Fondaparinux sodium

Pharmacological properties

fondaparinux is a synthetic selective inhibitor of activated factor x (ha). the antithrombotic activity of fondaparinux is the result of selective inhibition of factor xa mediated by antithrombin iii (at iii). by selectively binding to at iii, fondaparinux potentiates (approximately 300 times) the initial neutralization of factor xa with antithrombin iii. the neutralization of factor xa interrupts the coagulation chain and inhibits both the formation of thrombin and the formation of blood clots. fondaparinux does not inactivate thrombin (activated factor iia) and has no effect on platelets.

At recommended doses, fondaparinux does not affect the results of conventional coagulation tests, such as activated partial thromboplastin time (APTT), activated clotting time or prothrombin time / international normalized ratio (INR) in blood plasma, bleeding time and fibrinolytic activity. However, isolated reports have been received about an increase in APTT when using the drug at a dose of 2.5 mg.

Fondaparinux does not cross-react with the blood plasma of patients with heparin-induced thrombocytopenia.

Pharmacokinetics Suction. After sc administration, fondaparinux is rapidly absorbed (absolute bioavailability - 100%). With a single sc administration at a dose of 2.5 mg of fondaparinux to healthy young volunteers_max in blood plasma (average 0.34 mg / l) was achieved 2 hours after drug administration. A plasma concentration of half C_maxachieved 25 minutes after administration.

In healthy elderly people, the pharmacokinetics of fondaparinux is linear in the dose range of 2–8 mg sc. With the introduction of 1 time per day, a stable equilibrium concentration in the blood plasma is reached after 3-4 days with an increase of 1.3 times C_max and AUC. The average (CV%) pharmacokinetic parameters of fondaparinux in equilibrium in patients undergoing hip surgery and receiving fondaparinux at a dose of 2.5 mg / day were: C_max in blood plasma - 0.39 mg / l (31%), the time of its achievement - 2.8 hours (18%), the minimum concentration - 0.14 mg / l (56%). In elderly patients who underwent surgery for a fracture of the femur, the equilibrium concentrations of fondaparinux were:_max - 0.50 mg / l (32%), the minimum - 0.19 mg / l (58%).

In the treatment of acute deep vein thrombosis and pulmonary thromboembolism in patients receiving Aricstra at a dose of 5 mg (body weight 50 kg), 7.5 mg (body weight 50-100 kg inclusive) and 10 mg (body weight 100 kg) 1 time per day, the average pharmacotherapeutic parameters were similar.

Distribution. In healthy volunteers, after subcutaneous and iv administration, fondaparinux is distributed in such a way that most of it is in the blood and only a small amount is in the extravascular fluid. The volume of distribution of fondaparinux is 7–11 liters. In vitro, fondaparinux is highly (at least 94%) and specifically binds to the AT III protein. The binding of fondaparinux with other plasma proteins, including platelet factor IV and red blood cells, is negligible.

Metabolism. In vivo, fondaparinux metabolism has not been studied, since in patients with normal renal function, most of the administered dose is excreted unchanged in the urine.

Fondaparinux is excreted mainly by the kidneys unchanged, in healthy individuals 64–77% of a single dose is excreted in the urine for 72 hours. T_½ it is about 17 hours in young healthy people and about 21 hours in healthy elderly people.

Special patient groups

Impaired renal function. Compared with patients with normal renal function (creatinine clearance (CC) 80 ml / min), clearance is 1.2–1.4 times lower in patients with mild renal impairment (CC 50–80 ml / min) and on average 2 times lower in patients with moderate impaired renal function (CC 30–50 ml / min).In severe renal impairment (CC 30 ml / min), clearance is approximately 5 times lower than in the case of normal renal function. Corresponding final T_½ amounted to 29 hours with moderate renal failure and 72 hours - severe. A similar relationship between the clearance of fondaparinux and the severity of renal failure was observed in the treatment of patients with deep vein thrombosis and pulmonary embolism.

