ARIXTRA Fondaparinux Sodium 2.5mg / 0.5mL Solution for IV/SC Injection 0.5mL 10's
RXDRUG-DR-XY27863-10
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Features
Brand
Arixtra
Full Details
Dosage Strength
2.5 mg / 0.5 ml
Drug Ingredients
- Fondaparinux
Drug Packaging
Solution for Injection (I.V./S.C.) 10's
Generic Name
Fondaparinux Sodium
Dosage Form
Solution For Injection (I.V./S.C.)
Registration Number
DR-XY27863
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Prevention of venous thromboembolic events (VTE) in patients undergoing major orthopedic surgery of the lower limbs eg, hip fracture (including extended prophylaxis); knee replacement surgery; hip replacement surgery.
Prevention of VTE in patients undergoing abdominal surgery who are at risk of thromboembolic complications.
Prevention of VTE in medical patients who are at risk of thromboembolic complications due to restricted mobility during acute illness.
Treatment of acute deep vein thrombosis (DVT) and acute pulmonary embolism (PE).
Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) acute coronary syndrome for the prevention of death, myocardial infarction and refractory ischemia. Arixtra has been shown to reduce all cause mortality in patients with UA/NSTEMI.
Treatment of ST segment elevation myocardial infarction (STEMI) acute coronary syndrome for the prevention of death and myocardial re-infarction in patients who are managed with thrombolytics or who initially are to receive no other form of reperfusion therapy. Arixtra has been shown to reduce all cause mortality in patients with STEMI.
Prevention of VTE in patients undergoing abdominal surgery who are at risk of thromboembolic complications.
Prevention of VTE in medical patients who are at risk of thromboembolic complications due to restricted mobility during acute illness.
Treatment of acute deep vein thrombosis (DVT) and acute pulmonary embolism (PE).
Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) acute coronary syndrome for the prevention of death, myocardial infarction and refractory ischemia. Arixtra has been shown to reduce all cause mortality in patients with UA/NSTEMI.
Treatment of ST segment elevation myocardial infarction (STEMI) acute coronary syndrome for the prevention of death and myocardial re-infarction in patients who are managed with thrombolytics or who initially are to receive no other form of reperfusion therapy. Arixtra has been shown to reduce all cause mortality in patients with STEMI.
Dosage/Direction for Use
Adults: Prevention of VTE: Orthopedic and Abdominal Surgery: Recommended Dose: 2.5 mg once daily, administered postoperatively by SC injection.
The timing of the 1st dose should be no earlier than 6 hrs following surgical closure and only after hemostasis has been established (see Precautions).
Treatment should be continued until the risk of venous thromboembolism has diminished, usually until the patient is ambulant, at least 5-9 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 Arixtra should be considered for up to an additional 24 days (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Medical Patients at Risk of Thromboembolic Complications: Recommended Dose: 2.5 mg once daily administered by SC injection. A treatment duration of 6-14 days has been clinically studied in medical patients (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Treatment of DVT and PE: Recommended Dose: Patient >100 kg: 10 mg; 50-100 kg: 7.5 mg; <50 kg: 5 mg. To be administered by SC injection once daily.
Treatment should be continued for at least 5 days and until adequate oral anticoagulation is established (INR 2-3). Concomitant treatment with vitamin K antagonists should be initiated as soon as possible, usually within 72 hrs. The usual duration of Arixtra treatment is 5-9 days (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Treatment of UA/NSTEMI: Recommended Dose: 2.5 mg once daily, administered by SC injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge.
If a patient is to undergo PCI while on Arixtra, UFH as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of Arixtra (see Precautions).
The timing of restarting SC Arixtra after sheath removal should be based on clinical judgment. In the UA/NSTEMI, clinical trial, treatment with Arixtra was restarted no earlier than 2 hrs after sheath removal.
In patients who are to undergo CABG surgery, Arixtra where possible, should not be given during the 24 hrs before surgery and may be restarted 48 hrs postoperatively.
Treatment of STEMI: Recommended Dose: 2.5 mg once daily. The 1st dose of Arixtra is administered IV and subsequent doses are administered by SC injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge.
If a patient is to undergo non-primary PCI while on Arixtra, UFH as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of Arixtra (see Precautions).
