Immunate (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Takeda Manufacturing Austria AG (Austria)

Contact Information

BAXTER (USA)

ATC Code

B02BD06 (Von Willebrand factor and Coagulation Factor VIII in combination)

Dosage Forms

	Immunate	Lyophilisate for preparation of solution for intravenous administration 250 IU: vial 1 pc. in a kit with solvent and a set for dissolution and administration
		Lyophilisate for preparation of solution for intravenous administration 500 IU: vial 1 pc. in a kit with solvent and a set for dissolution and administration
		Lyophilisate for preparation of solution for intravenous administration 1000 IU: vial 1 pc. in a kit with solvent and a set for dissolution and administration

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration white or white with a yellowish tint, free from foreign particles.

Excipients: human albumin, glycine, lysine hydrochloride, sodium chloride, sodium citrate dihydrate, calcium chloride dihydrate.

Solvent: water for injections – 10 ml.

* – Factor VIII activity was determined in accordance with the International Standard (WHO) for Factor VIII concentrates.
** – Von Willebrand factor collagen-binding activity was determined in accordance with the Plasma Standard of the International Society on Thrombosis and Haemostasis Standardization Committee.

Vials (1) in a kit with solvent (vial 1 pc.), a set for dissolution and administration of the drug (transfer filter needle, disposable syringe, transfusion butterfly needle, sterile injection needle) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration white or white with a yellowish tint, free from foreign particles.

Excipients: human albumin, glycine, lysine hydrochloride, sodium chloride, sodium citrate dihydrate, calcium chloride dihydrate.

Solvent: water for injections – 5 ml.

* – Factor VIII activity was determined in accordance with the International Standard (WHO) for Factor VIII concentrates.
** – Von Willebrand factor collagen-binding activity was determined in accordance with the Plasma Standard of the International Society on Thrombosis and Haemostasis Standardization Committee.

Vials (1) in a kit with solvent (vial 1 pc.), a set for dissolution and administration of the drug (transfer filter needle, disposable syringe, transfusion butterfly needle, sterile injection needle) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration white or white with a yellowish tint, free from foreign particles.

Excipients: human albumin, glycine, lysine hydrochloride, sodium chloride, sodium citrate dihydrate, calcium chloride dihydrate.

Solvent: water for injections – 5 ml.

* – Factor VIII activity was determined in accordance with the International Standard (WHO) for Factor VIII concentrates.
** – Von Willebrand factor collagen-binding activity was determined in accordance with the Plasma Standard of the International Society on Thrombosis and Haemostasis Standardization Committee.

Vials (1) in a kit with solvent (vial 1 pc.), a set for dissolution and administration of the drug (transfer filter needle, disposable syringe, transfusion butterfly needle, sterile injection needle) – cardboard packs.

Clinical-Pharmacological Group

Blood coagulation factor VIII preparation

Pharmacotherapeutic Group

Hemostatic agents; vitamin K and other hemostatic agents; blood coagulation factors

Pharmacological Action

Immunate is a highly purified lyophilized concentrate of the complex of blood coagulation factors VIII and von Willebrand, prepared from human plasma, double virus-inactivated (vapor heat treatment and solvent-detergent treatment).

The Factor VIII/Von Willebrand factor complex consists of 2 molecules, Factor VIII (FVIII) and von Willebrand factor (VWF), with different physiological functions. Activated Factor VIII is a co-factor for the activation of Factor IX, which accelerates the conversion of Factor X to activated Factor X. Activated Factor X is necessary for the conversion of prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin, and a clot is formed. Hemophilia A is an inherited sex-linked disorder of the blood coagulation system caused by FVIII deficiency, resulting in patients developing profuse bleeding or hemorrhages into joints, muscles, or internal organs, both as a result of trauma and surgery, and spontaneously. Replacement therapy increases the FVIII content in plasma and thereby temporarily corrects the factor deficiency and reduces the tendency to bleed.

VWF, in addition to its function as a protein stabilizing FVIII in plasma, promotes platelet adhesion to the site of vascular injury, participates in platelet aggregation, and is necessary for replacement therapy in patients with von Willebrand disease.

Pharmacokinetics

After administration of the drug, the increase in FVIII activity in plasma is 80-120% of the expected. In pharmacokinetic studies, the in vivo recovery of FVIII after administration of Immunate averaged about 100%.

The activity of FVIII in blood plasma decreases along a biphasic exponential curve. In the initial phase, its distribution between the intravascular bed and extravascular tissue fluids occurs with a T_1/2 from plasma of 3-6 h; approximately from 2/3 to 3/4 of the intravenously administered FVIII remains in the vascular bed. The subsequent slow phase possibly reflects the degradation of FVIII. In this phase, T_1/2 ranges from 8-20 h, averaging 12 h. This reflects the true biological T_1/2 of FVIII. In the aforementioned pharmacokinetic studies of Immunate using dependent and independent model methods, the mean T_1/2 of FVIII was 11 h.

