INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARIXTRAÒ (ARIXTRAÒ)

Composition:

Active substance: fondaparinux sodium;

1 syringe (0.5 ml) contains 2.5 mg of fondaparinux sodium;

Excipients: sodium chloride, water for injections, hydrochloric acid or sodium hydroxide.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: a pre-filled glass syringe containing a clear or almost clear, colorless liquid practically free from visible particles.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01AX05.

Pharmacological properties.

Pharmacodynamics.

Fondaparinux is a synthetic selective inhibitor of activated factor X (Xa). The antithrombotic activity of fondaparinux results from selective inhibition of factor Xa mediated by antithrombin III (AT III). By selectively binding to AT III, fondaparinux potentiates (approximately 300-fold) the initial neutralization of factor Xa by antithrombin III. Neutralization of factor Xa interrupts the blood coagulation cascade and inhibits both thrombin generation and thrombus formation. The drug does not inactivate thrombin (activated factor II) and has no effect on platelets.

At a dose of 2.5 mg, fondaparinux does not affect the results of standard coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT), or prothrombin time (PT)/international normalized ratio (INR) in plasma, nor does it alter bleeding time or fibrinolytic activity. However, isolated reports of increased aPTT have been observed.

Fondaparinux does not cross-react with serum in patients with heparin-induced thrombocytopenia.

Pharmacokinetics.

Absorption.

After subcutaneous administration, the drug is rapidly and completely absorbed (absolute bioavailability – 100%). Following a single subcutaneous dose of 2.5 mg fondaparinux administered to young healthy volunteers, maximum plasma concentration (mean C_max = 0.34 mg/L) was achieved within 2 hours after dosing. Plasma concentration equal to half of the above-mentioned maximum concentration was reached within 25 minutes after administration.

In elderly healthy volunteers, the pharmacokinetics of fondaparinux are linear within the dose range of 2–8 mg subcutaneously. With once-daily subcutaneous administration, steady-state plasma concentration is achieved within 3–4 days, with a 1.3-fold increase in C_max and AUC (area under the curve).

Mean (coefficient of variation – CV, %) pharmacokinetic parameters of fondaparinux at steady state in patients who underwent hip surgery and received fondaparinux 2.5 mg once daily were: C_max – 0.39 mg/L (31%), T_max – 2.8 hours (18%), and C_min – 0.14 mg/L (56%). In elderly patients undergoing surgery for hip fracture, steady-state concentrations of fondaparinux were: C_max – 0.50 mg/L (32%), C_min – 0.19 mg/L (58%).

Distribution.

The volume of distribution is limited, ranging from 7 to 11 L. In vitro, fondaparinux binds extensively and specifically to the protein AT III, with the degree of binding dependent on drug concentration in plasma (from 98.6% to 97.0% over a concentration range of 0.5 to 2 mg/L). Binding of fondaparinux to other plasma proteins, including platelet factor 4, is negligible.

Since fondaparinux does not significantly bind to other plasma proteins except antithrombin III, drug interactions via displacement from protein binding are not expected.

Metabolism.

Although a complete evaluation has not been performed, there is no evidence of fondaparinux metabolism or formation of active metabolites.

Fondaparinux does not inhibit cytochrome CYP450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro. Therefore, interactions with other medicinal products via inhibition of CYP-mediated metabolism are not expected in vivo.

Elimination.

Fondaparinux is primarily excreted unchanged by the kidneys, accounting for 64–77% in healthy volunteers. The elimination half-life (T_1/2) is approximately 17 hours in young healthy volunteers and about 21 hours in healthy elderly volunteers.

Special patient groups.

Renal impairment.

Compared to patients with normal renal function (creatinine clearance > 80 mL/min), plasma clearance is 1.2–1.4 times lower in patients with mild renal impairment (creatinine clearance 50–80 mL/min) and on average two-fold lower in patients with moderate renal impairment (creatinine clearance 30–50 mL/min). In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma clearance is approximately five times lower than in those with normal renal function. Corresponding terminal half-lives were 29 hours in moderate and 72 hours in severe renal insufficiency. A similar relationship between fondaparinux clearance and severity of renal impairment was observed in patients treated for deep vein thrombosis.