The timing of restarting SC Arixtra after sheath removal should be based on clinical judgment. In the STEMI, clinical trial, treatment with Arixtra was restarted no earlier than 3 hrs after sheath removal.
In patients who are to undergo CABG surgery, Arixtra where possible, should not be given during the 24 hrs before surgery and may be restarted 48 hrs postoperatively.
Special Populations: Elderly (from 75 Years): Arixtra should be used with caution in elderly patients as renal function decreases with age. In patients undergoing surgery, the timing of the 1st dose of Arixtra requires strict adherence. (See Precautions.)
Patients with Body Weight <50 kg: Patients with body weight <50 kg are at increased risk of bleeding. In patients undergoing surgery, the timing of the 1st dose of Arixtra requires strict adherence. (See Precautions.)
Renal Impairment: Prevention of VTE: No dosage reduction is required in patients with CrCl ≥30mL/min.
In patients with a CrCl of between 20-30 mL/min in whom the physician determines that the benefit of thromboprophylaxis exceeds the risk, a dose of 1.5 mg daily or 2.5 mg on alternate days (each dose approximately 48 hrs apart) is recommended (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Fondaparinux is not recommended for use in patients with a CrCl of <20 mL/min (see Precautions).
In patients undergoing surgery, the timing of the 1st dose of fondaparinux requires strict adherence.
Treatment of VTE: No dosage reduction is required in patients with a CrCl ≥30 mL/min.
Fondaparinux should not be used in patients with a CrCl of <30 mL/min (see Precautions).
Treatment of UA/NSTEMI and STEMI: Arixtra is not recommended for use in patients with a CrCl of <20 mL/min (see Precautions). No dosage reduction is required for patients with a CrCl ≥20 mL/min.
Hepatic Impairment: No dosing adjustment of Arixtra is necessary (see Pharmacology: Pharmacokinetics under Actions). In patients with severe hepatic impairment, Arixtra should be used with caution (see Precautions).
Administration: SC: The sites of SC injection 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.
Arixtra is intended for use under a physician's guidance. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up as necessary. Proper training in SC injection technique should be provided. Instruction for self-administration is included in the package leaflet (see Instructions for Use and Handling under Cautions for Usage).
IV (First Dose in STEMI Patients Only): IV administration should be through an existing IV line either directly or using a small volume (25 or 50 mL) 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 IV tubing should be well flushed with saline after injection to ensure that all of Arixtra is administered. If administered via a minibag, the infusion should be given over 1-2 mins.
The timing of the 1st dose should be no earlier than 6 hrs following surgical closure and only after hemostasis has been established (see Precautions).
Treatment should be continued until the risk of venous thromboembolism has diminished, usually until the patient is ambulant, at least 5-9 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 Arixtra should be considered for up to an additional 24 days (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Medical Patients at Risk of Thromboembolic Complications: Recommended Dose: 2.5 mg once daily administered by SC injection. A treatment duration of 6-14 days has been clinically studied in medical patients (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Treatment of DVT and PE: Recommended Dose: Patient >100 kg: 10 mg; 50-100 kg: 7.5 mg; <50 kg: 5 mg. To be administered by SC injection once daily.
Treatment should be continued for at least 5 days and until adequate oral anticoagulation is established (INR 2-3). Concomitant treatment with vitamin K antagonists should be initiated as soon as possible, usually within 72 hrs. The usual duration of Arixtra treatment is 5-9 days (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Treatment of UA/NSTEMI: Recommended Dose: 2.5 mg once daily, administered by SC injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge.
If a patient is to undergo PCI while on Arixtra, UFH as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of Arixtra (see Precautions).
The timing of restarting SC Arixtra after sheath removal should be based on clinical judgment. In the UA/NSTEMI, clinical trial, treatment with Arixtra was restarted no earlier than 2 hrs after sheath removal.
In patients who are to undergo CABG surgery, Arixtra where possible, should not be given during the 24 hrs before surgery and may be restarted 48 hrs postoperatively.
Treatment of STEMI: Recommended Dose: 2.5 mg once daily. The 1st dose of Arixtra is administered IV and subsequent doses are administered by SC injection. Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge.
If a patient is to undergo non-primary PCI while on Arixtra, UFH as per standard practice should be administered during PCI, taking into account the patient's potential risk of bleeding, including the time since the last dose of Arixtra (see Precautions).
