Amrostak solopharm (Solution) Instructions for Use

Marketing Authorization Holder

Grotex, LLC (Russia)

ATC Code

B01AX05 (Fondaparinux sodium)

Active Substance

Fondaparinux sodium (Rec.INN registered by WHO)

Dosage Form

Amrostak solopharm

Solution for intravenous and subcutaneous administration 2.5 mg/0.5 ml: syringes or ampoules 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous and subcutaneous administration transparent, colorless or slightly yellowish.

Excipients: sodium chloride, 0.01M hydrochloric acid or 0.005M sodium hydroxide solution, water for injections.

0.5 ml – glass syringes* (2) – contour cell packs (5) – cardboard boxes.
0.5 ml – colorless glass ampoules (5) – contour cell packs (2) – cardboard boxes.
0.5 ml – colorless glass ampoules (10) – contour cell packs (1) – cardboard boxes.

* equipped with safety devices or protective needle labels, or without safety devices or protective needle labels.

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Antithrombotic agent

Pharmacological Action

Synthetic selective inhibitor of activated factor X (Xa). Antithrombotic activity is the result of selective inhibition of factor Xa, mediated by antithrombin III. By selectively binding to antithrombin III, Fondaparinux sodium potentiates (approximately 300 times) the initial neutralization of factor Xa by antithrombin III (ATIII). Neutralization of factor Xa interrupts the coagulation cascade and inhibits both thrombin formation and thrombus formation.

Fondaparinux sodium does not inactivate thrombin (activated factor IIa) and does not affect platelets.

When used at a dose of 2.5 mg, it does not affect the results of conventional coagulation tests such as aPTT, activated clotting time (ACT) or prothrombin time (INR) in blood plasma, nor bleeding time or fibrinolytic activity.

Fondaparinux does not cause cross-reactions with serum from patients with heparin-induced thrombocytopenia.

Pharmacokinetics

After subcutaneous administration, Fondaparinux sodium is completely and rapidly absorbed from the injection site (absolute bioavailability 100%). After a single subcutaneous administration of the drug at a dose of 2.5 mg to young healthy volunteers, C_max in blood plasma was reached 2 hours after administration and was 0.34 mg/l. Plasma concentrations equal to half of the above C_max were reached 25 minutes after administration.

The V_d of fondaparinux sodium is limited (7-11 L). In vitro, Fondaparinux sodium is highly and specifically bound to the ATIII protein, with the degree of binding depending on the plasma concentration of the substance (98.6-97.0% in the concentration range of 0.5-2 mg/l). The binding of fondaparinux sodium to other plasma proteins (including platelet factor IV) is insignificant.

Since the binding of Fondaparinux sodium to plasma proteins, with the exception of ATIII, is insignificant, no interaction with other drugs due to displacement from protein binding sites is expected.

No data indicating metabolism of fondaparinux sodium were found.

Fondaparinux sodium does not inhibit the CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 isoenzymes in vitro.

T_1/2 is about 17 hours in young healthy individuals and about 21 hours in elderly healthy individuals. 64-77% of Fondaparinux sodium is excreted by the kidneys unchanged.

In patients over 75 years of age, the plasma clearance of fondaparinux sodium was 1.2-1.4 times lower than in persons under 65 years of age. In healthy elderly individuals, the pharmacokinetics of fondaparinux sodium is linear in the dose range of 2-8 mg subcutaneously. When administered once daily, steady-state C_ss in plasma is achieved after 3-4 days with a 1.3-fold increase in C_max and AUC values.

Compared with patients with normal renal function (CrCl>80 ml/min), the plasma clearance of Fondaparinux sodium is 1.2-1.4 times lower in patients with mild renal impairment (CrCl 50-80 ml/min) and on average 2 times lower in patients with moderate renal impairment (CrCl 30-50 ml/min). In severe renal failure (CrCl<30 ml/min), the plasma clearance of Fondaparinux sodium is approximately 5 times lower than with normal renal function. T_1/2 was 29 hours with moderate and 72 hours with severe renal impairment.

The clearance of Fondaparinux sodium from plasma increases with increasing body weight (9% increase per 10 kg).

Indications

Prevention of venous thromboembolic complications in patients undergoing major orthopedic surgery on the lower extremities (including surgical interventions for hip fracture, large-volume replacement surgery on the knee or hip).

Prevention of venous thromboembolic complications in patients undergoing abdominal surgery, in the presence of risk factors for thromboembolic complications.

Prevention of venous thromboembolic complications in non-surgical patients in the presence of risk factors for such complications due to limited mobility during the acute period of the disease.

Treatment of acute coronary syndrome, expressed as: unstable angina or myocardial infarction without ST-segment elevation, to prevent myocardial infarction or refractory ischemia; myocardial infarction with ST-segment elevation to prevent death, recurrent myocardial infarction in patients receiving thrombolytic therapy or patients not initially receiving reperfusion therapy.

Treatment of acute symptomatic superficial vein thrombosis of the lower extremities without concomitant deep vein thrombosis.

ICD codes

Dosage Regimen

Administer subcutaneously or intravenously.

For prevention of venous thromboembolism in major orthopedic or abdominal surgery: administer 2.5 mg subcutaneously once daily.

