Antithrombin III human (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Takeda Manufacturing Austria AG (Austria)

Manufactured By

Takeda Manufacturing Austria AG (Austria)

Solvent Manufacturer

SIEGFRIED HAMELN, GmbH (Germany)

ATC Code

B01AB02 (Antithrombin III)

Active Substance

Antithrombin III

Antithrombin III (Rec.INN registered by WHO)

Dosage Forms

	Antithrombin III human	Lyophilisate for preparation of solution for infusion 500 IU: vial 1 pc. in a set with solvent and a set for dissolution and administration
		Lyophilisate for preparation of solution for infusion 1000 IU: vial 1 pc. in a set with solvent and a set for dissolution and administration

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a loose solid mass or powder of pale yellow or pale green color. Solvent (water for injections): transparent colorless liquid. Reconstituted solution: a clear or slightly opalescent yellow solution, practically free of visible particles.

Excipients: dextrose monohydrate – 100 mg, sodium chloride – 90 mg, trisodium citrate dihydrate – 10 mg, tris(hydroxymethyl)aminomethane – 10 mg.

Solvent water for injections – 10 ml.

500 IU – glass vials (1) in a set with solvent (vial 10 ml 1 pc.) and a set for dissolution and administration (filter needle (5 µm), transfer needle, vent needle, disposable needle, butterfly needle) – cardboard boxes.

* 1 IU of antithrombin III (according to WHO standards) corresponds to the activity of antithrombin III in 1 ml of fresh normal human plasma.
The activity of antithrombin III (IU) is determined relative to the WHO international standard for antithrombin III concentrates.

Lyophilisate for preparation of solution for infusion as a loose solid mass or powder of pale yellow or pale green color. Solvent (water for injections): transparent colorless liquid. Reconstituted solution: a clear or slightly opalescent yellow solution, practically free of visible particles.

Excipients: dextrose monohydrate – 200 mg, sodium chloride – 180 mg, trisodium citrate dihydrate – 20 mg, tris(hydroxymethyl)aminomethane – 20 mg.

Solvent water for injections – 20 ml.

1000 IU – glass vials (1) in a set with solvent (vial 20 ml 1 pc.) and a set for dissolution and administration (filter needle (5 µm), transfer needle, vent needle, disposable needle, butterfly needle) – cardboard boxes.

* 1 IU of antithrombin III (according to WHO standards) corresponds to the activity of antithrombin III in 1 ml of fresh normal human plasma.
The activity of antithrombin III (IU) is determined relative to the WHO international standard for antithrombin III concentrates.

Clinical-Pharmacological Group

Anticoagulant. Antithrombin III preparation

Pharmacotherapeutic Group

Direct-acting anticoagulant agent

Pharmacological Action

Direct-acting anticoagulant. Antithrombin III (antithrombin), which is a glycoprotein with a molecular weight of 58 kDa and containing 432 amino acid residues, belongs to the serpin superfamily (serine protease inhibitors). It is one of the most important natural inhibitors of blood coagulation. It most strongly inhibits factors such as thrombin and factor Xa, as well as factors of the contact activation of the intrinsic coagulation system and the factor VIIa/tissue factor complex. The activity of antithrombin is significantly enhanced in the presence of heparin, and the anticoagulant effect of heparin depends on the presence of antithrombin.

Antithrombin contains two functionally important domains. The first domain contains the active center and the cleavage site for proteases, such as thrombin, which is a necessary condition for the formation of a stable protease-inhibitor complex. The second is the glycosaminoglycan-binding domain, responsible for interaction with heparin and related compounds, which accelerates the inhibition of thrombin. The complexes of inhibitors and coagulation factors are removed via the reticuloendothelial system.

The activity of antithrombin in adults normally varies in the range of 80-120%, in newborns these levels are about 40-60%.

Pharmacokinetics

According to pharmacokinetic studies, the mean T_1/2 of antithrombin is approximately 3 days. With concomitant heparin therapy, the T_1/2 of antithrombin may decrease to approximately 1.5 days.

Indications

Congenital or acquired antithrombin deficiency within a wide variety of clinical disorders (acquired antithrombin deficiency may be a consequence of either increased consumption or loss of protein, or impaired synthesis of antithrombin).