The timing of restarting SC Arixtra after sheath removal should be based on clinical judgment. In the STEMI, clinical trial, treatment with Arixtra was restarted no earlier than 3 hrs after sheath removal.
In patients who are to undergo CABG surgery, Arixtra where possible, should not be given during the 24 hrs before surgery and may be restarted 48 hrs postoperatively.
Special Populations: Elderly (from 75 Years): Arixtra should be used with caution in elderly patients as renal function decreases with age. In patients undergoing surgery, the timing of the 1st dose of Arixtra requires strict adherence. (See Precautions.)
Patients with Body Weight <50 kg: Patients with body weight <50 kg are at increased risk of bleeding. In patients undergoing surgery, the timing of the 1st dose of Arixtra requires strict adherence. (See Precautions.)
Renal Impairment: Prevention of VTE: No dosage reduction is required in patients with CrCl ≥30mL/min.
In patients with a CrCl of between 20-30 mL/min in whom the physician determines that the benefit of thromboprophylaxis exceeds the risk, a dose of 1.5 mg daily or 2.5 mg on alternate days (each dose approximately 48 hrs apart) is recommended (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Fondaparinux is not recommended for use in patients with a CrCl of <20 mL/min (see Precautions).
In patients undergoing surgery, the timing of the 1st dose of fondaparinux requires strict adherence.
Treatment of VTE: No dosage reduction is required in patients with a CrCl ≥30 mL/min.
Fondaparinux should not be used in patients with a CrCl of <30 mL/min (see Precautions).
Treatment of UA/NSTEMI and STEMI: Arixtra is not recommended for use in patients with a CrCl of <20 mL/min (see Precautions). No dosage reduction is required for patients with a CrCl ≥20 mL/min.
Hepatic Impairment: No dosing adjustment of Arixtra is necessary (see Pharmacology: Pharmacokinetics under Actions). In patients with severe hepatic impairment, Arixtra should be used with caution (see Precautions).
Administration: SC: The sites of SC injection 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.
Arixtra is intended for use under a physician's guidance. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up as necessary. Proper training in SC injection technique should be provided. Instruction for self-administration is included in the package leaflet (see Instructions for Use and Handling under Cautions for Usage).
IV (First Dose in STEMI Patients Only): IV administration should be through an existing IV line either directly or using a small volume (25 or 50 mL) 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 IV tubing should be well flushed with saline after injection to ensure that all of Arixtra is administered. If administered via a minibag, the infusion should be given over 1-2 mins.
Overdosage
Symptoms: Arixtra doses above the recommended regimen may lead to an increased risk of bleeding.
Treatment: Overdose associated with bleeding complications should lead to treatment discontinuation and search for the primary cause. Initiation of appropriate therapy which may include surgical hemostasis, blood replacements, fresh plasma transfusion, plasmapheresis should be considered.
Treatment: Overdose associated with bleeding complications should lead to treatment discontinuation and search for the primary cause. Initiation of appropriate therapy which may include surgical hemostasis, blood replacements, fresh plasma transfusion, plasmapheresis should be considered.
Contraindications
Known hypersensitivity to fondaparinux sodium or any of the excipients of Arixtra.
Active clinically significant bleeding, acute bacterial endocarditis.
Active clinically significant bleeding, acute bacterial endocarditis.
Special Precautions
Route of Administration: Arixtra must not be administered IM (see Dosage & Administration).
PCI and Risk of Guiding Catheter Thrombus: In STEMI patients undergoing primary PCI for reperfusion, the use of Arixtra prior to and during PCI is not recommended. In UA/NSTEMI and STEMI patients undergoing nonprimary PCI, the use of Arixtra as the sole anticoagulant during PCI is not recommended, therefore UFH should be used according to standard practice (see Dosage & Administration).
