Arixtra

Fondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa).

The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII) mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no known effect on platelet function.
Pharmacology: Pharmacodynamics: At the 2.5 mg dose, fondaparinux does not have a clinically relevant affect on routine coagulation tests, such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma, nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of 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 anti factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. The international standards of heparin or low molecular weight heparin (LMWH) are not appropriate for this use. As a result, the concentration of fondaparinux is expressed as milligrams of the fondaparinux calibrator/litre.
Pharmacokinetics: Absorption: After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of ARIXTRA 2.5 mg to young healthy subjects, peak plasma concentration, mean C_max of 0.34 mg/L, is reached in approximately 2 hours. Plasma concentrations of half the mean C_max values are reached 25 min post-dosing.
In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily subcutaneous dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in C_max and AUC. Following a single i.v. bolus administration to healthy elderly subjects, the pharmacokinetics of fondaparinux are linear over the therapeutic range.
In patients undergoing hip replacement surgery receiving ARIXTRA 2.5 mg once daily subcutaneously, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L.
In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 to 100 kg) and 10 mg (body weight greater than 100 kg) subcutaneously once daily, the body weight adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.
Distribution: In healthy adults, intraveneously or subcutaneously administered fondaparinux distributes mainly in blood and only to a minor extent in extravascular fluid, as demonstrated by steady state and non steady state apparent volume of distribution of 7 to 11 L. In vitro, fondaparinux is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins, including platelet Factor 4 (PF4) or red blood cells.
Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.
Elimination: Fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals, 64 to 77% of a single subcutaneous or intravenous dose is eliminated in urine in 72 hours. The elimination half-life is about 17 hours in healthy young subjects and about 21 hours in healthy elderly subjects. In patients with normal renal function, the mean fondaparinux clearance is 7.82 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 (creatinine clearance 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) and approximately 55% lower in patients with severe renal impairment (less than 30 mL/min), compared to patients with normal renal function. The associated terminal half-life values were 29 hours in moderate and 72 hours in patients with severe renal impairment. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients.
Prevention of VTE: A population pharmacokinetic model was developed using data obtained from patients undergoing major orthopaedic 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 2.5 mg on alternate days were similar to those seen in patients with mild to moderate renal impairment (creatinine clearance 30 to 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, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), C_max and AUC were decreased by 22% and 39%, respectively, as compared to subjects with normal liver function. The lower plasma concentrations of fondaparinux were attributed to reduced binding to ATIII secondary to the lower ATIII plasma concentrations in subjects with hepatic impairment thereby resulting in increased renal clearance of fondaparinux.
The pharmacokinetics of ARIXTRA has not been studied in patients with severe hepatic impairment (see Dosage & Administration and Precautions).
Elderly: Fondaparinux elimination is prolonged in patients over 75 years old. In studies evaluating ARIXTRA 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients over 75 years old as compared to patients less than 65 years old. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.
Gender: No gender differences were observed after adjustment for body weight.
Race: Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, based on the results of population pharmacokinetic analysis conducted in patients undergoing orthopaedic surgery, no plasma clearance differences were observed between black and Caucasian patients.
Body weight: In patients weighing less than 50 kg the total clearance of fondaparinux sodium is decreased by approximately 30% (see Precautions).

Prevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs such as: hip fracture, including extended prophylaxis; knee replacement surgery;  hip replacement surgery.
Prevention of Venous Thromboembolic Events (VTE) in patients undergoing abdominal surgery who are at risk of thromboembolic complications.
Prevention of Venous Thromboembolic Events (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).
Treatment of acute Pulmonary Embolism (PE).
Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) in patients whom urgent (<120 mins) invasive management [Percutaneous Coronary Intervention (PCI)] is not indicated.
Adjunctive treatment of ST segment elevation myocardial infarction (STEMI) in patients who are managed with thrombolytics or who initially are to receive no other form of reperfusion therapy.