Hepatic impairment.

According to pharmacokinetic data, the concentration of unbound fondaparinux is expected to remain unchanged in patients with mild to moderate hepatic impairment, and therefore dose adjustment is not required. After a single subcutaneous dose of fondaparinux in patients with moderate hepatic impairment (Child–Pugh class B), C_max and AUC of total (bound and unbound) fondaparinux were reduced by 22% and 39%, respectively, compared to patients with normal hepatic function. The lower plasma concentration of fondaparinux is explained by reduced binding to AT III, as plasma AT III concentrations are lower in patients with hepatic impairment. As a result, renal clearance of fondaparinux is increased.

The pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic impairment (see ↔Dosage and administration» and ↔Special precautions»).

Children.

The use of fondaparinux in children for prevention of venous thromboembolism or for treatment of superficial venous thrombosis or acute coronary syndrome (ACS) has not been studied in this population.

Elderly patients.

Renal function may decline with age; therefore, elimination of fondaparinux may be impaired in patients over 75 years of age. After orthopedic surgery, total plasma clearance of fondaparinux was approximately 1.2–1.4 times lower in patients over 75 years of age compared to those under 65 years. A similar relationship between drug clearance and age was observed in patients treated for deep vein thrombosis.

Gender.

No differences in pharmacokinetics between male and female patients were observed after dose adjustment for body weight.

Race.

Specific pharmacokinetic studies assessing racial differences have not been conducted. However, studies in healthy volunteers of Mongoloid race did not reveal differences in pharmacokinetic profile compared to healthy volunteers of Caucasian race. No differences in plasma clearance of the drug were observed between African and Caucasian race patients undergoing orthopedic surgery.

Body weight.

Plasma clearance of fondaparinux increases with increasing body weight (by 9% per 10 kg increase in body weight).

Clinical characteristics.

Indications.

Prevention of venous thromboembolism in patients after major orthopedic surgeries on the lower limbs, including hip fracture (including extended prophylaxis), and hip and knee replacement surgeries.

Prevention of venous thromboembolism in patients after abdominal surgery who are at high risk of thromboembolic complications, for example, patients undergoing abdominal surgery due to malignancy.

Prevention of venous thromboembolism in patients at high risk of such complications due to prolonged immobilization during the acute phase of illness, such as heart failure and/or acute respiratory disorders, and/or acute infectious or inflammatory diseases.

Treatment of unstable angina or non-ST-segment elevation myocardial infarction in patients for whom immediate (< 120 min) invasive intervention (percutaneous coronary intervention – PCI) is not indicated (see ↔Special precautions»).

Treatment of ST-segment elevation myocardial infarction in patients treated with thrombolytics, or in those who did not initially receive other forms of reperfusion therapy.

Contraindications.

Known hypersensitivity to the active substance or to any of the excipients of the drug. Active clinically significant bleeding. Acute bacterial endocarditis. Severe renal impairment (creatinine clearance < 20 mL/min).

Interaction with other medicinal products and other forms of interaction.

Medicinal products that may increase the risk of bleeding should not be used concomitantly with Arixtra® except for vitamin K antagonists used for the treatment of venous thromboembolism (see ↔Special precautions»). If such concomitant use is necessary, it should be carried out under close monitoring.

Clinical studies with fondaparinux have demonstrated that its concomitant use with oral anticoagulants (warfarin), antiplatelet agents (acetylsalicylic acid), nonsteroidal anti-inflammatory drugs (piroxicam), and cardiac glycosides (digoxin) does not significantly affect the pharmacokinetics of fondaparinux. The fondaparinux dose (10 mg) used in interaction studies exceeded the dose recommended for current indications.

