Feiba

The product is supplied as a freeze-dried substance accompanied by the solvent.
FEIBA is available in sizes of 500 U, to be dissolved in 10 ml of sterilised water for injections. Each pack also includes a kit for reconstitution and injection.
The reconstituted product is intended for intravenous administration.
See Table 1:
Click on icon to see table/diagram/image

FEIBA also contains factors II, IX and X mainly in non-activated form as well as activated factor VII; factor VIII coagulant antigen (F VIII C: Ag) is present in a concentration of up to 0.1 U/lU FEIBA. The factors of the kallikrein-kinin system are present only in trace amounts, if at all.

Treatment and prophylaxis of bleeding in haemophilia A patients with F VIII inhibitor.
Treatment and prophylaxis of bleeding in haemophilia B patients with FIX inhibitor.
Treatment and prophylaxis of bleeding in non haemophiliacs with acquired inhibitors to factors VIII, XI, XII.
In one case FEIBA was successfully used in patient with an inhibitor, suffering from von Willebrand's disease.
FEIBA was also used in combination with Factor VIII concentrate for a continual long term therapy to achieve a complete and permanent elimination of the F VIII inhibitor so as to allow for regular treatment with F VIII concentrate as in patients without inhibitor.

Dosage: Treatment should be initiated and supervised by a physician experienced in the management of hemophilia.
The dosage and duration of the therapy depend on the severity of the disorder of haemostasis, on the location and extent of the bleeding and on the clinical condition of the patient.
Dosage and frequency of administration should always be guided by the clinical efficacy in the individual case.
As a general guide a dose of 50 to 100 U of FEIBA per kg body weight (bw) is recommended, however, a single dose of 100 U/kg body weight and a daily dose of 200 U/kg body weight should not be exceeded unless the severity of bleeding warrants and justifies the use of higher doses. See Precautions.
Coagulation tests such as the whole blood clotting time (WBCT), the thromboelastogramme (TEG, r-value), and the aPTT usually show only a minor shortening and may not correlate with clinical improvement. Consequently, these tests are only of very limited value in monitoring FEIBA therapy.
Spontaneous Haemorrhage: Joint, Muscle and Soft Tissue Haemorrhage: For minor to moderate bleedings a dose of 50-75 U/kg bw is recommended at 12-hour intervals.
Treatment should be continued until clear signs of clinical improvement appear, such as relief of pain, reduction of swelling or mobilization of the joint.
For major muscle and soft tissue haemorrhage, such as retro peritoneal bleeding, a dose of 100 U/kg bw at 12-hour intervals is recommended.
Mucous Membrane Haemorrhage: A dose of 50 U/kg bw is recommended to be given every 6 hour with careful monitoring of the patient (visible bleeding site, repeated measurements of haematocrit). If the haemorrhage does not stop, the dose may be increased to 100 U/kg bw. (Do not exceed the maximum daily dose of 200 U/kg bw.)
Other Severe Haemorrhages: Severe haemorrhages, such as CNS bleedings have been effectively treated with doses of 100 U/kg bw at 12-hour intervals. In individual cases FEIBA may be given at 6-hour intervals until clear clinical improvement is achieved. (Do not exceed the maximum daily dose of 200 U/kg bw.)
In surgical interventions, an initial dose of 100 U/kg body weight may be administered preoperatively, and a further dose of 50-100 U/kg body weight may be administered after 6-12 hours. As a post-operative maintenance dose, 50-100 U/kg body weight may be administered at 6-12-hour intervals; dosage, dosage intervals and duration of the peri- and post-operative therapy are guided by the surgical intervention, the patient's general condition and the clinical efficacy in each individual case. (The maximum daily dose of 200 U/kg body weight must not be exceeded.)
In high responder patients with a history of frequent bleeding, FEIBA can be given concomitant to F VIII concentrate in a dose range of 50 to 100 U/kg bw twice a day until the reduction of the factor VIII inhibitor to 1 B.U.*
*1 Bethesda Unit is defined as that amount of antibody that will inhibit 50% of the F VIII activity off fresh average human plasma after incubation for 2 hours at 37°C.
Prophylaxis of bleeding in patients with a high inhibitor titre and frequent haemorrhages after failed immune tolerance induction (ITI) or when an ITI is not considered: A dose of 70-100 U/kg body weight every other day is recommended. If necessary, the dose may be increased to 100 U/kg body weight per day or it may be decreased gradually.
Administration: Reconstitute the product as described under Instructions for Use/Handling/Disposal under Cautions for Usage and inject or infuse slowly by the intravenous route. Do not exceed an injection/infusion rate of 2 U/kg bw per minute.
FEIBA must be administered as an intravenous injection or infusion. The rate of administration should ensure the comfort of the patient and should not exceed a maximum of 2 U/kg body weight per minute.
It is recommended that every time FEIBA is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
Monitoring: In case of inadequate response to treatment with the product, it is recommended that a platelet count be performed because a sufficient number of functionally intact platelets are considered to be necessary for the efficacy of the product.
Due to the complex mechanism of action, no direct monitoring of active ingredients is available. Coagulation tests such as whole blood clotting time (WBCT) and the aPTT may not correlate with clinical improvement.