Impaired liver function. In accordance with the pharmacokinetics of the drug, the concentration of unbound fondaparinux is expected to remain unchanged in patients with mild to moderate hepatic insufficiency, and therefore there is no need for dose adjustment. After a single sc administration of fondaparinux to patients with moderate hepatic impairment (class B on the Child-Pugh scale) C_max and AUC of fondaparinux decreased by 22 and 39%, respectively, compared with patients without impaired renal function. A lower concentration of fondaparinux in plasma is explained by a decrease in the degree of binding to AT III, since in patients with liver failure the concentration of AT III in blood plasma is lower. Thus, the result of this is an increase in renal clearance of fondaparinux.

In patients with severe hepatic insufficiency, the pharmacokinetics of fondaparinux has not been studied (see APPLICATION and SPECIAL INSTRUCTIONS).

Children. The use of fondaparinux in children has not been studied.

Elderly patients. Renal function may decline with age, therefore, excretion of fondaparinux in patients over the age of 75 years may deteriorate. After orthopedic surgery in the study, when using the drug at a dose of 2.5 mg once a day, the total clearance of fondaparinux was 1.2–1.4 times lower in patients over 75 years of age compared with patients under 65 years of age. A similar relationship between the clearance of fondaparinux and age has been identified in the treatment of patients with deep vein thrombosis and pulmonary embolism.

Floor. When adjusting the dose according to body weight, there were no discrepancies in the pharmacokinetics of sick men and women.

Race. Routine studies of pharmacokinetic differences were not performed. However, the results of studies involving healthy representatives of the Mongoloid race did not show differences in the pharmacokinetic profile compared with healthy representatives of the Caucasian race. There were no discrepancies in the clearance of the drug from the blood plasma of patients of the Negroid and Caucasoid race who underwent orthopedic surgery.

Body mass. The clearance of fondaparinux from blood plasma increases with increasing body weight (9% for every 10 kg of body weight).

Indications

Injection 2.5 mg

Prevention of venous thromboembolic complications in patients after extensive orthopedic surgery on the lower extremities, such as hip fracture surgery (including prolonged prophylaxis), knee or hip arthroplasty.

Prevention of venous thromboembolic complications in patients after abdominal surgery with a high risk of thromboembolic complications, for example, in patients after abdominal surgery due to cancer.

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

Treatment of unstable angina pectoris or myocardial infarction without ST segment elevation in patients who are not shown emergency (120 min) invasive intervention (percutaneous coronary intervention - PCI) (see SPECIAL INSTRUCTIONS).

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

RR for injection 7.5 mg

Treatment of acute deep vein thrombosis, treatment of acute pulmonary thromboembolism, except hemodynamically unstable patients or patients who need thrombolysis or pulmonary embolectomy.

Application

Arikstra is intended for sc or intravenous injection. do not use v / m.

Arikstra is administered by deep s / c injection, the patient should be in a prone position. The injection site should be changed - the left and right anterolateral or the left and right posterolateral walls of the abdomen. To avoid drug loss, do not remove the air bubble from the pre-filled syringe before injection. The needle should be inserted full length perpendicularly into the fold of skin sandwiched between the thumb and forefinger; during the entire introduction, the fold of the skin must be kept clamped. Arikstra is used only under medical supervision. S / c injection is administered in the same way as in the case of the use of a classic syringe.

Before using the injection solution, it is necessary to visually inspect for the absence of suspended particles and discoloration.

IV injection (only the first dose in the treatment of patients with myocardial infarction with ST segment elevation). It is administered iv through the existing iv system directly without dilution or with dilution in a small volume (25 or 50 ml) of 0.9% sodium chloride. To avoid drug losses, do not remove the air bubble from the pre-filled syringe before injection. After injection, the system or catheter should be thoroughly flushed with 0.9% sodium chloride r-rum to ensure that the drug has been fully administered. When diluting Arikstra with 0.9% sodium chloride solution, administration should be carried out within 1-2 minutes.

Before use, the injection solution must be visually checked for the absence of suspended particles and color changes.

Arixtra pre-filled syringes were developed using an automatic needle protection system to prevent damage after injection.

Any unused product or material must be disposed of in accordance with legal regulations.