Furthermore, the drug had no effect on the anticoagulant activity of warfarin (as measured by international normalized ratio – INR), on bleeding time during treatment with acetylsalicylic acid or piroxicam, or on the steady-state pharmacokinetics of digoxin.

Subsequent therapy with other anticoagulants.

If subsequent treatment with heparin or low-molecular-weight heparin is required, the first injection is usually administered one day after the last injection of fondaparinux.

If subsequent treatment with a vitamin K antagonist is required, fondaparinux therapy should be continued until the target INR value is achieved.

Special precautions for use.

Arixtra® should not be administered intramuscularly.

Percutaneous coronary intervention and risk of catheter thrombosis.

Arixtra® is not recommended for use before or during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction. Arixtra® is also not recommended as a sole anticoagulant before or during non-primary PCI in patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) who are at high risk and require urgent revascularization. These patients include those with refractory or recurrent angina associated with dynamic ST-segment changes, heart failure, life-threatening arrhythmias, or hemodynamic instability.

In patients with UA/NSTEMI or ST-segment elevation myocardial infarction (STEMI) undergoing non-primary PCI, the use of fondaparinux as the sole anticoagulant during PCI is not recommended due to an increased risk of catheter thrombosis. Therefore, during non-primary percutaneous coronary intervention, unfractionated heparin should be additionally administered according to standard practice (see dosing information in section "Dosage and administration").

Bleeding.

Like other anticoagulants, Arixtra® should be used with caution in patients with an increased risk of bleeding, including those with congenital or acquired bleeding disorders (e.g., platelet count < 50,000/mm³), active peptic ulcer disease, recent intracranial hemorrhage, recent neurosurgery or spinal surgery, or recent ophthalmologic surgery, as well as in special patient populations described below.

Prophylaxis of venous thromboembolism.

Drugs that may increase the risk of bleeding should not be used concomitantly with fondaparinux. These include desirudin, fibrinolytic agents, GP IIb/IIIa receptor antagonists, heparin, heparinoids, and low-molecular-weight heparin (LMWH). Medicinal products that may increase the risk of bleeding should not be used simultaneously with Arixtra®, except for vitamin K antagonists used for the treatment of venous thromboembolism. If concomitant use of a vitamin K antagonist is necessary, refer to the information provided in the section "Interaction with other medicinal products and other forms of interaction." Other antiplatelet agents (acetylsalicylic acid, dipyridamole, sulfinpyrazone, ticlopidine, or clopidogrel), as well as nonsteroidal anti-inflammatory drugs, should be used with caution. If such concomitant use is required, it should be performed under close monitoring.

Unstable angina/non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction.

Arixtra® should be used with caution in patients who are concurrently receiving other medicinal products that increase the risk of bleeding (such as GP IIb/IIIa receptor antagonists or thrombolytics).

Epidural anesthesia/spinal puncture.

The concomitant use of Arixtra® with epidural anesthesia or spinal puncture in patients undergoing major orthopedic surgery cannot exclude the possibility of developing epidural or spinal hematomas, which may result in long-term or permanent paralysis. The risk of such rare events is increased when postoperative indwelling epidural catheters are used or when other medicinal products affecting hemostasis are administered concomitantly.

Elderly patients.

The risk of bleeding is higher in elderly patients than in younger patients. Since renal function generally declines with age, fondaparinux elimination may be reduced in elderly patients, resulting in increased drug exposure (see "Pharmacological properties. Pharmacokinetics"). Therefore, Arixtra® should be used with caution in elderly patients (see "Dosage and administration").

Low body weight.

Prophylaxis of venous thromboembolism and treatment of unstable angina/NSTEMI and STEMI – In patients with body weight below 50 kg, there is an increased risk of bleeding. Fondaparinux elimination decreases with lower body weight. Therefore, Arixtra® should be used with caution in these patients (see "Dosage and administration").

Renal impairment.

Fondaparinux is predominantly eliminated via the kidneys.

