Immunine (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

B02BD04 (Blood coagulation factor IX)

Active Substance

Human coagulation factor IX

Human coagulation factor IX (Ph.Eur. European Pharmacopoeia)

Dosage Forms

	Immunine	Lyophilisate for preparation of solution for infusion 600 IU: vial 1 pc. in a set with solvent and a set for dissolution and administration
		Lyophilisate for preparation of solution for infusion 1200 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 powder or friable solid mass of white or light yellow color; the reconstituted solution should be from colorless to slightly yellowish and from clear to slightly opalescent; water for injections: a clear colorless liquid.

Excipients: sodium citrate dihydrate – 20 mg, sodium chloride – 40 mg.

Solvent water for injections – 5 ml (vials with a capacity of 6 ml).

Vials with a capacity of 20 ml (1) in a set with solvent (vial 1 pc.) and a set for dissolution and administration (adapter needle, air vent needle, filter needle, disposable syringe, transfusion butterfly needle, disposable injection needle) – cardboard packs.

*factor IX activity is determined using a one-stage in vitro clotting assay, calibrated against the current World Health Organization (WHO) International Standard for factor IX concentrates.

Lyophilisate for preparation of solution for infusion as a powder or friable solid mass of white or light yellow color; the reconstituted solution should be from colorless to slightly yellowish and from clear to slightly opalescent; water for injections: a clear colorless liquid.

Excipients: sodium citrate dihydrate – 40 mg, sodium chloride – 80 mg.

Solvent: water for injections – 10 ml (vials with a capacity of 10 ml).

Vials with a capacity of 20 ml (1) in a set with solvent (vial 1 pc.) and a set for dissolution and administration (adapter needle, air vent needle, filter needle, disposable syringe, transfusion butterfly needle, disposable injection needle) – cardboard packs.

*factor IX activity is determined using a one-stage in vitro clotting assay, calibrated against the current World Health Organization (WHO) International Standard for factor IX concentrates.

Clinical-Pharmacological Group

Blood coagulation factor IX preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Factor IX is a single-chain glycoprotein with a molecular weight of approximately 68,000 daltons. It is synthesized in the liver and is a vitamin K-dependent coagulation factor. Factor IX is activated by factor XIa via the intrinsic coagulation pathway or by the factor VII/tissue factor complex via the extrinsic coagulation pathway. Activated factor IX, in complex with factor VIII, activates factor X. Activated factor X converts prothrombin to thrombin. Under the action of thrombin, fibrinogen is converted to fibrin, which forms a clot. Hemophilia B is a hereditary sex-linked coagulation disorder due to reduced levels of factor IX and manifests as massive hemorrhages into joints, muscles, or internal organs, which occur either spontaneously or as a result of accidental trauma or surgery. Replacement therapy increases the plasma level of factor IX and thus temporarily corrects the factor deficiency and reduces the tendency to bleed.

Pharmacokinetics

The in vivo recovery of factor IX in response to administration of 1 IU/kg is 0.92±0.06 IU/100 ml (approximately 40%), the biological T_1/2 is approximately 20 h. After IV administration, C_max is reached within 10-30 min.

Indications

• Treatment and prevention of bleeding episodes in congenital or acquired factor IX deficiency (hemophilia B, hemophilia B with inhibitors to factor IX, acquired factor IX deficiency due to spontaneous development of inhibitors to factor IX).

ICD codes

Dosage Regimen

Treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia.

The doses and duration of replacement therapy depend on the severity of the factor IX deficiency, the location and intensity of the bleeding, and the clinical condition of the patient.

The amount of factor IX to be administered is expressed in International Units (IU) of activity, established relative to the current WHO International Standard for factor IX preparations.

Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to the international standard for factor IX concentrates).

One IU of factor IX activity is equivalent to the activity of factor IX contained in 1 ml of normal human plasma. The calculation of the required dose of factor IX is based on the empirical observation that the administration of 1 IU of factor IX per kg of body weight increases the plasma factor IX activity by 0.8% of the normal level.