Indications

• Treatment and prevention of bleeding in hereditary (hemophilia A) and acquired FVIII deficiencies;
• Von Willebrand disease with FVIII deficiency.

ICD codes

Dosage Regimen

The drug, after preparation of the solution, is administered intravenously slowly. Therapy should be initiated under the supervision of a physician experienced in the treatment of hemophilia. Doses and duration of replacement therapy depend on the degree of FVIII deficiency, location, intensity of bleeding, and severity of the patient’s clinical condition. The amount of FVIII administered is expressed in International Units (IU), which correspond to the generally accepted WHO standard for preparations containing FVIII. The activity of FVIII in plasma is expressed either as a percentage (corresponding to normal human plasma) or in International Units (corresponding to the International Standard for FVIII in plasma).

One International Unit (IU) of FVIII activity is equivalent to the same amount of FVIII in 1 ml of normal human plasma.

A. Dose calculation for hemophilia A

The calculation of the required dose of FVIII is based on the empirically established fact that the administration of 1 IU of FVIII per kg of body weight increases FVIII activity in plasma by 1.5-2% of normal activity. The dose of the drug is calculated according to the following formula:

Required dose of Immunate (IU FVIII) = body weight (kg) x desired FVIII increase (in%) x 0.5.

In each specific case, the amount of drug administered and the frequency of administration should be correlated with clinical effectiveness.

Bleeding and surgical interventions

In the case of the hemorrhagic episodes listed below, the plasma factor VIII activity should not be lower than recommended.

In some cases, especially at the beginning of therapy, administration of the drug in doses higher than calculated may be required.

During the course of treatment, it is recommended to determine FVIII activity in plasma to adjust the dose and frequency of drug administration. Accurate monitoring of replacement therapy based on coagulological study data (FVIII activity in plasma) is especially necessary during major surgical interventions. There may be individual variations in response to FVIII administration among patients, manifested in differences in in vivo recovery and T_1/2 indicators.

Long-term prophylaxis

For long-term prophylaxis in severe forms of hemophilia A, doses of 20-40 IU FVIII per kg of body weight every 2-3 days are recommended. In some cases, especially in younger patients, to prevent hemorrhage, it may be necessary to reduce the intervals between administrations or increase the doses of the drug.

B. Inhibitor forms of hemophilia A

If the expected increase in plasma factor activity cannot be achieved or bleeding cannot be stopped by administering calculated doses of the drug, it is necessary to test for the presence of inhibitors to FVIII. In patients with inhibitor titers below 10 Bethesda Units (BU) per 1 ml, the inhibitor can be neutralized by additional administration of human FVIII. In patients with an inhibitor titer above 10 BU/ml or with a history of high response (high-responders), it is generally not possible to effectively stop bleeding by administering FVIII. In these cases, appropriate specific anti-inhibitor therapy should be administered. Such therapy should be carried out exclusively by physicians experienced in the treatment of patients with hemophilia.

C. Von Willebrand disease with Factor VIII deficiency

Immunate is indicated as replacement therapy for patients with von Willebrand disease with reduced Factor VIII activity. Replacement therapy with Immunate for the purpose of stopping and preventing bleeding associated with surgical interventions is carried out in accordance with the recommendations for patients with hemophilia A.

Preparation of the drug solution

The Immunate solution is prepared immediately before administration. The prepared solution retains chemical and physical stability for 3 hours at a temperature of 20-25°C (68-77°F), however, it should be used immediately after preparation, as it does not contain preservatives. The user is responsible for the conditions and duration of storage of the prepared solution. Do not use a cloudy solution or a solution with inclusions. The unused solution must be disposed of appropriately.

1. Warm the vial with the solvent (sterile water for injections) to room temperature (not higher than 37°C (98.6°F)).
2. Remove the protective caps from the vials with the concentrate and the solvent and disinfect the rubber stoppers of both vials.
3. Place, and then press firmly, the wavy edge of the transfer system onto the vial with the solvent.
4. Remove the protective cap from the other end of the transfer system. Do not touch the exposed end of the system.
5. Turn the vial with the solvent over the vial with the dry concentrate and pierce the center of the stopper of the vial with the free end of the needle. Due to the vacuum, the solvent will flow into the vial with the drug. Wait about 1 min.
6. Disconnect the vials by pulling the needle of the transfer system out of the stopper of the vial with the drug. Since the drug dissolves easily, gently – if necessary – swirl the vial. Do not shake the vial with the drug. Do not invert the vial with the drug until its contents are withdrawn.
7. Parenteral preparations, such as Immunate, should be visually inspected for inclusions and color change after solution preparation and before administration. Even with careful adherence to the solution preparation instructions, small particles may occasionally be visible. They are removed by the filter included in the kit. This does not reduce the concentration of the pharmaceutically active ingredient stated on the label.