Prophylaxis of venous thromboembolism. Patients with creatinine clearance < 50 ml/min are at increased risk of bleeding and venous thromboembolism and should be treated with caution (see "Dosage and administration", "Contraindications", and "Pharmacological properties. Pharmacokinetics"). Clinical data in patients with creatinine clearance < 30 ml/min are limited.

Unstable angina/NSTEMI and STEMI. Clinical data on the use of fondaparinux 2.5 mg once daily for the treatment of unstable angina, NSTEMI, and STEMI in patients with creatinine clearance between 20–30 ml/min are limited. Therefore, the decision to use fondaparinux should be based on an individual assessment of the benefit-risk ratio (see "Dosage and administration" and "Contraindications").

Severe hepatic impairment.

Prophylaxis of venous thromboembolism and treatment of unstable angina/NSTEMI and STEMI. Dose adjustment of fondaparinux is not required. However, the drug should be used with caution due to the increased risk of bleeding associated with coagulation factor deficiency in patients with severe hepatic impairment (see "Dosage and administration").

Heparin-induced thrombocytopenia.

Fondaparinux does not bind to platelet factor 4 and does not cross-react with serum from patients with heparin-induced type II thrombocytopenia. Arixtra® should be used with caution in patients with a history of heparin-induced thrombocytopenia. The efficacy and safety of Arixtra® in patients with heparin-induced type II thrombocytopenia have not been studied. Isolated cases of heparin-induced thrombocytopenia have been reported in patients treated with fondaparinux. The causal relationship between Arixtra® treatment and the occurrence of heparin-induced thrombocytopenia has not been established.

Latex allergy.

The needle cap of the pre-filled syringe contains dry natural rubber latex, which may cause allergic reactions in latex-sensitive individuals.

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical experience with the use of this medicinal product in pregnant women is currently limited. Animal studies are insufficient to determine effects on pregnancy, embryofetal development, parturition, and postnatal development due to limited exposure. Therefore, Arixtra® should not be used during pregnancy except when the expected benefit outweighs the potential risk to the fetus.

Breastfeeding.

Arixtra® is excreted into the milk of rats, but it is unknown whether the drug passes into human breast milk. Breastfeeding is not recommended during treatment with this medicinal product. However, oral absorption of the drug by the infant is unlikely.

Fertility.

There are no data on the effect of fondaparinux on human fertility. In animal studies, no effect on fertility was observed.

Ability to influence reaction rate while driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive a vehicle or operate machinery have not been conducted; however, the possibility of adverse reactions affecting the nervous system should be considered.

Method of Administration and Dosage

Administration Method

Arixtra® is intended for subcutaneous or intravenous injection. Do not administer intramuscularly.

Subcutaneous Injection

When Arixtra® is administered as a deep subcutaneous injection, the patient should be in a lying position. Injection sites should be alternated between the left and right anterolateral or left and right posterolateral abdominal wall. To avoid loss of the drug, do not expel the air bubble from the pre-filled syringe before injection. Insert the needle fully at a perpendicular angle into a skin fold held between the thumb and index finger; maintain the skin fold pinched throughout the injection.

Arixtra® must only be used under medical supervision.

Administer the subcutaneous injection in the same manner as with a conventional syringe.

Intravenous Injection (only the first dose in the treatment of patients with ST-segment elevation myocardial infarction)

Administer intravenously through an existing intravenous line either undiluted or diluted in a small volume (25 or 50 mL) of 0.9% sodium chloride solution. To avoid loss of the drug, do not expel the air bubble from the pre-filled syringe before injection. After injection, flush the line or catheter thoroughly with 0.9% sodium chloride solution to ensure complete delivery of the medication. If Arixtra® is diluted with 0.9% sodium chloride solution, the administration should be completed within 1–2 minutes.

Before use, visually inspect the injection solution for the presence of visible particles or discoloration.