In a clinical trial comparing 2 dose regimens of UFH during nonprimary PCI, fondaparinux-treated UA/NSTEMI patients were randomized to receive either 'standard dose UFH' (median dose 85 U/kg) or 'low dose UFH' (median dose 50 U/kg). The incidence of peri-PCI major bleeding was 1.2% with 'standard dose UFH' and 1.4% with 'low dose UFH' (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Clinical trials have shown a low but increased risk of guiding catheter thrombus in patients treated solely with Arixtra for anticoagulation during PCI compared to control. Incidences in nonprimary PCI in UA/NSTEMI were 1% versus 0.3% (Arixtra vs enoxaparin) and in primary PCI in STEMI were 1.2% versus 0% (Arixtra vs control). In fondaparinux-treated UA/NSTEMI patients randomized to receive 'standard dose' or 'low dose' regimens of UFH during nonprimary PCI, the incidences of catheter thrombus were 0.1% and 0.5%, respectively (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Hemorrhage: Arixtra, like other anticoagulants, must be used with caution in conditions with an increased risk of hemorrhage (eg, congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, recent intracranial hemorrhage, shortly after brain, spinal or ophthalmic surgery).
Prevention and Treatment of VTE: Other medicinal products enhancing the risk of hemorrhage, with the exception of vitamin K antagonists used concomitantly for treatment of VTE, should not be administered with Arixtra. If co-administration is essential, close monitoring is recommended (see Interactions).
Prevention of VTE Following Surgery (Timing of First Arixtra Injection): The timing of the 1st injection requires strict adherence. The 1st dose should be given no earlier than 6 hrs following surgical closure and only after hemostasis has been established. Administration before 6 hrs has been associated with an increased risk of major bleeding. Patient groups at particular risk are those from 75 years of age, body weight of <50 kg or renal impairment with CrCl of <50 mL/min.
Treatment of UA/NSTEMI and STEMI: Arixtra should be used with caution in patients who are being treated concomitantly with other medicinal products that increase the risk of hemorrhage (eg, GPIIb/IIIa inhibitors or thrombolytics).
Spinal/Epidural, Anesthesia/Spinal Puncture: Epidural or spinal hematomas that may result in long-term or permanent paralysis can occur with the use of anticoagulants and spinal/epidural anesthesia 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 hemostasis.
Low Bodyweight: Patients with body weight <50 kg are at increased risk of bleeding. Elimination of Arixtra decreases with weight decrease. Arixtra should be used with caution in these patients (see Dosage & Administration).
Renal Impairment: The plasma clearance of fondaparinux decreases with the severity of renal impairment and is associated with an increased risk of hemorrhage (see Pharmacology: Pharmacokinetics under Actions). Patients with renal impairment, particularly those with a CrCl of <30 mL/min are at increased risk of both major bleeding episodes and VTE.
Prevention of VTE: There are limited clinical data available for the use of fondaparinux for prevention of VTE patients with CrCl <20 mL/min. Therefore, fondaparinux is not recommended for prevention of VTE in these patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Treatment of VTE: There are limited clinical data available for the use of fondaparinux for treatment of VTE in patients with CrCl of <30 mL/min. Therefore, fondaparinux is not recommended for the treatment of VTE in these patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Treatment of UA/NSTEMI and STEMI: There are limited clinical data available for the use of Arixtra for the treatment of UA/NSTEMI and STEMI in patients with CrCl between 20-30 mL/min. Therefore, the physician should determine if the benefit of treatment outweighs the risk (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration). Arixtra is not recommended in patients with a CrCl of <20 mL/min.
Severe Hepatic Impairment: In patients with an elevation in prothrombin time, the use of Arixtra should be considered with caution, because of an increased risk of bleeding due to a possible deficiency of coagulation factors in patients with severe hepatic impairment (see Dosage & Administration).
Heparin-Induced Thrombocytopenia (HIT): Arixtra does not bind to platelet factor 4 and does not cross-react with sera from patients with HIT-type II. It should be used with caution in patients with a history of HIT. The efficacy and safety of Arixtra have not been formally studied in HIT-type II. Rare spontaneous reports of HIT in patients treated with Arixtra have been received. To date, a causal association between treatment with Arixtra and the occurrence of HIT has not been established.
Latex Allergy: The needle shield of the pre-filled syringe contains dry natural latex rubber that has the potential to cause allergic reactions in latex-sensitive individuals.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed.
Use in Children: The safety and efficacy of Arixtra in patients <17 years has not been established (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Use in Elderly: 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 Arixtra. Arixtra should be used with caution in elderly patients (see Dosage & Administration).
Use in Pregnancy: There are limited clinical data available on exposed pregnancies. Arixtra should not be prescribed to pregnant women unless the benefit outweighs the risk.