Step-by-step instructions for using the drug Arikstra

1. Wash hands thoroughly with soap and water and dry them with a towel.

2. Remove the syringe from its packaging and make sure that:

• the expiration date has not expired,
• the solution is transparent and colorless, and also does not contain particles,
• the syringe was not open or damaged.

3. Take a comfortable sitting or lying position.

Select a location in the lower abdominal region (abdomen) at least 5 cm below the navel.

Use the left and right side of the lower abdomen alternately with each injection. This will help reduce the severity of the discomfort at the injection site.

If an injection into the lower abdominal region is not possible, consult a nurse or doctor.

4. Clean the injection site with an alcohol wipe.

5. Remove the needle cap by first turning it and then pulling it in a straight line from the syringe body.

Dispose of the needle cap.

Important Note. Do not touch the needle and do not allow the needle to touch any surface before injection.

It is considered normal if small air bubbles are detected in this syringe. You should not try to remove these air bubbles before the injection - some of the drug may be lost.

6. Gently squeeze cleansed skin to form a crease. Hold the crease between the thumb and forefinger throughout the injection.

7. Hold the syringe with your fingertips.

Insert the full-length needle at a right angle into the skin fold.

8. Enter the entire contents of the syringe by pushing the piston all the way.

9.Release the piston and the needle will automatically come out of the skin and return to the protective cap, where it will be closed forever.

Do not dispose of the used syringe in household waste. Dispose of it according to the instructions.

Prevention of venous thromboembolism

Extensive orthopedic and abdominal surgery. The recommended dose of Arikstra for adults is 2.5 mg 1 time per day after surgery as a sc injection.

The initial dose should be administered no earlier than 6 hours after completion of the operation, provided hemostasis is achieved.

Treatment should be carried out to reduce the risk of developing thromboembolism, usually before transferring the patient to outpatient treatment, at least 5–9 days after surgery. Experience shows that in patients who underwent surgery for a hip fracture, there is a risk of deep vein thrombosis for more than 9 days. Such patients are recommended additional prophylactic use of Arikstra for up to 24 days.

Patients at risk of thromboembolic complications due to prolonged restriction of mobility. The recommended dose of Arikstra is 2.5 mg 1 time per day as a sc injection. The duration of treatment in this case is 6-14 days.

Unstable angina pectoris / myocardial infarction without ST segment elevation. The recommended dose of Arikstra is 2.5 mg 1 time per day as a sc injection. Treatment should begin as soon as possible after diagnosis and continue for up to 8 days.

Patients who are shown percutaneous coronary intervention during the treatment with Arikstroi should use unfractionated heparin during such an intervention, taking into account the potential risk of bleeding in the patient, including the time after the last dose of fondaparinux (see SPECIAL INSTRUCTIONS). The resumption time p / to the use of Arikstra after removal of the catheter is determined based on the clinical condition of the patient. In a clinical study of relatively unstable angina pectoris / myocardial infarction without ST segment elevation, the resumption of treatment with Arikstroy began no earlier than 2 hours after removal of the catheter.

Myocardial infarction with ST segment elevation. The recommended dose of Arikstra is 2.5 mg 1 time per day. The first dose of Arikstra is administered iv, the subsequent doses are administered by sc injection. Treatment should be started as soon as possible after diagnosis and continued until 8 days or until discharge.

Patients who need a non-primary percutaneous coronary intervention during treatment with Arikstroi should use unfractionated heparin during such an intervention, given the potential risk of bleeding in the patient, including the time after the last dose of fondaparinux (see SPECIAL INSTRUCTIONS). The resumption time of s / c use of Arikstra after removal of the catheter should be determined based on the clinical condition of the patient. In a clinical study of relatively unstable angina pectoris / myocardial infarction with ST segment elevation, the resumption of treatment with Arikstroy began no earlier than 3 hours after removal of the catheter.

Patients who are prescribed coronary bypass surgery. Patients with myocardial infarction with ST-segment elevation or with unstable angina pectoris / myocardial infarction without ST-segment elevation who are prescribed coronary bypass surgery should not use fondaparinux if possible within 24 hours before surgery, and its administration can be resumed 48 hours after surgery.