The pre-filled syringes of Arixtra® are equipped with an automatic needle protection system designed to prevent needlestick injuries after injection.

Any unused medication or waste material must be disposed of in accordance with local regulations.

Step-by-Step Instructions for Using Arixtra®

Wash your hands thoroughly with soap and water, then dry them with a towel.
Remove the syringe from its packaging and check that:
- the expiration date of the medication has not passed,
- the solution is clear, colorless, and free of particles,
- the syringe has not been previously opened or damaged.
Adopt a comfortable sitting or lying position.

Select a site in the lower part of the abdominal area (stomach), at least 5 cm below the navel (Figure A).

Alternate between the left and right sides of the lower abdomen with each injection. This will help reduce discomfort at the injection site.

If injecting into the lower abdominal area is not possible, consult your nurse or doctor for assistance.

Figure A

Clean the injection site with an alcohol wipe.

Remove the needle cap, first twisting it (Figure B1), then pulling it straight away from the syringe barrel (Figure B2). Dispose of the needle cap. Important note Do not touch the needle and avoid letting the needle contact any surface before injection. It is normal if you see small air bubbles in this syringe. Do not try to remove these air bubbles before injection – you may lose some of the medication if you do.	Figure B1 Figure B2
6. Gently pinch the cleaned skin to form a skin fold. Hold the skin fold between your thumb and index finger throughout the injection (Figure C).	Figure C

7. Hold the syringe firmly with your fingertips. Insert the needle fully at a right angle into the skin fold. (Figure D).	Figure D

Inject ALL of the syringe contents by pushing the plunger fully down (Figure E).
	Figure E
Release the plunger, and the needle will automatically retract from the skin and return into the protective cap, where it will be permanently enclosed (Figure F).
	Figure F

Do not dispose of used syringes in household waste. Dispose of them according to the instructions provided by your doctor or pharmacist.

Prevention of venous thromboembolism.

Major orthopedic and abdominal surgery.

The recommended dose of Arixtra® for adults is 2.5 mg once daily after surgery by subcutaneous injection.

The initial dose should be administered no sooner than 6 hours after completion of surgery, provided hemostasis has been achieved.

Treatment should continue until the risk of thromboembolic complications has decreased, usually until the patient is discharged to outpatient care, for no less than 5–9 days after surgery. Clinical experience shows that patients undergoing hip fracture surgery remain at risk of venous thromboembolism for more than 9 days. Such patients are recommended to receive additional prophylactic treatment with Arixtra® for up to 24 days.

Patients at high risk of thromboembolic complications based on individual risk assessment.

The recommended dose of Arixtra® is 2.5 mg once daily by subcutaneous injection. The duration of treatment in such cases is 6 to 14 days.

Unstable angina/non-ST-segment elevation myocardial infarction.

The recommended dose of Arixtra® is 2.5 mg once daily by subcutaneous injection. Treatment should be initiated as soon as possible after diagnosis and continued for up to 8 days or until hospital discharge, whichever occurs earlier.

Patients undergoing percutaneous coronary intervention (PCI) during Arixtra® treatment should receive unfractionated heparin during the procedure, taking into account the potential risk of bleeding, including the time elapsed since the last dose of fondaparinux (see "Special precautions"). The timing for resuming subcutaneous Arixtra® after catheter removal should be based on the patient’s clinical condition. In a clinical trial on unstable angina/non-ST-segment elevation myocardial infarction, Arixtra® treatment was resumed no sooner than 2 hours after catheter removal.

ST-segment elevation myocardial infarction.

The recommended dose of Arixtra® is 2.5 mg once daily. The first dose of Arixtra® should be administered intravenously, and subsequent doses by subcutaneous injection. Treatment should be initiated as soon as possible after diagnosis and continued for up to 8 days or until hospital discharge, whichever occurs earlier.