Adults: Prevention of VTE: Orthopaedic and abdominal surgery: the recommended dose of ARIXTRA is 2.5 mg once daily, administered post-operatively by subcutaneous injection.
The timing of the first dose should be no earlier than 6 hours following surgical closure, and only after haemostasis has been established (see Precautions).
Treatment should be continued until the risk of venous thrombo-embolism has diminished, usually until the patient is ambulant, at least 5 to 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.
Medical patients at risk of thromboembolic complications: the recommended dose of ARIXTRA is 2.5 mg once daily administered by subcutaneous injection. A treatment duration of 6 to 14 days has been clinically studied in medical patients.
Treatment of DVT and PE: The recommended dose of ARIXTRA to be administered by subcutaneous injection once daily is: 5 mg for body weight less than 50 kg; 7.5 mg for body weight 50 to 100 kg; 10 mg for body weight greater than 100 kg.
Treatment should be continued for at least 5 days and until adequate oral anticoagulation is established (International Normalised Ratio 2 to 3). Concomitant treatment with vitamin K antagonist should be initiated as soon as possible, usually within 72 hours. The usual duration of ARIXTRA treatment is 5 to 9 days.
Treatment of Unstable Angina/Non-ST Segment Elevation Myocardial Infection (UA/NSTEMI): The recommended dose of ARIXTRA is 2.5 mg once daily, administered by subcutaneous 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 percutaneous coronary intervention (PCI) while on ARIXTRA, unfractionated heparin (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 subcutaneous 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 hours after sheath removal.
In patients who are to undergo coronary artery bypass graft (CABG) surgery, ARIXTRA where possible, should not be given during the 24 hours before surgery and may be restarted 48 hours post-operatively.
Treatment of ST Segment Elevation Myocardial Infarction (STEMI): The recommended dose of ARIXTRA is 2.5 mg once daily. The first dose of ARIXTRA is administered intravenously and subsequent doses are administered by subcutaneous injection.
Treatment should be initiated as soon as possible following diagnosis and continued for up to 8 days or until hospital discharge.
If a patients is to undergo non-primary percutaneous coronary intervention (PCI) while on ARIXTRA, unfractionated heparin (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 subcutaneous ARIXTRA after sheath removal should be based on clinical judgment. In the STEMI clinical trial treatment with ARIXTRA was restarted no earlier than 3 hours after sheath removal.
In patients who are to undergo coronary artery bypass graft (CABG) surgery, ARIXTRA where possible, should not be given during the 24 hours before surgery and may be restarted 48 hours post-operatively.
Special Populations: Children: The safety and efficacy of ARIXTRA in patients under the age of 17 has not been established.
Elderly (from 75 years): ARIXTRA should be used with caution in elderly patients as renal function decreases with age (see Renal Impairment as follows and Precautions). In patients undergoing surgery, the timing of the first dose of ARIXTRA requires strict adherence (see Precautions).
Patients with body weight less than 50 kg: Patients with body weight below 50 kg are at increased risk of bleeding (see Precautions). In patients undergoing surgery, the timing of the first dose of ARIXTRA requires strict adherence (see Precautions).
Renal Impairment: Prevention of VTE: No dosage reduction is required in patients with a creatinine clearance greater than or equal to 30 mL/min. In patients with a creatinine clearance of between 20 to 30 mL/min in whom the physician determines that the benefit of thromboprophylaxis exceeds the risk, a dose of 2.5 mg on alternate days (each dose approximately 48 hours apart) is recommended (see Pharmacology: Pharmacokinetics under Actions and Precautions).
ARIXTRA is not recommended for use in patients with a creatinine clearance of less than 20 mL/min (see Precautions).
In patients undergoing surgery, the timing of the first dose of ARIXTRA requires strict adherence.
Treatment of VTE: No dosage reduction is required in patients with a creatinine clearance greater than or equal to 30 mL/min.
ARIXTRA should not be used in patients with a creatinine clearance of less than 30 mL/min (see Precautions).
Treatment of UA/NSTEMI and STEMI: ARIXTRA is not recommended for use in patients with a creatinine clearance of less than 20 mL/min (see Precautions). No dosage reduction is required for patients with a creatinine clearance greater than or equal to 20 mL/min.
Hepatic Impairment: No dosing adjustment of ARIXTRA is necessary in patients with mild to moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). In patients with severe hepatic impairment, ARIXTRA should be used with caution (see Precautions).
Method of Administration: Subcutaneous administration: The sites of subcutaneous 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 subcutaneous injection technique should be provided.
Intravenous administration (first dose in STEMI patients only): Intravenous administration should be through an existing intravenous 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 intravenous tubing should be well flushed with saline after injection to ensure that all of the medicinal product is administered. If administered via a mini-bag, the infusion should be given over 1 to 2 minutes.

Symptoms and Signs: 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 haemostasis, blood replacements, fresh plasma transfusion, plasmapheresis should be considered.

Known hypersensitivity to ARIXTRA or any of the excipients.
Active clinically significant bleeding.
Acute bacterial endocarditis.
Severe renal impairment defined by creatinine <20 mL/min.