Use in Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding is not recommended during treatment with Arixtra.
PCI and Risk of Guiding Catheter Thrombus: In STEMI patients undergoing primary PCI for reperfusion, the use of Arixtra prior to and during PCI is not recommended. In UA/NSTEMI and STEMI patients undergoing nonprimary PCI, the use of Arixtra as the sole anticoagulant during PCI is not recommended, therefore UFH should be used according to standard practice (see Dosage & Administration).
In a clinical trial comparing 2 dose regimens of UFH during nonprimary PCI, fondaparinux-treated UA/NSTEMI patients were randomized to receive either 'standard dose UFH' (median dose 85 U/kg) or 'low dose UFH' (median dose 50 U/kg). The incidence of peri-PCI major bleeding was 1.2% with 'standard dose UFH' and 1.4% with 'low dose UFH' (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Clinical trials have shown a low but increased risk of guiding catheter thrombus in patients treated solely with Arixtra for anticoagulation during PCI compared to control. Incidences in nonprimary PCI in UA/NSTEMI were 1% versus 0.3% (Arixtra vs enoxaparin) and in primary PCI in STEMI were 1.2% versus 0% (Arixtra vs control). In fondaparinux-treated UA/NSTEMI patients randomized to receive 'standard dose' or 'low dose' regimens of UFH during nonprimary PCI, the incidences of catheter thrombus were 0.1% and 0.5%, respectively (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Hemorrhage: Arixtra, like other anticoagulants, must be used with caution in conditions with an increased risk of hemorrhage (eg, congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, recent intracranial hemorrhage, shortly after brain, spinal or ophthalmic surgery).
Prevention and Treatment of VTE: Other medicinal products enhancing the risk of hemorrhage, with the exception of vitamin K antagonists used concomitantly for treatment of VTE, should not be administered with Arixtra. If co-administration is essential, close monitoring is recommended (see Interactions).
Prevention of VTE Following Surgery (Timing of First Arixtra Injection): The timing of the 1st injection requires strict adherence. The 1st dose should be given no earlier than 6 hrs following surgical closure and only after hemostasis has been established. Administration before 6 hrs has been associated with an increased risk of major bleeding. Patient groups at particular risk are those from 75 years of age, body weight of <50 kg or renal impairment with CrCl of <50 mL/min.
Treatment of UA/NSTEMI and STEMI: Arixtra should be used with caution in patients who are being treated concomitantly with other medicinal products that increase the risk of hemorrhage (eg, GPIIb/IIIa inhibitors or thrombolytics).
Spinal/Epidural, Anesthesia/Spinal Puncture: Epidural or spinal hematomas that may result in long-term or permanent paralysis can occur with the use of anticoagulants and spinal/epidural anesthesia 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 hemostasis.
Low Bodyweight: Patients with body weight <50 kg are at increased risk of bleeding. Elimination of Arixtra decreases with weight decrease. Arixtra should be used with caution in these patients (see Dosage & Administration).
Renal Impairment: The plasma clearance of fondaparinux decreases with the severity of renal impairment and is associated with an increased risk of hemorrhage (see Pharmacology: Pharmacokinetics under Actions). Patients with renal impairment, particularly those with a CrCl of <30 mL/min are at increased risk of both major bleeding episodes and VTE.
Prevention of VTE: There are limited clinical data available for the use of fondaparinux for prevention of VTE patients with CrCl <20 mL/min. Therefore, fondaparinux is not recommended for prevention of VTE in these patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Treatment of VTE: There are limited clinical data available for the use of fondaparinux for treatment of VTE in patients with CrCl of <30 mL/min. Therefore, fondaparinux is not recommended for the treatment of VTE in these patients (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Treatment of UA/NSTEMI and STEMI: There are limited clinical data available for the use of Arixtra for the treatment of UA/NSTEMI and STEMI in patients with CrCl between 20-30 mL/min. Therefore, the physician should determine if the benefit of treatment outweighs the risk (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration). Arixtra is not recommended in patients with a CrCl of <20 mL/min.
Severe Hepatic Impairment: In patients with an elevation in prothrombin time, the use of Arixtra should be considered with caution, because of an increased risk of bleeding due to a possible deficiency of coagulation factors in patients with severe hepatic impairment (see Dosage & Administration).