The use of Antithrombin III human is indicated in patients with plasma antithrombin activity of less than 70% of normal for the prevention of thrombotic and thromboembolic complications. The administration of antithrombin may be particularly valuable in the following cases:

• Surgical procedures in patients with congenital antithrombin III deficiency;
• Pregnancy and childbirth in patients with congenital antithrombin III deficiency;
• Insufficient response to heparin or its absence;
• Presence or risk of developing disseminated intravascular coagulation (for example, in combined trauma, septic complications, shock, preeclampsia and other disorders associated with acute consumption coagulopathy);
• Presence or risk of thrombosis in patients with nephrotic syndrome or inflammatory bladder diseases;
• Surgical intervention or bleeding in patients with severe liver failure, especially in patients receiving treatment with coagulation factor concentrates.

ICD codes

Dosage Regimen

Treatment should be initiated under the supervision of a physician experienced in the treatment of patients with antithrombin deficiency.

In congenital deficiency, the dose should be selected individually for each patient, taking into account family history regarding thromboembolic conditions, existing clinical risk factors and laboratory results.

In cases of acquired deficiency, the doses and duration of replacement therapy depend on the plasma antithrombin level, the presence of signs of increased antithrombin metabolism, as well as the underlying disease and the severity of the clinical condition. The dose and frequency of administration are always established based on clinical efficacy and laboratory results in each specific case.

The number of units of antithrombin administered is expressed in IU, which are calculated relative to the current WHO standard for antithrombin. The activity of antithrombin in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to the international standard for antithrombin in plasma).

1 IU of antithrombin activity is equivalent to the activity of antithrombin in 1 ml of normal human plasma. The calculation of the required dose of antithrombin is based on empirical data that 1 IU of antithrombin per 1 kg of body weight increases plasma antithrombin activity by approximately 2%.

Initial dose is calculated using the following formula:

Required dose (IU) = body weight (kg) × (target level – baseline activity level [%]) × 0.5

The initial target antithrombin activity depends on the clinical situation. If replacement therapy is indicated, the dose should be sufficient to achieve the target antithrombin activity, as well as to maintain an effective level. The dose should be determined and monitored based on laboratory measurements of antithrombin activity, which should be performed at least 2 times a day, preferably immediately before the next administration. The dose should be adjusted in the presence of laboratory and clinical signs of increased antithrombin metabolism. Antithrombin activity should be maintained above 80% throughout the course of treatment, unless clinical features indicate the need to maintain a different effective level.

Usually, the initial dose for congenital deficiency is 30-50 IU/kg. Subsequently, the dose and interval between administrations, as well as the duration of treatment, should be adapted to the biochemical data and clinical situation.

The use of antithrombin III in children under 6 years of age has not been sufficiently studied.

Rules for preparation and administration of the solution

The drug is administered intravenously. The maximum rate of administration is 5 ml/min.

Reconstitute the contents of the vial with Antithrombin III human immediately before administration. For this purpose, only the supplied set for dissolution and administration should be used. The resulting solution must be used immediately after reconstitution, as the drug does not contain preservatives. Before administration, the solution should be visually inspected for the presence of foreign particles or color change. Do not use cloudy solutions or solutions with sediment. Unused solution must be disposed of in accordance with established rules.

Preparation of the solution

1. Warm the closed solvent vial to room temperature (not higher than 37°C (98.6°F)).
2. Remove the protective caps from the vials with the lyophilisate and the solvent and disinfect the rubber stoppers on both vials.
3. Twist and then remove the protective cap from one end of the supplied transfer needle. Pierce the stopper of the solvent vial with the free end of the needle.
4. Remove the protective cap from the other end of the transfer needle, without touching the needle itself.
5. Turn the solvent vial over and pierce the stopper of the lyophilisate vial with the free end of the needle. The solvent will flow into the lyophilisate vial under vacuum.
6. Separate the vials by removing the needle from the drug vial. Gentle swirling or rotating the vial will speed up the dissolution of the powder.
7. After complete dissolution of the drug, to settle the foam, pierce the stopper of the drug vial. Then remove the vent needle.

Administration of the resulting solution

1. Twist and then remove the protective cap from the supplied filter needle and attach the needle to a sterile disposable syringe. Draw the solution into the syringe.
2. Disconnect the filter needle from the syringe and slowly (maximum administration rate 5 ml/min) administer the solution intravenously, using the supplied disposable needle (butterfly needle).

Adverse Reactions

The following side effects are based on post-marketing experience for this type of drug. These adverse reactions were not observed during clinical trials. Definition of frequency of adverse effects: very common (≥1/10), common (<1/10-≥1/100), uncommon (<1/100-≥1/1000), rare (<1/1000-≥1/10,000), very rare (<1/10,000).