Route of administration: ARIXTRA must not be administered intramuscularly (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 non-primary 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 two dose regimens of UFH during non-primary 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'.
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 non-primary PCI in UA/NSTEMI were 1.0% vs 0.3% (ARIXTRA vs. enoxaparin) and in primary PCI in STEMI were 1.2% vs 0% (ARIXTRA vs. control). In fondaparinux-treated UA/NSTEMI patients randomised to receive "standard dose" or "low dose" regimens of UFH during non-primary PCI, the incidences of catheter thrombus were 0.1% and 0.5%, respectively.
Haemorrhage: ARIXTRA, like other anticoagulants must be used with caution in conditions with an increased risk of haemorrhage, (such as congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, recent intracranial haemorrhage, shortly after brain, spinal or ophthalmic surgery).
Prevention and treatment of VTE: Other medicinal products enhancing the risk of haemorrhage, 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 first injection requires strict adherence. The first dose should be given no earlier than 6 hours following surgical closure, and only after haemostasis has been established. Administration before 6 hours 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 less than 50 kg, or renal impairment with creatinine clearance less than 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 haemorrhage (such as GPIIb/IIIa inhibitors or thrombolytics).
Spinal/epidural anaesthesia/spinal puncture: Epidural or spinal haematomas that may result in long-term or permanent paralysis can occur with the use of anticoagulants and spinal/epidural anaesthesia or spinal puncture. The risk of these rare events may be higher with post-operative use of indwelling epidural catheters or the concomitant use of other medicinal products affecting haemostasis.
Elderly patients: 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).
Low body weight: Patients with body weight less than 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 haemorrhage (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment, particularly those with a creatinine clearance of less than 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 in patients with creatinine clearance less than 20 mL/min. Therefore, ARIXTRA 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 creatinine clearance of less than 30 mL/min. Therefore, ARIXTRA 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 on the use of ARIXTRA for the treatment of UA/NSTEMI and STEMI in patients with creatinine clearance between 20 to 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 creatinine clearance of less than 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: ARIXTRA does not bind to platelet factor 4 and does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (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.
Pregnancy: There are limited clinical data available on exposed pregnancies. ARIXTRA should not be prescribed to pregnant women unless the benefit outweighs the risk.
Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breast-feeding is not recommended during treatment with ARIXTRA.

Pregnancy: There are limited clinical data available on exposed pregnancies. ARIXTRA should not be prescribed to pregnant women unless the benefit outweighs the risk.
Lactation: Fondaparinux is excreted in rat milk but it is not known whether fondaparinux is excreted in human milk. Breast-feeding is not recommended during treatment with ARIXTRA.

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 (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); 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: Post-operative wound infections.
Blood and lymphatic system disorders: Common: Anaemia, bleeding (various sites including rare cases of intracranial/intracerebral and retroperitoneal bleedings), purpura.
Uncommon: Thrombocytopenia, thrombocythaemia, abnormal platelets, coagulation disorder.
Immune system disorders: Rare: Allergic reaction (including very rare reports of angioedema, anaphylactoid/anaphylactic reaction).
Metabolism and nutrition disorders: Rare: Hypokalaemia.
Nervous system disorders: Uncommon: Headache.
Rare: Anxiety, confusion, dizziness, somnolence, vertigo.
Vascular disorders: Rare: Hypotension.
Respiratory, thoracic and mediastinal disorders: Rare: Dyspnoea, coughing.
Gastrointestinal disorders: Uncommon: Nausea, vomiting.
Rare: Abdominal pain, dyspepsia, gastritis, constipation, diarrhoea.
Hepatobiliary disorders: Uncommon: Abnormal liver function tests, hepatic enzymes increased. Rare: Bilirubinaemia.
Skin and subcutaneous tissue disorders: Uncommon: Rash, pruritus, wound secretion.
General disorders and administration site conditions: Common: Oedema.
Uncommon: Fever.
Rare: Reaction at injection site, chest pain, leg pain, fatigue, flushing, syncope.

Fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4) in vitro. Thus, ARIXTRA is not expected to interact with other medicinal products in vivo by inhibition of CYP-mediated metabolism.
Since fondaparinux does not bind significantly to plasma proteins other than ATIII, no interaction with other medicinal products by protein binding displacement are expected.
In clinical studies performed with fondaparinux, the concomitant use of warfarin (oral anticoagulant), acetylsalicylic acid (platelet inhibitor), piroxicam (non-steroidal anti inflammatory), and digoxin (cardiac glycoside) did not significantly affect the pharmacokinetics or pharmacodynamics of fondaparinux. In addition fondaparinux neither influenced the INR activity of warfarin, nor the bleeding time under acetylsalicylic acid or piroxicam treatment, nor the pharmacokinetics or pharmacodynamics of digoxin at steady state.

Store below 25°C. Do not freeze.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AX05 - fondaparinux ; Belongs to the class of other antithrombotic agents.

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