Patients undergoing non-primary percutaneous coronary intervention during Arixtra® treatment should receive unfractionated heparin during the procedure, taking into account the potential risk of bleeding, including the time elapsed since the last dose of fondaparinux (see "Special precautions"). The timing for resuming subcutaneous Arixtra® after catheter removal should be based on the patient’s clinical condition. In a clinical trial on ST-segment elevation myocardial infarction, Arixtra® treatment was resumed no sooner than 3 hours after catheter removal.

Patients undergoing coronary artery bypass grafting (CABG).

In patients with ST-segment elevation myocardial infarction or unstable angina/non-ST-segment elevation myocardial infarction who are scheduled for coronary artery bypass grafting (CABG), fondaparinux should be avoided, if possible, for 24 hours before surgery. Treatment may be resumed 48 hours after surgery.

Special patient groups.

Children.

The safety and efficacy of Arixtra® in children have not been established.

Prevention of venous thromboembolism after surgery.

In surgical patients aged ≥75 years and/or with body weight <50 kg and/or with renal impairment (creatinine clearance 20–50 mL/min), strict adherence to the timing of the first fondaparinux injection is required.

The first dose of fondaparinux should not be administered earlier than 6 hours after surgical wound closure. Injection should not be performed before hemostasis is achieved (see section "Special precautions").

Elderly patients (aged 75 years and older).

Arixtra® should be used with caution in elderly patients, as renal function declines with age (see "Special precautions").

Patients with body weight less than 50 kg.

Prevention of venous thromboembolism and treatment of unstable angina/non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. Patients with body weight less than 50 kg have an increased risk of bleeding. The clearance of fondaparinux decreases with lower body weight. Fondaparinux should be used with caution in such patients (see "Special precautions").

Renal impairment.

Prevention of venous thromboembolism. Dose adjustment is not required in patients with mild renal impairment (creatinine clearance >50 mL/min).

In patients with creatinine clearance of 20–50 mL/min, the recommended dose upon physician’s prescription is 1.5 mg once daily (see "Special precautions" and "Pharmacological properties. Pharmacokinetics").

Arixtra® is not recommended for patients with creatinine clearance below 20 mL/min.

Unstable angina/non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. Arixtra® is contraindicated in patients with creatinine clearance below 20 mL/min (see "Contraindications"). Dose adjustment is not required for patients with creatinine clearance of 20 mL/min or higher.

Hepatic impairment.

Prevention of venous thromboembolism and treatment of unstable angina/non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. Dose adjustment is not required in patients with mild to moderate hepatic impairment. Arixtra® should be used with caution in patients with severe hepatic impairment, as this patient group has not been studied (see "Special precautions" and "Pharmacological properties. Pharmacokinetics").

Children.

The safety and efficacy of Arixtra® in children have not been established.

Overdose.

Exceeding the recommended doses of Arixtra® may increase the risk of bleeding. There is no known antidote for fondaparinux.

In case of overdose associated with hemorrhagic complications, treatment should be discontinued and the underlying cause of bleeding investigated. Consideration should be given to appropriate therapeutic measures such as surgical hemostasis, volume replacement, blood transfusion, fresh frozen plasma transfusion, or plasmapheresis.

Adverse Reactions

The most frequently reported serious adverse reactions associated with fondaparinux use are hemorrhagic complications (at various sites, including rare cases of intracranial/intracerebral and retroperitoneal bleeding) and anemia. Fondaparinux should be used with caution in patients with an increased risk of bleeding (see "Special Warnings and Precautions for Use").

The safety of fondaparinux at a dose of 2.5 mg has been evaluated in the following populations:

3595 patients following major orthopedic surgery of the lower limbs, who received the drug for up to 9 days;
327 patients following hip fracture surgery, treated for 3 weeks after an initial 1-week prophylaxis period;
1407 patients following abdominal surgery, treated for up to 9 days;
425 medically ill patients at risk of thromboembolic complications, treated for up to 14 days;
10057 patients treated for acute coronary syndrome presenting as unstable angina or non-ST-segment elevation myocardial infarction;
6036 patients treated for acute coronary syndrome presenting as ST-segment elevation myocardial infarction.

