Immunine VH

IMMUNINE® VH

Baxter

Factor IX Concentrate (Human)

Blood Coagulation Factor

Action And Clinical Pharmacology: Coagulation factor IX is one of the clotting factors found in normal human blood and is required for normal clot formation.

I.V. administration of Immunine VH, factor IX concentrate (human) vapor heated, Immuno provides an increase in plasma levels of factor IX and can temporarily correct the coagulation defect of patients with factor IX deficiency.

The in vivo recovery and half-life of Immunine VH were evaluated in 26 patients with severe hemophilia B (factor IX levels below 1%) and no bleeding at the time of testing. The patients received a single infusion of 50 to 70 units Immunine VH per kg body weight. The mean increase in the patients’ factor IX plasma levels was 0.92% per administered IU factor IX per kg body weight, corresponding to a recovery of 41%. The average biological half-life was approximately 17 hours. These data are based on calculations using the new International Standard for human blood coagulation factors II, IX and X in Concentrates Code 84/681.

The effectiveness of the vapor heating process used in the manufacture of Immunine VH to inactivate virus was evaluated in in vitro spiking experiments using human immunodeficiency virus type I (HIV-1) as a target virus as well as the following model viruses: pseudorabies virus (PRV, an enveloped DNA virus as a model for hepatitis B virus), Tick-Borne encephalitis virus (TBEV, a small enveloped RNA virus as a model for HCV) and equine rhinovirus type-1 (ERV-1, a nonenveloped RNA virus as a model for hepatitis A virus). The 2-step vapor heating resulted in virus titer reductions by factors of >10.6 logs for HIV-1, >15.5 logs for TBEV, >12.0 logs for PRV, and >11.5 logs for ERV-1.

In addition to the 2-step vapor heating process, the ability of other stages in manufacture (adsorption onto DEAE-sephadex, TWEEN-80 treatment, ion exchange chromatography, hydrophobic interaction chromatography) to remove and inactivate virus was also evaluated. These steps were found to result in additional virus titer reductions by factors of >12.3 logs for HIV-1, >12.3 logs for TBEV, and 6.3 logs for PRV and 3.0 logs for ERV-1.

In prospective clinical studies as well as in postmarketing surveys, the risk of transfusion-transmitted viral infections was followed up in patients given factor concentrates of the prothrombin complex subjected to the same vapor heat treatment as Immunine VH. Using the criteria established by the ISTH, 45 patients were evaluated for non-A/non-B transmission and 27 for hepatitis B transmission. In addition, 42 patients were evaluated for HCV seroconversion, and 105 for HIV seroconversion. No cases of product related viral hepatitis or HIV transmission were observed.

Indications And Clinical Uses: Therapy and prophylaxis of bleeding episodes caused by congenital or acquired factor IX deficiency.

Contra-Indications: Disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis. Following interruption of these processes by suitable means, Immunine VH, factor IX concentrate (human) vapor heated, Immuno should only be given for the management of life-threatening bleeding.

Manufacturers’ Warnings In Clinical States: This product is prepared from pooled human plasma which may contain the causative agents of hepatitis and other viral diseases. Prescribed manufacturing procedures utilized at the plasma collection centres, plasma testing laboratories, and the fractionation facilities are designed to reduce the risk of transmitting viral infection. However, the risk of the transmission of infective agents – also of hitherto unknown origin – cannot be totally excluded.

Individuals who receive infusion of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly non-A/non-B hepatitis.

In patients with a risk of thrombosis (e.g., patients with a history of severe liver disease, thrombophilia, or a tentative or definite diagnosis of angina pectoris, coronary heart disease or myocardial infarction) the factor IX level should not be raised beyond 60% of normal. In addition, these patients – as well as patients receiving high doses of human blood coagulation factor IX concentrate for major surgery – should be monitored for the development of DIC and/or thrombosis.

In patients with suspected DIC, replacement therapy should be stopped immediately.

Precautions: Immunine VH, factor IX concentrate (human) vapor heated, Immuno should not be administered at a rate exceeding 2 mL/min.

If hypersensitivity reactions occur during administration of Immunine VH, the injection/infusion should be stopped. Minor reactions may be controlled by antihistamines, while the therapy of severe hypotensive reactions follows the current guidelines of shock treatment.

Immunine VH contains less than 0.1 IU heparin per mL. In case of surgical intervention in hemophilia B patients receiving replacement therapy with Immunine VH, perioperative thrombosis prophylaxis with low-dose heparin is recommended in those situations where such a prophylaxis would normally be indicated in patients having no coagulation defect.

Immunine VH contains not more than 5 g TWEEN-80 per mL.

Appropriate vaccination should be considered in factor IX deficient patients.

Drug Interactions: No pharmacologic interactions with other drugs are currently known.

As for any blood coagulation factor concentrate, Immunine VH, factor IX concentrate (human) vapor heated, Immuno should not be mixed with other drugs. It is advisable to rinse a common venous access with isotonic saline prior to and after infusion of Immunine VH.

Pregnancy and Lactation: The safety of human blood coagulation factor IX concentrate for use in human pregnancy has not been established in controlled clinical trials. Therefore, human blood coagulation factor IX concentrate may be used only if clearly needed during pregnancy and lactation.

Adverse Reactions: As with any infused plasma derivative, hypersensitivity reactions (e.g., fever, urticaria, nausea, vomiting, dyspnea, drop in blood pressure, shock) may occur rarely.

In rare cases, replacement therapy with human blood coagulation factor IX concentrates may lead to the formation of circulating antibodies which inhibit factor IX.

The possibility of thromboembolic complications cannot be entirely ruled out. This applies particularly to patients at risk for thrombosis and/or receiving high-dose therapy.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Based on experience with conventional prothrombin complex preparations, overdosage of factor IX concentrates may result in an increased risk of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism (see Precautions).