Some reported thromboembolic events have occurred with doses above 200 U/kg. If signs or symptoms of thromboembolic events are observed, the infusion should be stopped immediately and appropriate diagnostic and therapeutic measures initiated. See Warnings and Precautions.

FEIBA must not be used in the following situations if therapeutic alternatives to FEIBA are available: Hypersensitivity to the product.
Disseminated intravascular Coagulation (DIC): Laboratory and/or clinical symptoms which are clearly indicative of DIC.
Laboratory, histological and/or clinical signs of liver damage; due to the delayed clearance of activated coagulation factors such patients are at an increased risk of developing DIC.
Myocardial infarction, Acute Thrombosis and/or Embolism: In patients with a tentative or definite diagnosis of coronary heart disease as well as in patients with acute thrombosis and/or embolism the use of FEIBA is only indicated in life-threatening bleeding episodes.

Viral Safety: Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, [e.g., viruses]. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses.
The measures taken are considered effective for enveloped viruses such as HIV, HBV, and HCV and for the nonenveloped viruses HAV. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. in hemolytic anaemia).
Appropriate vaccination (against hepatitis A and B) should be considered for patients in regular/repeated receipt of plasma-derived products including FEIBA.
It is recommended that every time FEIBA is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Special Precautions for Use: Allergic-Type Hypersensitivity Reactions: FEIBA can precipitate allergic-type hypersensitivity reactions that have included, urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been reported.
At the first sign or symptom of an infusion/hypersensitivity reaction, FEIBA administration should be stopped and medical care initiated as appropriate.
When considering re-exposure to FEIBA in patients with known or suspected hypersensitivity to the product, the expected benefit and the risk of re-exposure must be carefully weighed, taking into account the known or suspected type of the patient's hypersensitivity (allergic or non-allergic), including potential remedial and/or preventative therapy or alternative therapeutic agents.
Minor reactions may be controlled by antihistamines. In case of shock, the current medical standards for shock treatment are to be observed.
As the quantity of sodium in the maximum daily dose may exceed 200 mg, special care should be taken with individuals on a low sodium diet.
Risk of Thromboembolic Events: Thromboembolic events, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, have occurred in the course of treatment with FEIBA.
Some of these events occurred with doses above 200 U/kg/day or in patients with other risk factors (including DIC, advanced atherosclerotic disease, crush injury or septicemia) for thromboembolic events. Concomitant treatment with recombinant Factor VIIa may increase the risk of developing a thromboembolic event.
The possible presence of such risk factors should always be considered in patients with congenital and acquired hemophilia.
FEIBA should be used with particular caution in patients at risk of DIC, arterial or venous thrombosis.
Thrombotic microangiopathy (TMA) has not been reported in FEIBA clinical studies. Cases of TMAs were reported in an emicizumab clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding. The safety and efficacy of FEIBA for breakthrough bleeding in patients receiving emicizumab has not been established. Consider the benefits and risks if FEIBA must be used in a patient receiving emicizumab prophylaxis. If treatment with FEIBA is considered required for patients receiving emicizumab, patients must be closely monitored by their physicians.
At the first signs or symptoms of thromboembolic events, the infusion should be stopped immediately and appropriate diagnostic and therapeutic measures initiated.
Monitoring of Therapy: Single dose of 100 U/kg bw and daily dose of 200 U/kg bw should not be exceeded unless the severity of bleeding warrants and justifies the use of higher doses.
When used to stop bleeding, the product should be given only for as long as absolutely necessary to achieve the therapeutic goal.
In case of significant clinical changes in blood pressure, pulse rate, respiratory distress, chest pain and cough, the infusion should be stopped promptly and appropriate diagnostic and therapeutic measures are to be initiated.