The adverse reactions listed below are categorized by organ systems and frequency of occurrence. Frequency is classified as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and very rare (< 1/10000). Adverse reactions are listed in decreasing order of severity; these adverse reactions should be interpreted in the context of the surgical and medical background of the patient.

*System Organ Class*	*Adverse reactions in patients after major orthopedic surgery of the lower limbs and/or abdominal surgery*	*Adverse reactions in medically ill patients*
Infections and infestations	Isolated: postoperative wound infections.
Blood and lymphatic system	Common: postoperative bleeding, anemia. Uncommon: bleeding (epistaxis, gastrointestinal bleeding, haemoptysis, haematuria, hematoma), thrombocytopenia, purpura, thrombocytosis, appearance of abnormal platelets, coagulation disorders.	Common: bleeding (hematoma, haematuria, haemoptysis, bleeding from gums). Uncommon: anemia.
Immune system	Isolated: allergic reactions (including isolated reports of angioneurotic edema, anaphylactoid/anaphylactic reaction).	Isolated: allergic reactions (including isolated reports of angioneurotic edema, anaphylactoid/anaphylactic reaction).
Metabolism and nutrition disorders	Isolated: hypokalemia.
Nervous system	Isolated: anxiety, somnolence, vertigo, dizziness, headache, confusion.
Cardiovascular system	Isolated: arterial hypotension.
Respiratory system and thoracic organs	Isolated: dyspnea, cough.	Uncommon: dyspnea.
Gastrointestinal tract	Uncommon: nausea, vomiting. Isolated: abdominal pain, dyspepsia, gastritis, constipation, diarrhea.
Hepatobiliary system	Uncommon: increased levels of liver enzymes, abnormalities in liver function tests. Isolated: increased serum bilirubin levels.
Skin and subcutaneous tissues	Uncommon: rash, pruritus.	Uncommon: rash, pruritus.
General disorders and administration site conditions	Uncommon: edema, peripheral edema, fever, wound discharge. Isolated: chest pain, increased fatigue, hyperemia, leg pain, genital edema, sensation of warmth, loss of consciousness.	Uncommon: chest pain.

In other studies or during post-marketing use, rare cases of intracranial/intracerebral and retroperitoneal bleeding have been reported.

The adverse reaction profile observed in the acute coronary syndrome treatment studies program is consistent with the adverse reactions identified when the drug is used for the prevention of venous thromboembolism.

Bleeding was a commonly reported event in patients with unstable angina/non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. The incidence of confirmed major bleeding was 2.1% (fondaparinux) and 4.1% (enoxaparin) during the period up to and including day 9 in the phase III study on unstable angina/non-ST-segment elevation myocardial infarction, and the incidence of confirmed severe bleeding according to modified TIMI criteria was 1.1% (fondaparinux) and 1.4% (control group [unfractionated heparin/placebo]) during the period up to and including day 9 in the phase III study on ST-segment elevation myocardial infarction.

In the phase III study on unstable angina/non-ST-segment elevation myocardial infarction, the most frequently reported non-hemorrhagic adverse reactions (reported in at least 1% of participants in the fondaparinux group) were headache, chest pain, and atrial fibrillation.

In the phase III study in patients with ST-segment elevation myocardial infarction, the most frequently reported non-hemorrhagic adverse reactions (reported in at least 1% of participants in the fondaparinux group) were atrial fibrillation, pyrexia, chest pain, headache, ventricular tachycardia, vomiting, and arterial hypotension.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store below 25°C. Keep out of the reach of children.

Incompatibilities.

ArixtraÒ must not be mixed with other medicinal products, as compatibility studies have not been conducted.

Packaging. 10 pre-filled syringes with automatic safety system in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aspen Notte Dame de Bonderville.

Manufacturer's address.

1, rue de l’Abbaye, 76960 Notte Dame de Bonderville, France.