Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

WARNINGS
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.

Patients should be informed of the early signs of hypersensitivity reactions, for example erythema, skin rash, generalized urticaria, pruritus, breathing difficulties/dyspnoea, tightness of the chest, general indisposition, dizziness and drop in blood pressure up to allergic shock.

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 suspected hypersensitivity to the product or any of its components, 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.

Thrombotic and Thromboembolic Events
Thrombotic and 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 septicaemia) for thromboembolic events. Concomitant treatment with recombinant Factor Vlla (rFVIIa) likely increases the risk of developing a thromboembolic event. The risk of thrombotic and thromboembolic events may be increased with high doses of FEIBA.

The possible presence of such risk factors should always be considered in patients with congenital and acquired haemophilia.

FEIBA should be used with particular caution and only if there are no therapeutic alternatives in patients with an increased risk of thromboembolic complications. These include, but are not limited to, patients with a history of coronary heart disease, liver disease, DIC, arterial or venous thrombosis, post-operative immobilization, elderly patients and neonates.

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.
Therefore, benefit-risk evaluation of FEIBA to be administered to emicizumab exposed patients is required, and patients must be closely monitored by their physicians (see also section 4.5).
If signs or symptoms of thrombotic and thromboembolic events are observed, the infusion/injection should be stopped immediately and appropriate diagnostic and therapeutic measures initiated.

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.
When used to stop bleeding, the product should be given only for as long as absolutely necessary to achieve the therapeutic goal.

Therapy monitoring
Individual doses of 100 U/kg body weight and daily doses of 200 U/kg body weight must not be exceeded. Patients receiving 100 U/kg body weight or more must be monitored carefully, particularly for the development of DIC and/or acute coronary ischaemia and for symptoms of other thrombotic or thromboembolic events. High doses of FEIBA should be administered only as long as strictly necessary – in order to stop a haemorrhage.

If clinically significant changes in blood pressure or pulse rate, respiratory distress, coughing or chest pain occur, the infusion is to be discontinued immediately and appropriate diagnostic and therapeutic measures are to be initiated. Significant laboratory parameters for DIC are a drop in fibrinogen, a drop of the thrombocyte count and/or the presence of fibrin/fibrinogen degradation products (FDP). Other parameters for DIC are a clearly prolonged thrombin time, prothrombin time or aPTT. In patients with inhibitor haemophilia or with acquired inhibitors to factors VIII, IX and/or XI, the aPTT is prolonged by the underlying disease.

Patients with inhibitor haemophilia or with acquired inhibitors to coagulation factors, who are treated with FEIBA, may have increased bleeding tendency as well as increased risk of thrombosis at the same time.

Laboratory tests and clinical efficacy
In vitro tests, such as aPTT, whole blood coagulation time (WBCT) and thromboelastograms (TEG) as proof of efficacy do not have to correlate with the clinical picture. Therefore, attempts to normalize these values by increasing the dose of FEIBA cannot be successful, and are even to be strongly rejected because of the possible risk of triggering a DIC through overdosing.

Significance of the thrombocyte count
If the response to treatment with FEIBA is inadequate, conducting a thrombocyte count is recommended since a sufficient number of functionally intact thrombocytes is necessary for the efficacy of FEIBA.

PRECAUTIONS
Thrombotic and Thromboembolic Complications
In the following situations, FEIBA is to be applied only if no reaction to treatment with suitable blood coagulation factor concentrates can be expected – e.g., in case of a high inhibitor titre and a life- threatening haemorrhage or risk of bleeding (e.g. post-traumatically or postoperatively): 
•   Disseminated intravascular coagulation (DIC): laboratory findings and/or clinical symptoms •   Liver damage: Due to the delayed clearance of activated coagulation factors, patients with impaired liver function are at increased risk of developing DIC.
•   Coronary heart disease, acute thrombosis and/or embolism.

Patients who receive FEIBA should be monitored for the development of DIC, acute coronary ischaemia, and signs and symptoms of other thrombotic or thromboembolic events. At the first signs or symptoms of thrombotic and thromboembolic events, the infusion/ injection should be stopped immediately and appropriate diagnostic and therapeutic measures initiated.

Discordant Response to Bypassing Agents
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.

Anamnestic Responses
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.

Interference with Laboratory Tests
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).
Paediatric population
Case reports and limited clinical trial data suggest that FEIBA can be used in children younger than 6 years of age. The same dose regimen as in adults should be adapted to the child’s clinical condition.

Elderly
There are only limited clinical trial data with the use of FEIBA in elderly patients.

Prophylactic use in haemophilia B patients with inhibitors
Due to the rarity of the disease, only limited clinical data is available for the prophylaxis of bleeding in haemophilia B patients (literature case reports, n = 6, clinical data in prophylaxis study 090701, n = 1 and PASS-EU-006, n=1).

Transmission of infectious agents
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. 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.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped virus 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. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/ repeated receipt of human plasma-derived products including FEIBA.

Sodium

FEIBA contains approximately 80 mg sodium per vial, equivalent to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7 Effects on ability to drive and use machines
FEIBA has no, or negligible, influence on the ability to drive or to use machines.