Treatment of acute deep vein thrombosis and acute pulmonary thromboembolism. The recommended dose of Arikstra for sc administration:

• 5 mg - for patients with a body weight of 50 kg;
• 7.5 mg - for patients weighing 50-100 kg;
• 10 mg - for patients with a body weight of 100 kg.

The injection is administered 1 time per day, the duration of treatment should be at least 5 days, and it can be stopped no earlier than the opportunity arises to conduct adequate therapy with oral anticoagulants (INR value 2-3). Concomitant therapy with oral anticoagulants should be started as early as possible, usually within 72 hours. The average duration of use of the drug in clinical trials was 7 days, clinical experience with the drug for more than 10 days is limited.

Special groups of patients

Children. Safety and efficacy of Arikstra in children have not been established.

Prevention of venous thromboembolic complications after surgery. In case of surgery, the time of the first injection of fondaparinux should be strictly observed in patients aged ≥75 years and / or body weight of 50 kg, and / or with impaired renal function with a CC of 20-50 ml / min.

The first dose of fondaparinux should be administered no earlier than 6 hours after the closure of the surgical wound. Injection should not be performed until hemostasis has been established (see SPECIAL INSTRUCTIONS).

Elderly patients (75 years). Arikstra should be used with caution in elderly patients, since kidney function decreases with age (see SPECIAL INSTRUCTIONS)

Patients weighing 50 kg

Prevention of venous thromboembolic complications and treatment of unstable angina pectoris / myocardial infarction without ST segment elevation and myocardial infarction with ST segment elevation. Patients weighing 50 kg have an increased risk of bleeding. Excretion of fondaparinux decreases with a decrease in body weight. In such patients, fondaparinux should be used with caution (see SPECIAL INSTRUCTIONS).

Renal failure

Prevention of venous thromboembolism. Patients with mild renal impairment (CC ≥ 50 ml / min) do not require dose adjustment.

According to the doctors prescription, patients with QC of 20-50 ml / min are recommended to use the drug at a dose of 1.5 mg / day (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES, Pharmacokinetics).

Patients with CC 20 ml / min Arikstra is not recommended.

Unstable angina pectoris / myocardial infarction without ST segment elevation and myocardial infarction with ST segment elevation. Arikstra should not be used to treat patients with CC of 20 ml / min (see CONTRAINDICATIONS). Dose adjustment in patients with CC ≥20 ml / min is not required.

Impaired liver function. Prevention of venous thromboembolic complications and treatment of unstable angina pectoris / myocardial infarction without ST segment elevation and myocardial infarction with ST segment elevation. Dose adjustment is not required for patients with mild to moderate hepatic insufficiency. In patients with severe hepatic insufficiency, Arikstra should be used with caution, since this group of patients has not been investigated (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES, Pharmacokinetics).

Children. Safety and efficacy of Arikstra in children have not been established.

Contraindications

An established allergy to the active substance or components of the drug; active clinically significant bleeding; acute bacterial endocarditis; severe renal failure (CC 20 ml / min).

Side effects

The most commonly reported serious adverse reactions with fondaparinux are hemorrhagic complications (in various areas, 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 instructions).

The safety of fondaparinux at a dose of 2.5 mg was studied in such populations:

• 3595 patients after extensive orthopedic surgery on the lower extremities in whom the drug was used for a period of up to 9 days;
• 327 patients after surgery for a hip fracture who were treated for 3 weeks after initial prophylaxis for 1 week;
• 1407 patients after surgery in the abdominal cavity who were treated for a period of up to 9 days;
• 425 therapeutic patients at risk of developing thromboembolic complications who were treated for up to 14 days;
• 10 057 patients treated in connection with acute coronary syndrome, manifested by unstable angina pectoris or myocardial infarction without ST segment elevation;
• 6036 patients treated for acute coronary syndrome, manifested myocardial infarction with ST segment elevation.

The following adverse reactions are presented by organs and systems and frequency of occurrence. The frequency of occurrence is classified as very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000); adverse reactions are indicated in decreasing order of severity; these adverse reactions should be interpreted taking into account the surgical and medical context.

In other studies or during