The required dose is calculated using the following formula:

Required dose = body weight (kg) x desired increase in factor IX level (%) x 1.2

When calculating the amount of drug to be administered and determining the frequency of administration, one should always be guided by clinical effectiveness in each individual case. Factor IX preparations rarely require administration more than once a day. For the bleeding episodes mentioned below, the factor IX activity should not fall below the specified level during the corresponding period.

The following table can be used as a guide for calculating doses for bleeding episodes and surgical interventions.

Dosage control of the drug should be carried out by a physician. The table provided can serve as an auxiliary guide.

Under certain circumstances, higher doses than calculated may be required, especially for initial doses.

During treatment, it is recommended to determine the factor IX level to verify the correct dose selection and frequency of repeated infusions. In particular, careful monitoring of replacement therapy by coagulation analysis (plasma factor IX activity) is necessary in the case of extensive surgical interventions. Individual patients may respond differently to factor IX, with different factor IX recovery levels and different T_1/2.

For long-term prevention of bleeding in patients with severe hemophilia B, doses of 20 to 40 IU/kg body weight are usually prescribed at intervals of 3 to 4 days.

In some cases, especially in young patients, shorter intervals between administrations or higher doses may be necessary.

There are insufficient data on the use of Immunine in children under 6 years of age.

Patients should be monitored for the possible development of inhibitors to factor IX. If the expected plasma factor IX activity level is not achieved, or bleeding is not controlled by the administration of an appropriate dose of the drug, an investigation for the presence of inhibitors to factor IX should be performed. In patients with high inhibitor levels, therapy with factor IX may be ineffective and other therapeutic options should be considered. The management of such patients should be carried out by physicians experienced in the treatment of patients with hemophilia.

If the inhibitor titer is less than 10 Bethesda units (BU) per 1 ml, administration of an additional amount of human coagulation factor IX may neutralize the inhibitor. In patients with inhibitor titers above 10 BU or with a high level of anamnestic response, the possibility of using activated or non-activated prothrombin complex concentrates or recombinant activated factor VII should be considered. These types of therapy should be carried out by physicians experienced in the treatment of patients with hemophilia.

Method of administration

Immunine must be reconstituted strictly immediately before administration. The solution should be clear or slightly opalescent. A cloudy solution or a solution with particulates should not be used. The prepared solution should be used promptly (the preparation does not contain preservatives). Any unused solution residue should be disposed of appropriately.

Preparation of the concentrate solution

1. Bring the sealed vial with solvent (water for injections) to room temperature (maximum to 37°C (98.6°F)).
2. Remove the protective caps from the vials with the lyophilisate and the solvent and disinfect the rubber stoppers of both vials.
3. Remove the protective packaging from one end of the supplied adapter needle by twisting and pulling it. Insert the free end of the needle into the rubber stopper of the solvent vial.
4. Carefully remove the protective packaging from the other end of the adapter needle without touching the open end.
5. Turn the solvent vial upside down, place it over the vial with the lyophilisate, and insert the free end of the needle into this vial through the rubber stopper. The solvent will flow into the lyophilisate vial under vacuum.
6. Disconnect the vials by removing the adapter needle from the lyophilisate vial. Gently shake or rotate the lyophilisate vial to accelerate dissolution.
7. After the lyophilisate is completely dissolved, insert the supplied air vent needle into the vial, and all foam will settle. Remove the air vent needle.

The chemical and physical stability of the finished solution is 6 hours at room temperature. However, due to the risk of microbiological contamination, Immunine should be used immediately after preparation of the solution. The finished solution should not be stored in the refrigerator.

Administration

1. Remove the protective packaging from the supplied filter needle by twisting and pulling it, and attach the needle to a sterile disposable syringe. Draw the solution into the syringe.