Laboratory results indicative of DIC are decreased fibrinogen values, decreased platelet count, and/or presence of fibrin/fibrinogen degradation products (FOP). Other indications of DIC include significantly prolonged thrombin time, prothrombin time, or aPTT.
Non-Haemophilic Patients: Non-haemophilic patients with acquired inhibitor against factors VIII, XI or XII may have both, a bleeding tendency and an increased risk of thrombosis at the same time.
Laboratory Tests and Clinical Efficacy: In vitro tests to control efficacy such as aPTT, whole blood clotting time (WBCT), and thromboelastogramme (TEG) may not correlate with clinical improvement. For this reason, attempts to normalize these values by increasing the dose of FEIBA may not be successful and are strongly discouraged because of the potential hazard of inducing DIC by overdosage.
Significance of Platelet Count: In case of inadequate response to treatment with FEIBA it is recommended to perform a platelet count, since a sufficient number of functionally intact platelet is considered necessary for the efficacy of FEIBA.
Precautions: Due to patient-specific factors the response to a bypassing agent can vary, and in a given bleeding situation patients experiencing insufficient response to one agent may respond to another agent. In case of insufficient response to one bypassing agent, use of another agent should be considered.
Administration of FEIBA to patients with inhibitors may result in an initial "anamnestic" rise in inhibitor levels. Upon continued administration of FEIBA, inhibitors may decrease over time.
Clinical and published data suggest that the efficacy of FEIBA is not reduced.
After administration of high doses of FEIBA, the transitory rise of passively transferred Hepatitis B surface antibodies may result in misleading interpretation of positive results in serological testing.
FEIBA contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D, may interfere with some serological tests for red cell antibodies, such as antiglobulin test (Coombs test).
The amount of sodium in the maximum daily dose may exceed the recommended daily allowance of dietary sodium for patients on a low sodium diet. In these patients, the amount of sodium from the product should be calculated and taken into account when determining dietary sodium intake.
FEIBA 500 U contains approximately 40 mg sodium (calculated) per vial.
The recording of the product name and batch number is strongly recommended following each administration of this product in order to be able to identify the batch of product received.
Effects on Ability to Drive and Use Machines: There are no indications that the product may impair the ability to drive or to operate machines.
Use in Children: Case reports and limited clinical trial data suggest that FEIBA can be used in children younger than 6 years of age.

There are no adequate data from the use of FEIBA in pregnant or lactating women.
No animal reproduction studies have been conducted with FEIBA.
Physicians should balance the potential risks and only prescribe FEIBA if clearly needed, taking into consideration that pregnancy and the postpartum period confer an increased risk of thromboembolic events, and several complications of pregnancy that are associated with an increased risk of DIC.
Due to the increased risk of thrombosis during pregnancy, FEIBA should only be used under careful medical monitoring and if no alternative therapy is available.
See Warnings for information on Parvovirus B19 infection.

Adverse Reactions From Clinical Trials: The adverse reactions presented in this section have been reported from 2 studies with FEIBA for the treatment of bleeding episodes in pediatric and adult patients with hemophilia A or B and inhibitors to factors VIII or IX. One study also enrolled acquired hemophilia patients with factor VIII inhibitors (2 of 49 patients). (See Table 2.)

Click on icon to see table/diagram/image

Post-marketing Adverse Reactions: The following adverse reactions have been reported in the post-marketing experience.
BLOOD AND LYMPHATIC SYSTEM DISORDERS: Disseminated intravascular coagulation.
IMMUNE SYSTEM DISORDERS: Anaphylactic reaction.
NERVOUS SYSTEM DISORDERS: Paresthesia, Thrombotic stroke, Embolic stroke.
CARDIAC DISORDERS: Myocardial infarction, Tachycardia.
VASCULAR DISORDERS: Thrombosis, Venous thrombosis, Arterial thrombosis, Hypertension, Flushing.
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Pulmonary embolism, Bronchospasm, Wheezing, Cough.
GASTROINTESTINAL DISORDERS: Vomiting, Diarrhea, Abdominal discomfort.
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Urticaria, Pruritus.
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malaise, Feeling hot, Injection site pain.

