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. Neutralization 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.
At the 2.5 mg dose, fondaparinux does not have a clinically relevant effect on routine coagulation tests eg, activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/international normalized ratio (INR) tests in plasma, nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of elevated aPTT have been received at the 2.5 mg dose.
Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopenia (HIT) type II.
The pharmacodynamics/pharmacokinetics of fondaparinux are derived from fondaparinux plasma concentrations quantified via antifactor 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/liter.
Clinical Studies: Prevention of Venous Thromboembolism (VTE) in Patients Undergoing Major Orthopedic Surgery of the Lower Limbs Treated Up to 9 Days:
The clinical program included patients undergoing major orthopedic surgery of the lower limbs eg, hip fracture, major knee surgery or hip replacement surgery. Arixtra 2.5 mg once daily started 6-8 hrs postoperatively was compared with enoxaparin 40 mg once daily started 12 hrs before surgery or 30 mg twice daily started 12-24 hrs 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% vs 13.7%, respectively), irrespective of the type of surgery performed. The majority of endpoint events consisted mainly of distal deep vein thrombosis (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 hrs 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 hrs after surgery), the rate of major bleeding was 2.8%. In studies versus enoxaparin 30 mg twice daily started 12-24 hrs after surgery, major bleeding was observed in 1.9% of Arixtra patients treated with the recommended dose, compared to 1.1% with enoxaparin.
Prevention of VTE in Patients Undergoing Hip Fracture Surgery Treated for Up to 24 Days Following an Initial Prophylaxis of 1 Week: Following treatment with Arixtra 2.5 mg for 7±1 day, hip fracture surgery patients were randomized 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% vs 35%, respectively). Arixtra also provided a significant reduction in the rate of symptomatic VTE (0.3% vs 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 randomized 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 postoperative injection, for 7±2 days following abdominal surgery.
Arixtra was noninferior to dalteparin (VTE rates 4.6% vs 6.1%, respectively). The incidence of symptomatic VTE was similar between treatment groups (0.4% on Arixtra vs 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 hrs after surgery), the rate of major bleeding was 2.8%.
Prevention of VTE in Medical Patients: Acutely ill medical patients ≥60 years and expected to require bed rest for at least 4 days were randomized to receive either Arixtra 2.5 mg once daily or placebo for 6-14 days. Arixtra significantly reduced the overall rate of VTE compared to placebo (5.6% vs 10.5%, respectively). The majority of events were asymptomatic distal DVT. Arixtra also significantly reduced the rate of adjudicated fatal PE (0% vs 1.2%, respectively). Major bleeding was observed in 1 patient (0.2%) in each group.
Treatment of DVT and PE:
DVT: In patients with a confirmed diagnosis of acute symptomatic DVT, Arixtra 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight >100 kg) once daily, was compared to enoxaparin 1 mg/kg SC 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 2-3.
Arixtra was demonstrated to be noninferior 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 <50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight >100 kg) once daily, was compared to unfractionated heparin (UFH) IV bolus (5000 IU), followed by a continuous IV infusion adjusted to maintain 1.5-2.5 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 2-3.
Arixtra was demonstrated to be noninferior to UFH (VTE rates 3.8% and 5% 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.
Treatment of Unstable Angina or Non-ST Segment Elevation Myocardial Infarction (UA/NSTEMI):
A double-blind, randomized, noninferiority study (OASIS 5) assessed the safety and efficacy of Arixtra 2.5 mg SC once daily versus enoxaparin 1 mg/kg SC 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 at least 65 years. Approximately 40% and 17% of patients had mild [creatinine clearance (CrCl) 50 to <80 mL/min] or moderate (CrCl 30 to <50 mL/min) renal impairment, respectively.
The primary adjudicated endpoint was a composite of death, myocardial infarction (MI) and refractory ischemia (RI) within 9 days of randomization. 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, 0.9, 1.13, one-sided noninferiority 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, 0.8, 1, 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 coronary artery bypass graft (CABG) surgery, the incidence of major bleeding at day 9 was similar on Arixtra and enoxaparin (9.7% and 9.8%, respectively).