1. Remove the filter needle from the syringe and slowly administer the solution intravenously (maximum administration rate 2 ml/min) using the supplied transfusion butterfly needle (or the supplied disposable needle).

Infusion

When performing an infusion, a disposable infusion set with an appropriate filter should be used.

Adverse Reactions

The following adverse reactions have been reported with the use of the drug. Their frequency was estimated based on the following criteria: very common (>1/10), common (>1/100; <1/10), uncommon (> 1/1000; <1/100), rare ( >1/10000; <1/1000) and very rare (<1/10000).

1. Noted during clinical trials. Studies with Immunine containing heparin.

Total 277 administrations. Frequency of adverse reactions > 1/1000: <1/100, i.e., uncommon.

Skin: rash

Studies with Immunine not containing heparin.

Total 646 administrations. Frequency of adverse reactions >1/1000; <1/100, i.e., uncommon.

Respiratory system: tingling/irritation in the throat, dry cough.

Skin: itching

2. Noted during post-marketing studies.

All of the following side effects are observed very rarely ( <1/10,000).

Hematopoietic system neutralizing antibodies (inhibitors) to factor IX, DIC syndrome.

Immune system allergic reactions, severe anaphylaxis, angioedema, flushing, generalized rash, urticaria.

CNS headache, anxiety, paresthesia.

Cardiovascular system: tachycardia, myocardial infarction, decreased blood pressure, thromboembolic episodes, pulmonary embolisms, venous thrombosis.

Respiratory system wheezing.

Digestive system nausea, vomiting.

Skin rash.

Urinary system nephrotic syndrome.

General disorders and administration site conditions chills, burning and tingling at the injection site, fever, hypersensitivity reactions, drowsiness, chest tightness.

Uncommonly, patients treated with preparations containing factor IX have experienced hypersensitivity reactions or allergic reactions (including angioedema, burning and tingling at the injection site, chills, flushing, generalized rash, headache, urticaria, decreased blood pressure, drowsiness, nausea, anxiety, tachycardia, chest tightness, paresthesia, vomiting, wheezing). In some cases, these reactions progressed to severe anaphylaxis and developed in connection with the development of transient inhibitors to factor IX.

There are reports of the development of nephrotic syndrome during attempts to conduct an immune tolerance program in hemophilia patients with inhibitors and a history of allergic reactions.

Patients with hemophilia B may develop neutralizing antibodies (inhibitors) to factor IX. Clinically, the development of inhibitors is manifested by an insufficient effect of therapy. In such cases, it is recommended to consult with specialists from a hemophilia center. Currently, experience with the use of Immunine in patients previously untreated with coagulation factors is limited.

There is a potential risk of developing thromboembolic episodes in response to the administration of factor IX preparations, and this risk is higher with low-purity preparations. Cases of myocardial infarction, DIC syndrome, venous thrombosis, and pulmonary embolism have been reported with the use of low-purity factor IX preparations. The use of high-purity preparations rarely leads to such side effects.

Contraindications

• DIC syndrome and/or hyperfibrinolysis;
• Hypersensitivity to the active substance or excipients.

If such contraindications develop during treatment, Immunine can only be administered in case of life-threatening bleeding.

Use in Pregnancy and Lactation

Studies on the effect of factor IX on reproductive function in animals have not been conducted. Given that hemophilia B rarely occurs in women, there are no data on the use of factor IX during pregnancy and lactation. Therefore, factor IX should be used during pregnancy and lactation only if strictly indicated.

Pediatric Use

There are insufficient data on the use of Immunine in children under 6 years of age.

Special Precautions

As with the use of any protein preparation for intravenous administration, allergic hypersensitivity reactions may occur. In addition to factor IX, the preparation contains trace amounts of human proteins. Patients should be informed about the early signs of hypersensitivity reactions, including urticaria, generalized rash, chest tightness, wheezing, decreased blood pressure, and anaphylaxis. Patients should be advised to immediately discontinue treatment and consult a doctor if such symptoms occur. In case of anaphylactic shock, modern standard methods of anti-shock therapy should be used.

