Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: antithrombotic agents
ATC code: B01AX05
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. However, rare spontaneous reports of aPTT prolongation have been received.
Fondaparinux does not usually cross-react with sera from patients with heparin-induced thrombocytopaenia (HIT). However, rare spontaneous reports of HIT in patients treated with fondaparinux have been received.
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 observed in 2.8% of fondaparinux patients treated with the recommended dose, compared to 2.6% with enoxaparin.
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%) 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.
In a double-blind clinical study, 2,927 patients were randomised to receive fondaparinux 2.5mg once daily or dalteparin 5,000 IU once daily, with one 2,500 IU preoperative injection and a first 2,500 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% (47/1,027) with fondaparinux, versus 6.1%: (62/1,021) 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.
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.
A randomised, double blind, clinical trial (CALISTO) included 3002 patients with acute symptomatic isolated, spontaneous superficial-vein thrombosis of the lower limbs, at least 5 cm long, confirmed by compression ultrasonography. Patients were not included if they had concomitant DVT or superficial-vein thrombosis within 3 cm of the sapheno-femoral junction. Patients were excluded if they had severe hepatic impairment, severe renal impairment (creatinine clearance <30ml/min), low body weight (<50kg), active cancer, symptomatic PE or a recent history of DVT/PE (<6 months) or superficial-vein thrombosis (<90 days), or superficial-vein thrombosis associated with sclerotherapy or a complication of an IV line, or they were at high risk of bleeding.
Patients were randomised to receive fondaparinux 2.5 mg once daily or placebo for 45 days in addition to elastic stockings, analgesic and/or topical NSAIDS anti-inflammatory drugs. Follow-up continued up to Day 77. The study population was 64% female, with a median age of 58 years, 4.4% had a creatinine clearance <50ml/min.
The primary efficacy outcome, a composite of symptomatic PE, symptomatic DVT, symptomatic superficial-vein thrombosis extension, symptomatic superficial-vein thrombosis reoccurrence, or Death up to Day 47, was significantly reduced from 5.9% in placebo patients to 0.9% in those receiving fondaparinux 2.5 mg (relative risk reduction: 85.2%; 95% CIs, 73.7% to 91.7% [p<0.001]). The incidence of each thromboembolic component of the primary outcome was also significantly reduced in fondaparinux patients as follows: symptomatic PE [0 (0%) vs 5 (0.3%) (p=0.031)], symptomatic DVT [3 (0.2%) vs 18 (1.2%); relative risk reduction 83.4% (p<0.001)], symptomatic superficial-vein thrombosis extension [4 (0.3%) vs 51 (3.4%); relative risk reduction 92.2% (p<0.001)], symptomatic superficial-vein thrombosis reoccurrence [5 (0.3%) vs 24 (1.6%); relative risk reduction 79.2% (p<0.001)].
The mortality rates were low and similar between the treatments groups with 2 (0.1%) deaths in the fondaparinux group versus 1 (0.1%) death in the placebo group.
Efficacy was maintained up to Day 77 and was consistent across all predefined subgroups including patients with varicose veins and patients with superficial-vein thrombosis located below the knee.
Major bleeding during treatment occurred in 1 (0.1%) fondaparinux patient and in 1 (0.1%) placebo patient. Clinically relevant non major bleeding occurred in 5 (0.3%) fondaparinux patients and 8 (0.5%) placebo patients.
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 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%).
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.
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.
Elimination
The elimination half-life (ty2) 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.
Fondaparinux has not been investigated in this population for the prevention of VTE or for the treatment of superficial vein thrombosis.
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.
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 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.
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, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopaedic surgery.
Plasma clearance of fondaparinux increases with body weight (9% increase per 10 kg).
Following a single, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), total (i.e. bound and unbound) 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. Consequently, 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.
The pharmacokinetics of fondaparinux has not been studied in patients with severe hepatic impairment (see sections 4.2 and 4.4).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Animal studies are insufficient with respect to effects on toxicity to reproduction because of limited exposure.
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