Treatment of UA or NSTEMI in Patients Who Underwent Subsequent Percutaneous Coronary Intervention (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 randomized to receive 1 of 2 double-blind dose regimens of adjunctive UFH. All enrolled patients received Arixtra 2.5 mg SC, once daily for up to 8 days or until hospital discharge. Randomized 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 Arixtra treatment were comparable in both UFH groups.
The primary outcome was a composite of peri-PCI (defined as time of randomization up to 48 hrs post-PCI) adjudicated major or minor bleeding, or major vascular access site complications. (See table.)
Click on icon to see table/diagram/image
The incidences of catheter thrombus were 0.1% (1/1002) and 0.5% (5/1024), in patients randomized to "standard dose" and "low dose" UFH, respectively, during PCI.
Four (4) (0.3%) nonrandomized patients experienced thrombus in the diagnostic catheter during coronary angiography. Twelve (12) (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, randomized 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 12,000 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 at least 65 years. Approximately 40% and 14% of patients had mild (CrCl 50 to <80 mL/min) or moderate (CrCl 30 to <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 randomization. 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%, 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% 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%, respectively, experienced an event by day 30 (hazard ratio 0.79, 95% Cl, 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 hemorrhage, 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 hemorrhage at day 9 was 1.3% on Arixtra and 2% on control. In patients for whom primary PCI was chosen as the reperfusion strategy, the incidence of severe hemorrhage at day 9 was 1% on Arixtra and 0.4% on control. In patients who were treated without primary PCI or thrombolytic, the incidence of severe hemorrhage at day 9 was 1.2% on Arixtra and 1.5% on control.
In patients (n=234) undergoing nonprimary PCI, where it was recorded that they received adjunct UFH for anticoagulation during the procedure (238 procedures), the incidence of severe hemorrhage occurring post-PCI was low and similar for Arixtra (2.1%; 45 cases) and control (1.3%; 3 cases) at day 9.
In Arixtra-treated STEMI patients undergoing nonprimary PCI [n=311 (318 procedures)], in whom UFH was recommended for anticoagulation during the procedure, 1 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 hemorrhage at day 9 was 6.9% on Arixtra and 17.1% on control.
Use in Pediatric Patients:
Safety and effectiveness of Arixtra in pediatric patients have not been established.
In an open-label study, 24 pediatric patients diagnosed with venous thrombosis at study entry (with the exception of 1 patient who had an arterial thrombosis) were administered Arixtra. No patient had HIT although 1 patient had a medical history of HIT following extracorporeal circulation membrane oxygenation. The majority of patients were Hispanic (67%) and 58% were male. Ten (10) patients were 1 to ≤5 years of age (weight range 8-20 kg), 7 patients were 6 to ≤12 years of age (weight range 17-47 kg) and 7 patients were 13 to ≤18 years of age (weight range 47-130 kg). Arixtra was administered at an initial dose of 0.1 mg/kg SC once daily. Dosing was adjusted to achieve peak fondaparinux sodium concentrations (0.5-1 mg/L). One (1) patient received concomitant warfarin and Arixtra for 3 days during the study. The median duration of treatment in this study was 3.5 days.
The purpose of this study was to evaluate the pharmacokinetics and safety of Arixtra in a pediatric population. The majority of patients (88%) achieved target fondaparinux concentrations after the 1st dose of fondaparinux. Pharmacokinetic modeling and simulation demonstrated that the 0.1 mg/kg once daily dose resulted in fondaparinux concentrations that were similar to those observed in adults receiving Arixtra for the treatment of DVT or PE. There were no apparent differences in achieving the target fondaparinux concentration range among age groups.
Two (2) patients had reports of bleeding during the study. One (1) experienced hypertensive encephalopathy accompanied by intracranial bleeding on day 5 of therapy resulting in discontinuation of Arixtra. Minor gastrointestinal bleeding was reported in another patient on day 5 of therapy which resulted in temporary discontinuation of Arixtra.