In patients at high risk of thrombosis (for example, patients with a history of liver disease, thrombophilia, hypercoagulable states, angina pectoris, coronary artery disease or acute myocardial infarction, or in premature newborns), the factor IX level should not be raised above 60% of normal. Furthermore, these patients, as well as patients receiving high doses of human coagulation factor IX concentrate due to extensive surgical interventions, require constant laboratory monitoring for the timely detection of possible development of DIC and/or thrombosis. If DIC is suspected, therapy with the drug should be discontinued immediately.

When using medicinal products prepared from human blood or plasma, it is impossible to completely eliminate the risk of transmission of infectious agents. This also applies to pathogens of unknown origin. However, the risk of transmission of infections is minimized as a result of

• Careful selection of donors through examination and laboratory screening of individual plasma donations and plasma pools for HBsAg, anti-HIV and anti-HCV antibodies;
• Testing plasma pools for genomic sequences of HIV-1 and HIV-2, HAV, HBV, HCV and parvovirus B19;
• Technological steps for the removal and inactivation of pathogenic viruses and model viruses during the manufacturing process. The effectiveness of these technologies has been confirmed for HIV-1, HIV-2, HAV, HBV, and HCV.

The technologies used for removal and inactivation may have limited effectiveness against some non-enveloped viruses, such as, for example, parvovirus B19. Parvovirus B19 infection can be dangerous for pregnant women (fetal infection) and for patients with immunodeficiency or increased erythrocyte breakdown (for example, in hemolytic anemia).

Patients receiving therapy with coagulation factor concentrates are recommended to be vaccinated against hepatitis A and B.

The amount of sodium in the maximum daily dose of the drug may exceed 200 mg, which may be dangerous for persons on a low-sodium diet.

During repeated treatment with human coagulation factor IX products, patients should undergo appropriate regular laboratory testing to detect the possible development of neutralizing antibodies (inhibitors), measured in Bethesda Units (BU).

There are literature reports of an association between the development of factor IX inhibitors and the occurrence of allergic reactions. Therefore, patients with allergic reactions should be tested for the presence of inhibitors.

It should be noted that patients with inhibitors to factor IX have an increased risk of developing anaphylaxis upon repeated administration of factor IX. Due to the risk of allergic reactions when using factor IX concentrates, the initial administrations of factor IX should be carried out as prescribed by the attending physician under medical supervision to provide appropriate medical care in case of allergic reactions.

Since the use of factor IX has historically been associated with the development of thromboembolic complications, with a higher risk for low-purity products, the use of products containing factor IX in patients with signs of fibrinolysis and in patients with DIC syndrome may pose a potential hazard. Due to the potential risk of thromboembolic complications, when administering Immunine to patients with liver disease, patients in the postoperative period, newborns, or patients at risk of thrombotic events or DIC syndrome, clinical monitoring should be performed to detect early signs of thrombosis and consumption coagulopathy, with appropriate laboratory testing. In each of these cases, the expected benefit of treatment with Immunine should be weighed against the risk of such complications.

In the interest of patients, it is recommended to record the name and batch number of the Immunine drug each time it is administered.

Within the specified shelf life, patients may store Immunine at room temperature (not exceeding 25°C (77°F)) for up to 3 months. The date of starting storage at room temperature should be marked on the packaging.

Overdose

There are no reports of symptoms of overdose with human coagulation factor IX.

Drug Interactions

Pharmacological interactions with other medicinal products are currently unknown.

Like any factor concentrate, Immunine should not be mixed with other medicinal products.

Only the administration set provided in the kit should be used, as treatment may be ineffective due to adsorption of human coagulation factor onto the internal surfaces of some injection or infusion devices.

It is advisable to flush a common venous access with isotonic sodium chloride solution before and after administration of the drug.

Storage Conditions

The drug 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.

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.