Heparin-Induced Thrombocytopenia (HIT): Arixtra does not bind to platelet factor 4 and does not cross-react with sera from patients with HIT-type II. It should be used with caution in patients with a history of HIT. The efficacy and safety of Arixtra have not been formally studied in HIT-type II. Rare spontaneous reports of HIT in patients treated with Arixtra have been received. To date, a causal association between treatment with Arixtra and the occurrence of HIT has not been established.
Latex Allergy: The needle shield of the pre-filled syringe contains dry natural latex rubber that has the potential to cause allergic reactions in latex-sensitive individuals.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed.
Use in Children: The safety and efficacy of Arixtra in patients <17 years has not been established (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Use in Elderly: 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 Arixtra. Arixtra should be used with caution in elderly patients (see Dosage & Administration).
Use in Pregnancy: There are limited clinical data available on exposed pregnancies. Arixtra should not be prescribed to pregnant women unless the benefit outweighs the risk.
Use in Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding is not recommended during treatment with Arixtra.
Use In Pregnancy & Lactation
Use in Pregnancy: There are limited clinical data available on exposed pregnancies. Arixtra should not be prescribed to pregnant women unless the benefit outweighs the risk.
Use in Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding is not recommended during treatment with Arixtra.
Use in Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breastfeeding is not recommended during treatment with Arixtra.
Adverse Reactions
Adverse reactions are listed as follows by system organ class and frequency and indication. Frequencies are defined as: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000). These adverse reactions should be interpreted within the surgical or medical context of the indications.
Clinical Trial Data: Infections and Infestations: Rare: Postoperative wound infections.
Blood and Lymphatic System Disorders: Common: Anemia, bleeding (various sites including rare cases of intracranial/intracerebral and retroperitoneal bleedings), purpura. Uncommon: Thrombocytopenia, thrombocythemia, abnormal platelets, coagulation disorder.
Immune System Disorders: Rare: Allergic reaction (including very rare reports of angioedema, anaphylactoid/anaphylactic reaction).
Metabolism and Nutrition Disorders: Rare: Hypokalemia.
Nervous System Disorders: Uncommon: Headache. Rare: Anxiety, confusion, dizziness, somnolence, vertigo.
Vascular Disorders: Rare: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Rare: Dyspnea, coughing.
Gastrointestinal Disorders: Uncommon: Nausea, vomiting. Rare: Abdominal pain, dyspepsia, gastritis, constipation, diarrhea.
Hepatobiliary Disorders: Uncommon: Abnormal liver function tests, increased hepatic enzymes. Rare: Bilirubinemia.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash, pruritus, wound secretion.
General Disorders and Administration Site Conditions: Common: Edema. Uncommon: Fever. Rare: Injection site reaction, chest and leg pain, fatigue, flushing, syncope.
Clinical Trial Data: Infections and Infestations: Rare: Postoperative wound infections.
Blood and Lymphatic System Disorders: Common: Anemia, bleeding (various sites including rare cases of intracranial/intracerebral and retroperitoneal bleedings), purpura. Uncommon: Thrombocytopenia, thrombocythemia, abnormal platelets, coagulation disorder.
Immune System Disorders: Rare: Allergic reaction (including very rare reports of angioedema, anaphylactoid/anaphylactic reaction).
Metabolism and Nutrition Disorders: Rare: Hypokalemia.
Nervous System Disorders: Uncommon: Headache. Rare: Anxiety, confusion, dizziness, somnolence, vertigo.
Vascular Disorders: Rare: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Rare: Dyspnea, coughing.
Gastrointestinal Disorders: Uncommon: Nausea, vomiting. Rare: Abdominal pain, dyspepsia, gastritis, constipation, diarrhea.
Hepatobiliary Disorders: Uncommon: Abnormal liver function tests, increased hepatic enzymes. Rare: Bilirubinemia.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash, pruritus, wound secretion.
General Disorders and Administration Site Conditions: Common: Edema. Uncommon: Fever. Rare: Injection site reaction, chest and leg pain, fatigue, flushing, syncope.
Caution For Usage
Incompatibilities: In the absence of compatibility studies, Arixtra must not be mixed with other medicinal products.
Instructions for Use and Handling: Parenteral solutions should be inspected visually for particulate matter and discoloration prior to administration.