After SC dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single SC injection of fondaparinux 2.5 mg to young healthy subjects, peak plasma concentration, mean maximum peak concentration (Cmax
) of 0.34 mg/L, is reached in approximately 2 hrs. Plasma concentrations of half the mean Cmax
values are reached 25 min post-dosing.
In elderly healthy subjects, pharmacokinetics of fondaparinux is linear in the range of 2-8 mg by SC route. Following once-daily SC dosing, steady-state of plasma levels is obtained after 3-4 days with a 1.3-fold increase in Cmax
and area under the curve (AUC). Following a single IV 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 SC, the peak steady-state plasma concentration is, on average, 0.39-0.5 mg/L and is reached approximately 3 hrs post-dose. In these patients, the minimum steady-state plasma concentration is 0.14-0.19 mg/L. In patients with symptomatic DVT and pulmonary embolism undergoing treatment with Arixtra 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg) and 10 mg (body weight >100 kg) SC 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 1.2-1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46-0.62 mg/L.
In healthy adults, IV or SC administered fondaparinux distributes mainly in blood and only to a minor extent in extravascular fluid, as demonstrated by steady-state and nonsteady-state apparent volume of distribution of 7-11 L. In vitro
, fondaparinux is highly (at least 94%) and specifically bound to 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.
Fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals, 64-77% of a single SC or IV dose is eliminated in urine in 72 hrs. The elimination half-life (t½
) is about 17 hrs in healthy young subjects and about 21 hrs in healthy elderly subjects. In patients with normal renal function, the mean fondaparinux clearance is 7.82 mL/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 CrCl 50-80 mL/min, approximately 40% lower in patients with moderate renal impairment (CrCl 30-50 mL/min) and approximately 55% lower in patients with severe renal impairment (<30 mL/min), compared to patients with normal renal function. The associated terminal t½
values were 29 hrs in moderate and 72 hrs in patients with severe renal impairment. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients.
Prevention of Venous Thromboembolic Events (VTE):
A population pharmacokinetic model was developed using data obtained from patients undergoing major orthopedic surgery of the lower limbs (MOSLL) receiving fondaparinux and included patients with creatinine clearance as low as 23.5 mL/min. Pharmacokinetic simulations using this model showed that predicted average exposures of fondaparinux in patients with creatinine clearance between 20-30 mL/min receiving 1.5 mg once daily or 2.5 mg on alternate days were similar to those seen in patients with mild to moderate renal impairment (CrCl 30-80 mL/min) receiving 2.5 mg once daily (see Dosage & Administration and Precautions).
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, SC 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 fondaparinux has not been studied in patients with severe hepatic impairment (see Dosage & Administration and Precautions).
Pharmacokinetic parameters of Arixtra were characterized in a population pharmacokinetic analysis with sparse blood sampling data from 24 pediatric patients (1-18 years). Administration of a once-daily 0.1 mg/kg SC dose to pediatric patients resulted in similar fondaparinux exposure to that observed for adults administered recommended doses for the treatment of DVT or pulmonary embolism (PE) (see Clinical Studies as previously mentioned).
Fondaparinux elimination is prolonged in patients >75 years. 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 >75 years as compared to patients <65 years. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.
No gender differences were observed after adjustment for body weight.
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 orthopedic surgery, no plasma clearance differences were observed between Black and Caucasian patients.
In patients weighing <50 kg, the total clearance of fondaparinux sodium is decreased by approximately 30% (see Precautions).
Toxicology: Preclinical 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, mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, human lymphocyte chromosome aberration test, rat hepatocyte unscheduled DNA synthesis (UDS) test or rat micronucleus test.
Reproduction studies have been performed in rats and rabbits at SC doses up to 10 mg/kg/day (approximately 5 and 12 times human exposure at a dose of 2.5 mg, or 2 and 4 times human exposure at a dose of 7.5 mg, based on AUC) and have revealed no evidence of impaired fertility or harm to the fetus 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 fetus.