It explains how the Committee for Medicinal Products for Human Use CHMP assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of use for Arixtra. Arixtra is a solution for injection in a prefilled syringe. Arixtra contains the active substance fondaparinux sodium 1. Arixtra 1. It can also be used in adults at high risk because of their age or disease when they are having abdominal surgery or are forced to stay in bed because of an acute illness.
|Published (Last):||25 August 2010|
|PDF File Size:||5.65 Mb|
|ePub File Size:||4.87 Mb|
|Price:||Free* [*Free Regsitration Required]|
Manufacturer: Aspen. Distributor: Zuellig. Full Prescribing Info. Each syringe contains fondaparinux sodium 2. Pharmacotherapeutic Group: Antithrombotic agents. Pharmacology: Pharmacodynamics: Mechanism of Action: Fondaparinux is a synthetic and selective inhibitor of activated factor X Xa. 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. Pharmacodynamic Effects: At the 2. However, rare spontaneous reports of elevated aPTT have been received at the 2.
Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopenia HIT type II. 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. Arixtra 2. In a pooled analysis of these studies, Arixtra was associated with a significant decrease in VTE compared to enoxaparin 6.
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. In patients treated with Arixtra according to the recommended regimen 6 hrs after surgery , the rate of major bleeding was 2.
In studies versus enoxaparin 30 mg twice daily started hrs after surgery, major bleeding was observed in 1. Extended prophylaxis with Arixtra provided a significant reduction in the overall rate of VTE compared with placebo 1. Arixtra also provided a significant reduction in the rate of symptomatic VTE 0. Major bleeding, all at surgical site and none fatal, was observed in 2. Arixtra was noninferior to dalteparin VTE rates 4.
The incidence of symptomatic VTE was similar between treatment groups 0. Major bleeding was observed in 3. Arixtra significantly reduced the overall rate of VTE compared to placebo 5.
The majority of events were asymptomatic distal DVT. Major bleeding was observed in 1 patient 0. Arixtra was demonstrated to be noninferior to enoxaparin VTE rates 3. Major bleeding during the initial treatment period was observed in 1. The median treatment duration was 6 days in the Arixtra treatment group and 5 days in the enoxaparin treatment group. 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. 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.
In patients undergoing coronary artery bypass graft CABG surgery, the incidence of major bleeding at day 9 was similar on Arixtra and enoxaparin 9. All enrolled patients received Arixtra 2. 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. Four 4 0. Twelve 12 0. 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. This statistically significant benefit was observed as early as day 9 and was maintained through day In patients for whom a thrombolytic was chosen as the reperfusion strategy, Arixtra reduced the risk of death and re-MI at day Of the patients receiving thrombolytics treated with Arixtra or control, In patients for whom primary PCI was chosen as the reperfusion strategy, there was no efficacy benefit with Arixtra.
In patients who were treated without primary PCI or thrombolytic, Arixtra reduced the risk of death and re-MI at day Of the patients treated with Arixtra or control, 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. In patients for whom a thrombolytic was chosen as the reperfusion strategy, the incidence of severe hemorrhage at day 9 was 1. In patients who were treated without primary PCI or thrombolytic, the incidence of severe hemorrhage at day 9 was 1.
In these patients, the incidence of severe hemorrhage at day 9 was 6. 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.
Arixtra was administered at an initial dose of 0. Dosing was adjusted to achieve peak fondaparinux sodium concentrations 0. One 1 patient received concomitant warfarin and Arixtra for 3 days during the study.
The median duration of treatment in this study was 3. The purpose of this study was to evaluate the pharmacokinetics and safety of Arixtra in a pediatric population. Pharmacokinetic modeling and simulation demonstrated that the 0. 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. Following a single SC injection of fondaparinux 2.
Plasma concentrations of half the mean C max values are reached 25 min post-dosing. In elderly healthy subjects, pharmacokinetics of fondaparinux is linear in the range of mg by SC route. Following once-daily SC dosing, steady-state of plasma levels is obtained after days with a 1. 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. In these patients, the minimum steady-state plasma concentration is 0. The mean peak steady-state plasma concentration is in the range of 1. In these patients, the mean minimum steady-state plasma concentration is in the range of 0. Distribution: 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 L.
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 patients with normal renal function, the mean fondaparinux clearance is 7. 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.
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 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.
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. Children: Pharmacokinetic parameters of Arixtra were characterized in a population pharmacokinetic analysis with sparse blood sampling data from 24 pediatric patients years. Administration of a once-daily 0.
In studies evaluating Arixtra 2. 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 orthopedic surgery, no plasma clearance differences were observed between Black and Caucasian patients.