No adequate and well-controlled studies of the combined or sequential use of FEIBA and recombinant Factor VIIa, antifibrinolytics, or emicizumab have been conducted.
The possibility of thromboembolic events should be considered when systemic antifibrinolytics such as tranexamic acid and aminocarpoic acid are used during treatment with FEIBA. Therefore, antifibrinolytics should not be used for approximately 6 to 12 hours after the administration of FEIBA.
In cases of concomitant rFVIIa use, according to available in vitro data and clinical observations a potential drug interaction may occur (potentially resulting in adverse events such as a thromboembolic event).
Benefit-risk evaluation of FEIBA to be administered to emicizumab-exposed patients is required, and patients must be closely monitored by their physicians.

Incompatibilities: No compatibility studies have been performed with the product. Therefore, FEIBA must not be mixed with other medicinal products or solvents before administration as this might impair the efficacy and safety of the product. It is advisable to rinse a common venous access with isotonic saline prior to and after infusion of FEIBA.
Coagulation factors derived from human plasma may be adsorbed by the inner surfaces of certain types of injection/infusion devices. If this were to occur, it could result in failure of therapy. Therefore, only approved plastic injection/infusion devices may be used with FEIBA.
Instructions for Use/Handling/Disposal: FEIBA is to be reconstituted just prior to administration. Aseptic technique should be used throughout the entire reconstitution process and the solution should then be used immediately (as the preparation contains no preservatives).
Swirl gently until all material is dissolved. Ensure that FEIBA is completely dissolved; otherwise, active material will not pass through the device filter.
After reconstitution, the solution should be inspected for particulate matter and discoloration prior to administration.
Do not use solutions which are turbid or have deposits.
Any unused solution must be discarded appropriately.
Mixing of FEIBA with other products or substances must be avoided. It is advisable to flush venous access lines with isotonic saline prior to and after infusion of FEIBA.
If devices other than those supplied with FEIBA are used, ensure use of an adequate filter.
Reconstitution of dried substance: 1. Warm the unopened vial containing the solvent (sterilised water for injections) to room temperature, e.g. using a sterile water bath for warming within several minutes (max. +37°C).
2. Remove protective caps from the concentrate vial and solvent vial and disinfect the rubber stoppers of both.
3. Remove protective covering from one end of the supplied "transfer needle" by twisting and pulling. Insert the exposed needle through the rubber stopper of the solvent vial.
4. Remove protective covering from the other end of the transfer needle taking care not to touch the exposed end.
5. Invert the solvent vial over the concentrate vial, and insert the free end of the transfer needle through the rubber stopper of the concentrate vial. The solvent will be drawn into the concentrate vial by vacuum.
6. Disconnect the two vials by removing the needle from the concentrate vial. Gently agitate or rotate the concentrate vial to accelerate dissolution.
7. Upon complete reconstitution of the concentrate, insert the enclosed "aeration needle" provided and any foam will collapse. Remove aeration needle.
Injection/Infusion: 1. Remove protective covering from the supplied "filter needle" by twisting and pulling and fit the needle onto a sterile disposable syringe. Draw the solution into the syringe.
2. Disconnect the filter needle from the syringe and slowly inject the solution intravenously with the enclosed "winged set for injection" (or the enclosed disposable needle).
If administered by infusion, a disposable infusion set with adequate filter is to be used.
Do not exceed an injection/infusion rate of 2 units FEIBA per kg of body weight per minute.

Store at 2-8°C. Do not freeze.
Within the indicated shelf life the product may be stored at room temperature (max. +25°c) for a period of up to 6 months. No data are available on the effect of a subsequent (second) storage period at 2-8°C. The start of room temperature storage should be noted on the package.
SHELF LIFE: The freeze-dried product has a shelf life of two years.
Chemical and physical stability of the reconstituted product has been demonstrated for 3 hours at 20-25°C.
Considering microbiological aspects, FEIBA should be used immediately after reconstitution.
Reconstituted product must not be returned to the refrigerator.

Haemostatics

B02BD02 - coagulation factor VIII ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.

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