The following undesirable side effects reflect the types of reactions that may occur with the use of antithrombin. Their frequency is <1/10,000 (very rare).

Cardiovascular system tachycardia, decreased blood pressure, flushing of the skin.

Digestive system nausea, vomiting.

Immune system hypersensitivity or allergic reactions, (severe) anaphylaxis (including shock), angioedema, (generalized) urticaria, rash.

Nervous system headache, anxiety, tingling sensation in the body.

Respiratory system wheezing.

Laboratory and instrumental data platelet count less than 100,000/µl or a decrease in platelet count by 50 %.

General reactions: chills, drowsiness, chest tightness, fever, heparin-induced thrombocytopenia with antibodies (type II).

Local reactions burning and tingling sensation at the injection site.

Hypersensitivity or allergic reactions (which may include angioedema, burning or tingling at the injection site, chills, flushing of the skin, generalized urticaria, headache, rash, decreased blood pressure, drowsiness, nausea, anxiety, tachycardia, chest tightness, tingling sensation in the body, vomiting, wheezing) were observed infrequently, in some cases they may progress to severe anaphylaxis (including shock). In rare cases, fever was observed.

Heparin-induced thrombocytopenia with antibodies (type II) may occur in rare cases. A platelet count of less than 100,000/µl or a decrease in platelet count by 50 % may be observed.

Contraindications

• History of heparin-induced thrombocytopenia;
• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

Data on the safety of the use of human antithrombin preparations during pregnancy are limited.

The safety of Antithrombin III human in pregnant or breastfeeding women has not been established in controlled clinical trials.

Antithrombin III human should be administered to pregnant or breastfeeding women only if there are strict indications, considering that pregnancy carries an increased risk of thromboembolic events.

Pediatric Use

The use of antithrombin III in children under 6 years of age has not been sufficiently studied.

Special Precautions

As with any protein preparations for intravenous administration, the development of hypersensitivity reactions of an allergic type is possible. Careful monitoring for the development of any symptoms in patients throughout the entire infusion period is necessary. Patients should be informed about the early signs of hypersensitivity reactions, including rash, generalized urticaria, chest tightness, wheezing, decreased blood pressure, and anaphylaxis. If these symptoms occur after administration of the drug, patients should consult their doctor.

In case of shock, anti-shock therapy should be carried out in accordance with current medical standards.

Standard measures to prevent infections associated with the use of medicinal products manufactured from human blood or plasma include the selection of donors, screening of individual donations of donor plasma and plasma pools for specific markers of infections, and the inclusion of effective manufacturing steps for virus inactivation/removal. Despite this, when using medicinal products made from human blood or plasma, the possibility of transmission of infectious agents cannot be completely ruled out. This also applies to unknown or new viruses and other pathogens.

The measures taken are considered effective against enveloped viruses such as HIV, hepatitis B virus and hepatitis C virus. The measures taken may be insufficient against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection can be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., hemolytic anemia).

Patients who regularly or repeatedly receive antithrombin preparations derived from human plasma are recommended to be vaccinated against hepatitis A and B.

It is strongly recommended that each time Antithrombin III human is used, the name and batch number of the drug administered to each specific patient should be recorded.

Clinical monitoring and control of biochemical parameters during concomitant use of antithrombin and heparin

• To adjust the heparin dose and to avoid excessive reduction in coagulability, it is necessary to regularly, at frequent intervals, monitor the degree of anticoagulation (APTT and, if necessary, anti-FXa activity), especially in the first minutes and hours after the start of antithrombin use;
  – it is necessary to measure antithrombin levels daily to adjust the individual dose, since there is a risk of decreased antithrombin levels during long-term treatment with unfractionated heparin.

Effect on ability to drive vehicles and mechanisms

No effect on the ability to drive a car and work with mechanisms was observed.

Overdose

Symptoms of antithrombin overdose have not been described.

Drug Interactions

Replacement therapy with antithrombin when used concomitantly with heparin in therapeutic doses increases the risk of bleeding. The effect of antithrombin is significantly enhanced by heparin. The T_1/2 of antithrombin may significantly decrease when used concomitantly with heparin due to accelerated metabolism of antithrombin. Therefore, the concomitant use of antithrombin and heparin in a patient with an increased risk of bleeding should be monitored clinically and biochemically.

This medicinal product must not be mixed with other medicinal products.

Storage Conditions

The drug should be stored out of the reach of children at a temperature of 2°C (35.6°F) to 8°C (46.4°F). Do not freeze.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.