared to enoxaparin 1 mg/kg subcutaneously twice daily. Patients were treated for at least 5 days in conjunction with a vitamin K antagonist which was continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3.
ARIXTRA was demonstrated to be non-inferior to enoxaparin (VTE rates 3.9% and 4.1% at Day 97, respectively). Major bleeding during the initial treatment period was observed in 1.1% of ARIXTRA patients, compared to 1.2% with enoxaparin.
PE: In patients with a confirmed diagnosis of acute symptomatic PE, ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 kg to 100 kg) or 10 mg (body weight greater than 100 kg) once daily, was compared to unfractionated heparin (UFH) i.v. bolus (5000 IU), followed by a continuous iv infusion adjusted to maintain 1.5 to 2.5 times aPTT control value. Patients were treated for at least 5 days in conjunction with a Vitamin K antagonist which was continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2 to 3. ARIXTRA was demonstrated to be non-inferior to UFH (VTE rates 3.8% and 5.0% at Day 97, respectively). Major bleeding during the initial treatment period was observed in 1.3% of ARIXTRA patients, compared to 1.1% with UFH.
Pharmacokinetics: Absorption: After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of ARIXTRA 2.5 mg to young healthy subjects, peak plasma concentration, mean Cmax of 0.34 mg/L, is reached in approximately 2 hours. Plasma concentrations of half the mean Cmax values are reached 25 min post-dosing.
In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in Cmax and AUC. Following a single i.v. bolus administration to healthy elderly subjects, the pharmacokinetics of fondaparinux are linear over the therapeutic range.
In patients undergoing hip replacement surgery receiving ARIXTRA 2.5 mg once daily, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L.
In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 to 100 kg) and 10 mg (body weight greater than 100 kg) once daily, the body-weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.
Distribution: In healthy adults, intravenously or subcutaneously administered fondaparinux distributes mainly in blood and only to a minor extent in extravascular fluid, as demonstrated by steady state and non-steady state apparent volume of distribution of 7 to 11 L. In vitro, fondaparinux is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins, including platelet Factor 4 (PF4) or red blood cells.
Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.
Elimination: Fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals, 64 to 77% of a single dose is eliminated in urine in 72 hours. The elimination half-life is about 17 hours in healthy young subjects and about 21 hours in healthy elderly subjects. In patients with normal renal function, the mean fondaparinux clearance is 7.82mL/min.
Special Patient Populations: Renal impairment: Fondaparinux elimination is prolonged in patients with renal impairment since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal impairment (creatinine clearance 50 to 80 ml/min), approximately 40% lower in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) and approximately 55% lower in patients with severe renal impairment (less than 30 ml/min), compared to patients with normal renal function. The associated terminal half-life values were 29 hours in moderate and 72 hours in patients with severe renal impairment. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients. Due to the limited clinical data available, ARIXTRA should not be used in patients with severe renal impairment (see Precautions).
Hepatic impairment: Unbound concentrations of fondaparinux are expected to be unchanged in patients with mild to moderate hepatic impairment, and therefore, no dose adjustment is necessary based on pharmacokinetics. Following a single, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), Cmax and AUC were decreased by 22% and 39%, respectively, as compared to subjects with normal liver function. The lower plasma concentrations of fondaparinux were attributed to reduced binding to ATIII secondary to the lower ATIII plasma concentrations in subjects with hepatic impairment thereby resulting in increased renal clearance of fondaparinux.
The pharmacokinetics of ARIXTRA has not been studied in patients with severe hepatic impairment (see Dosage & Administration, Precautions).
Children: The use of ARIXTRA has not been investigated in children under the age of 17 years.
Elderly: Fondaparinux elimination is prolonged in patients over 75 years old. In studies evaluating ARIXTRA 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients over 75 years old as compared to patients less than 65 years old. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.
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, based on the results of population pharmacokinetic analysis conducted in patients undergoing orthopaedic surgery, no plasma clearance differences were observed between black and Caucasian patients.
Body weight: In patients weighing less than 50 kg the total clearance of fondaparinux sodium is decreased by approximately 30% (see Precautions).
Toxicology: Pre-clinical Safety Data: No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium.
Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test.
Reproduction studies have been performed in rats and rabbits at subcutaneous doses up to 10 mg/kg/day (approximately 5 and 12 times human exposure at a dose of 2.5mg, or 2 and 4 times human exposure at a dose of 7.5mg, based on AUC) and have revealed no evidence of impaired fertility or harm to the foetus due to fondaparinux sodium. Because animal reproduction studies are not always predictive of human response, ARIXTRA should not be prescribed to pregnant women unless the risk of VTE outweighs the potential risk to the foetus.