Initiate the first dose 6-8 hours post-operatively after ensuring hemostasis.

The usual treatment duration is 5-9 days; continue until the risk of thromboembolism subsides.

For treatment of acute coronary syndrome: administer 2.5 mg subcutaneously once daily.

Initiate treatment in conjunction with other indicated therapies; the usual duration is up to 8 days or until hospital discharge.

For treatment of superficial vein thrombosis: administer 2.5 mg subcutaneously once daily for 45 days.

Do not administer intramuscularly.

For subcutaneous administration, inject into the anterolateral or posterolateral abdominal wall; alternate injection sites.

Do not expel the air bubble from the syringe before injection to ensure complete delivery of the dose.

Contraindicated in patients with severe renal impairment (CrCl <30 ml/min).

Use with caution in patients with body weight <50 kg and moderate renal impairment (CrCl 30-50 ml/min) due to increased bleeding risk.

Monitor platelet count before initiation and during therapy.

Adverse Reactions

From the blood coagulation system bleeding.

From the body as a whole fatigue, weakness, fever, decreased blood pressure, dizziness, headache.

From the digestive system nausea, constipation, diarrhea, dyspepsia, abdominal pain.

From laboratory parameters decreased platelet count, increased activity of liver enzymes.

Local reactions mild skin irritation, pain, ecchymosis/hematoma and hyperemia.

Other serous discharge from the postoperative wound, edema, skin rash or itching, allergic reactions.

These side effects may also be a consequence of the surgery.

Contraindications

Active, clinically significant bleeding; acute bacterial endocarditis; severe renal failure (CrCl<30 ml/min); conditions associated with a risk of bleeding (blood coagulation disorders, including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease); gastric and duodenal ulcer in the acute phase; cerebral hemorrhage; cerebral aneurysm; uncontrolled arterial hypertension (increases the risk of cerebral hemorrhage); dissecting aortic aneurysm; diabetic retinopathy; repeated neurological or ophthalmological surgeries; spinal anesthesia (potential risk of hematoma); threatened abortion; severe liver dysfunction; body weight less than 50 kg; concomitant use with drugs such as fibrinolytics, heparin, heparinoids, glycoprotein IIb/IIIa receptor antagonists, antiplatelet agents, NSAIDs; age under 18 years; hypersensitivity to the active substance.

Use in Pregnancy and Lactation

Should not be used during pregnancy except in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

If use during lactation is necessary, breastfeeding should be discontinued. It is not known whether Fondaparinux sodium is excreted in human breast milk.

In experimental studies, it was shown that Fondaparinux sodium is excreted in the milk of lactating rats.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use with caution in severe liver dysfunction, because due to deficiency of coagulation factors, the risk of bleeding increases.

Use in Renal Impairment

Contraindicated in severe renal failure (CrCl<30 ml/min).

The risk of bleeding is increased in patients with renal impairment with CrCl<50 ml/min. Use with caution in this category of patients.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly individuals have an increased risk of bleeding. Since renal function usually decreases with age, the elimination of Fondaparinux sodium may be reduced in elderly patients, and thus the exposure to the active substance increases. Use with caution in this category of patients.

Special Precautions

Use with caution in patients with an increased risk of bleeding (for example, platelet count less than 50,000/µl), with severe renal failure and after recently suffered intracranial hemorrhages or surgical interventions on the brain or spinal cord, after ophthalmological surgeries; in children and adolescents under 17 years of age.

If prophylactic use of heparin or low molecular weight heparins is required after therapy with fondaparinux sodium, the first injection of heparins should be administered one day after the last administration of fondaparinux sodium.

If maintenance therapy with vitamin K antagonists is necessary, simultaneous administration of Fondaparinux sodium should be continued until the target INR value is achieved.

When using fondaparinux sodium simultaneously with epidural anesthesia or spinal puncture, the possibility of epidural or spinal hematomas, which can lead to paralysis, cannot be excluded. The risk of this rare complication may be increased with postoperative use of indwelling epidural catheters or simultaneous administration of other drugs affecting hemostasis.

Elderly individuals have an increased risk of bleeding. Since renal function usually decreases with age, the elimination of Fondaparinux sodium may be reduced in elderly patients, and thus the exposure to the active substance increases. Use with caution in this category of patients.

Patients with a body weight of less than 50 kg are more susceptible to the risk of bleeding, because the elimination of Fondaparinux sodium in these individuals is reduced. Use with caution in this category of patients.

The risk of bleeding is increased in patients with renal impairment with CrCl<50 ml/min. Use with caution in this category of patients.

Use with caution in severe liver dysfunction, because due to deficiency of coagulation factors, the risk of bleeding increases.

It is recommended to monitor platelet count before starting use and at the end of therapy. This is especially important in cases where maintenance treatment with heparin or low molecular weight heparins is planned.

Drug Interactions

Should not be used simultaneously with drugs that increase the risk of bleeding (desirudin, fibrinolytics, glycoprotein IIb/IIIa receptor antagonists, heparin, heparinoids or low molecular weight heparins). The danger of bleeding increases with simultaneous use with substances that may increase the risk of bleeding (acetylsalicylic acid, other NSAIDs, dipyridamole, sulfinpyrazone, ticlopidine, clopidogrel).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.