Administration

1. When drawing the prepared solution into the syringe, use the supplied filter needle to avoid the ingress of rubber stopper particles (risk of microembolism). Attach the filter needle to the supplied disposable syringe and pierce the rubber stopper with it.
2. Briefly remove the syringe from the filter needle. Air will enter the vial with the solution and settle the foam that has formed. Then draw the solution through the filter needle into the syringe.
3. Remove the syringe from the filter needle and administer the solution intravenously slowly (maximum administration rate – 2 ml/min) using the supplied system or the supplied disposable needle.

Adverse Reactions

In response to the administration of Factor VIII preparations, hypersensitivity reactions or allergic reactions (including angioedema, burning sensation at the injection site, skin hyperemia, urticaria, itching, chills, headache, arterial hypotension, drowsiness, nausea, vomiting, anxiety, tachycardia, feeling of tightness in the chest, stridor breathing) up to the development of anaphylactic shock have been extremely rarely observed. In rare cases, an increase in body temperature is possible.

Patients with hemophilia A may develop antibodies to Factor VIII (inhibitors), which clinically manifests as a lack of hemostatic effect in response to the therapy. In such cases, the patient should be consulted at a specialized hemophilia center.

Currently, there are no confirmed clinical data on the use of Immunate in previously untreated patients (PUPs), so such patients should be thoroughly examined for the presence of inhibitors by appropriate methods (Bethesda assay).

In response to the administration of high doses of the drug, hemolysis may be observed in patients with blood groups A(II), B(III), or AB(IV).

Contraindications

• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

Controlled studies confirming the safety of the use of human coagulation factor VIII concentrates during pregnancy and lactation have not been conducted. Therefore, during pregnancy and lactation, the drug should be prescribed only for strict indications.

Pediatric Use

Should be used with caution in children under 6 years of age who have rarely received treatment with FVIII preparations.

Special Precautions

The development of allergic reactions is possible, as with the intravenous administration of any protein preparations. In these cases, the administration of the drug should be stopped immediately and treatment should be carried out depending on the reaction and its severity. For mild reactions, anti-shock drugs are prescribed; in severe cases, anti-shock therapy is carried out.

Immunate is produced from human plasma. When using plasma or products made from human plasma, the risk of transmission of infectious agents, including those not yet known, cannot be completely excluded. However, the risk of transmission of infectious agents is maximally reduced due to the following measures:

• Thorough medical examination and selection of donors and screening testing of individual donations and plasma pools for HBsAg and antibodies to HIV and hepatitis C;
• Testing of plasma pools for genomic sequences of the hepatitis C virus;
• Inclusion in the manufacturing process of vapor heat treatment and solvent-detergent treatment to remove/inactivate viruses, the effectiveness of which has been proven on model viruses. The effectiveness of these methods against HIV-1, HIV-2, hepatitis C, A, and B has been confirmed.

The virus removal/inactivation methods used in the manufacturing process may be partially effective against some non-enveloped viruses, such as parvovirus B19. Infection caused by parvovirus B19 can lead to serious illness in pregnant women (fetal infection) and in patients with immunodeficiency or increased erythrocyte breakdown (e.g., in hemolytic anemia).

When treating with plasma-derived FVIII concentrates, appropriate vaccination of patients (against hepatitis A and B) is recommended.

When treating patients with hemophilia A, the development of such a complication as the appearance of neutralizing antibodies (inhibitors) to Factor VIII is possible. These inhibitors belong to the immunoglobulin G class, are directed against the procoagulant activity of Factor VIII, and are measured in Bethesda Units (BU) per 1 ml of plasma (modified Bethesda method). The risk of inhibitor development correlates with the use of human FVIII preparations, with the greatest risk of inhibitor development being the first 20 days of drug administration. Rarely, inhibitors can form after the first 100 days of treatment. For timely detection of inhibitors, careful clinical monitoring and laboratory examination of patients receiving treatment with human FVIII concentrates should be carried out.

Should be used with caution in children under 6 years of age who have rarely received treatment with FVIII preparations.

The sodium content in the maximum daily dose of the drug is 200 mg, which should be taken into account in persons on a low-sodium and salt-free diet.

Effect on the Ability to Drive Vehicles and Mechanisms

Immunate does not affect the ability to drive a car or perform work requiring increased concentration and motor reactions.

Overdose

Symptoms of overdose with human coagulation factor VIII preparations are unknown.

Drug Interactions

The interaction of human factor VIII preparations with other medicinal products is unknown.

Immunate should not be mixed with other medicinal products before administration, as this may impair the efficacy and safety of the preparation.

It is advisable to flush a shared venous access with isotonic (physiological) sodium chloride solution before and after administration of Immunate.

Storage Conditions

List B. The preparation should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Shelf Life

The shelf life is 2 years.

The chemical and physical stability of the prepared solution for intravenous administration is maintained for 3 hours at a temperature of 20-25°C (68-77°F).

From a microbiological point of view, the preparation may carry a risk of microbial contamination; therefore, the preparation should be used immediately after reconstitution.

If the prepared solution is not used immediately, the user is responsible for the storage time and conditions.

Dispensing Status

The preparation is available 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.