Dosage And Administration: Hemophilia B: For the calculation of the factor IX plasma levels as specified below it is assumed that one IU of Immunine VH, factor IX concentrate (human) vapor heated, Immuno per kg body weight increases the factor IX plasma level by approximately 0.8%.

Considering the patient’s preinfusion factor IX plasma level, the required dosage is administered using the following formula:

Immunine VH dose (in IU F IX)=body weight (kg)´desired increase in F IX (%)´1.2 IU/kg.

Regular determinations of the patient’s factor IX plasma level are necessary for monitoring the course of therapy and calculations of appropriate maintenance doses.

In general, Immunine VH is given every 24 hours, corresponding to the biological half-life of factor IX. For surgical prophylaxis the initial dose should be administered one hour prior to surgery. In the case of major surgical interventions, 12-hour treatment intervals should be maintained during the first postoperative days.

Prophylactic Maintenance Therapy: In prophylactic maintenance therapy of severe hemophilia B, a dosage of 20 to 30 IU/kg body weight twice per week was shown to be effective. Prophylactic dosage regimens should, however, be tailored to individual needs, and the decision on the need and dosage for prophylaxis should thus be made by the treating physician.

Hemophiliacs with Inhibitor to Factor IX: Replacement therapy with human blood coagulation factor IX is usually effective only in low responder patients with an inhibitor titer of less than 10 Bethesda Units. Since the response to human blood coagulation factor IX depends on the patient’s inhibitor titer, factor IX levels must be monitored frequently and the dose adjusted accordingly. In high responder inhibitor patients other therapeutic measures may be needed.

Reconstitution: Immunine VH, factor IX concentrate (human) vapor heated, Immuno is to be reconstituted only immediately before application. The solution should then be used promptly (the preparation does not contain any preservative). Any unused solution must be discarded. For reconstitution proceed as follows using aseptic technique:

1. Warm the unopened bottle containing Sterile Water for injection (diluent) to room temperature (not above 37°C).

2. Remove caps from the concentrate and diluent bottles to expose central portions of the rubber stoppers. Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry.

3. Remove protective covering from one end of the transfer needle by twisting and pulling. Insert the exposed end through the diluent bottle stopper.

4. Remove protective covering from the other end of the transfer needle taking care not to touch the exposed end. Invert diluent bottle over the concentrate bottle and insert the free end of the transfer needle through the concentrate bottle stopper. Diluent will be drawn into the concentrate bottle by vacuum.

5. Disconnect the 2 bottles by removing the needle from the concentrate bottle stopper. Gently agitate or rotate the concentrate bottle until all material is dissolved.

Do not refrigerate after reconstitution.

Injection: 1. After reconstituting the concentrate as described under Reconstitution, attach the enclosed filter needle to a sterile disposable syringe. Insert filter needle through the concentrate bottle stopper.

2. Inject air and withdraw solution into the syringe.

3. Remove and discard the filter needle. Attach a suitable i.v. needle or winged infusion set and inject solution i.v. (maximum rate 2 mL/min).

Infusion: If administered by infusion, a disposable infusion set with adequate filter is to be used (maximum rate of infusion: 2 mL/min).

Availability And Storage: Immunine VH, factor IX concentrate (human) vapor heated, Immuno, is a purified, sterile, freeze-dried concentrate of human blood coagulation factor IX. Immunine VH is standardized in terms of factor IX content and each vial is labeled with the factor IX content indicated in international units (IU). One IU of factor IX (based on the First International Standard for Factors II, IX and X in Coagulation Factor Concentrates Code 84/681) corresponds to the factor IX activity contained in 1 mL of fresh normal human plasma.

Immunine VH contains less than 2 IU of factors II, VII and X per mg protein; less than 0.1 IU heparin per mL and not more than 5 g TWEEN-80 per mL.

Immunine VH is prepared from pooled human plasma.

The manufacturing process includes key stages, among them a product-specific vapor heat treatment, that have been shown to result in removal and inactivation of infectious agents.

Immunine VH is a highly purified factor IX concentrate containing only traces of other coagulation factors (less than 0.02 IU of factors II, VII and X per IU factor IX). In preclinical trials utilizing extremely high doses of Immunine VH, no thrombotic adverse reactions were observed.

Individual donations of human plasma are combined to form plasma pools. Prior to being used for manufacture of Immunine VH, each plasma pool is tested for the presence of genome sequences of the human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), and hepatitis C virus (HCV) using IQ-PCR.

To prevent the transmission of infective agents by the administration of Immunine VH, prescribed procedures are used for the collection and testing of the source plasma and during the manufacture of the product. They include measures taken for donor and plasma selection, as well as virus removal and inactivation steps during manufacturing.

When stored between 2 and 8°C, Immunine VH, factor IX concentrate (human) vapor heated, Immuno is stable until the date indicated on the label. Within the indicated shelf-life, Immunine VH may temporarily be stored at room temperature (up to 25°C) for a period of 3 months. Record the period of storage at room temperature below the expiration date indicated on the package label. Discard product if stored at room temperature for greater than 3 months. Immunine VH must not be used beyond the expiration date indicated on each pack. The reconstituted solution should be used immediately after preparation (contains no preservative), it should not be refrigerated and any unused portion of it should be discarded.

Immunine VH, factor IX concentrate (human) vapor heated, Immuno, is supplied in a single dose vial accompanied by a vial of Sterile Water for Injection for diluent, USP for diluent, a sterile transfer needle and a sterile filter needle.

IMMUNINE® VH Baxter Factor IX Concentrate (Human) Blood Coagulation Factor

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