Arixtra is administered by SC or IV injection. It must not be administered by IM injection.
The SC injection is administered in the same way as with a standard syringe. Intravenous administration should be through an existing IV line either directly or using a small volume (25 or 50 mL) 0.9% saline minibag.
Arixtra 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.
Instructions for Use: Parts of the syringe: Needle shield, plunger, finger grip and security sleeve.
Wash hands thoroughly with soap and water and dry them with a towel. Remove the syringe from the carton and check if the expiry date has not passed; the solution is clear and colorless and does not contain particles; the syringe has not been opened or damaged. Sit or lie down in a comfortable position. Choose a spot in the lower abdominal (tummy) area, at least 5 cm below the belly button. Alternate the left and right side of the lower abdominal area at each injection. This will help to reduce the discomfort at the injection site. If injecting in the lower abdominal area is not possible, ask the nurse or physician for advice. Clean the injection area with an alcohol wipe. Remove the needle shield by first twisting it and then pulling it in a straight line away from the body of the syringe. Discard the needle shield.
Important Note: Do not touch the needle or allow it to touch any surface prior to injection.
The presence of a small air bubble in the syringe is normal. Do not try to remove the air bubble before making the injection (some of the medicine may be lost).
Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger during the entire injection. Hold the syringe firmly by the finger grip. Insert the full length of the needle at right angles into the skin fold. Inject all the contents of the syringe by pressing down on the plunger as far as it goes.
Release the plunger and the needle will withdraw automatically from the skin and go back into the security sleeve where it will be locked permanently. Do not dispose of the used syringe in household waste. Dispose of it as the physician or pharmacist has instructed.
Instructions for Use and Handling: Parenteral solutions should be inspected visually for particulate matter and discoloration prior to administration.
Arixtra is administered by SC or IV injection. It must not be administered by IM injection.
The SC injection is administered in the same way as with a standard syringe. Intravenous administration should be through an existing IV line either directly or using a small volume (25 or 50 mL) 0.9% saline minibag.
Arixtra 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.
Instructions for Use: Parts of the syringe: Needle shield, plunger, finger grip and security sleeve.
Wash hands thoroughly with soap and water and dry them with a towel. Remove the syringe from the carton and check if the expiry date has not passed; the solution is clear and colorless and does not contain particles; the syringe has not been opened or damaged. Sit or lie down in a comfortable position. Choose a spot in the lower abdominal (tummy) area, at least 5 cm below the belly button. Alternate the left and right side of the lower abdominal area at each injection. This will help to reduce the discomfort at the injection site. If injecting in the lower abdominal area is not possible, ask the nurse or physician for advice. Clean the injection area with an alcohol wipe. Remove the needle shield by first twisting it and then pulling it in a straight line away from the body of the syringe. Discard the needle shield.
Important Note: Do not touch the needle or allow it to touch any surface prior to injection.
The presence of a small air bubble in the syringe is normal. Do not try to remove the air bubble before making the injection (some of the medicine may be lost).
Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger during the entire injection. Hold the syringe firmly by the finger grip. Insert the full length of the needle at right angles into the skin fold. Inject all the contents of the syringe by pressing down on the plunger as far as it goes.
Release the plunger and the needle will withdraw automatically from the skin and go back into the security sleeve where it will be locked permanently. Do not dispose of the used syringe in household waste. Dispose of it as the physician or pharmacist has instructed.
Storage
Store at temperatures not exceeding 25°C. Do not freeze.
If Arixtra 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 hrs.
If Arixtra 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 hrs.
Action
Pharmacotherapeutic Group: Antithrombotic agents.
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.
Pharmacodynamic Effects: 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.
Anti-Xa Activity: 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.
Extended Prophylaxis: 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.)
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.
Pharmacodynamic Effects: 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.
Anti-Xa Activity: 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.
Extended Prophylaxis: 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.)
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.
Pharmacokinetics: Absorption: 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.
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 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.
Elimination: 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).
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, 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).
Children: 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).
Elderly: 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.
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.
Body Weight: 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.
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.
Pharmacokinetics: Absorption: 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.
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 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.
Elimination: 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).
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, 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).
Children: 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).
Elderly: 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.
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.
Body Weight: 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.
MedsGo Class
Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)
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