FEIBA 100 u/ml Powder and solvent for solution for infusion

- Treatment of bleeding in hemophilia A patients with inhibitors.

- Treatment of bleeding in hemophilia B patients with inhibitors if no other specific treatment is available (see section 5.1).

- Treatment of bleeding in non-hemophiliacs with acquired inhibitors to factor VIII.

- Prophylaxis of bleeding in hemophilia A patients with inhibitors who have experienced a significant bleed or are at high risk of significant bleeding.

FEIBA can be used for all age groups.

The treatment is to be initiated and monitored by a physician experienced in the treatment of coagulation disorders.

Posology

Dosage and duration of treatment depend on the severity of the haemostatic disorder, the localization and the extent of the bleeding, as well as the clinical condition of the patient.

Dosage and frequency of administration should always be guided by the clinical efficacy in each individual case.

As a general guideline, a dose of 50 – 100 U FEIBA per kg body weight is recommended; a single dose of 100 U/kg body weight and a maximum daily dose of 200 U/kg body weight must not be exceeded unless the severity of bleeding warrants and justifies the use of higher doses. See section 4.4.

Paediatric population

The experience in children under 6 years of age is limited; the same dose regimen as in adults should be adapted to the child's clinical condition.

1) Spontaneous bleeding

Joint, muscle and soft tissue hemorrhage

A dose of 50 – 75 U/kg body weight at 12-hour intervals is recommended for minor to moderately severe bleeding. The treatment is to be continued until a clear improvement of the clinical symptoms, e.g. reduction of pain, decrease of swelling or increase of joint mobility, occurs.

For severe muscle and soft tissue bleeding, e.g. retroperitoneal hemorrhages, a dose of 100 U/kg body weight at 12-hour intervals is recommended.

Mucous membrane hemorrhage

A dose of 50 U/kg body weight every 6 hours under careful monitoring of the patient (visual control of bleeding, repeated determination of hematocrit) is recommended. If the bleeding does not stop, the dose may be increased to 100 U/kg body weight, however a daily dose of 200 U/kg body weight must not be exceeded.

Other severe hemorrhages

In severe hemorrhage, such as CNS bleeding, a dose of 100 U/kg body weight at 12-hour intervals is recommended. In individual cases, FEIBA may be administered at 6-hour intervals, until clear improvement of the clinical condition is achieved. (The maximum daily dose of 200 U/kg body weight must not be exceeded!)

2) Surgery

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 postoperative 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 postoperative 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!)

3) Prophylaxis in hemophilia A patients with inhibitors

Prophylaxis of bleeding in patients with a high inhibitor titer and frequent hemorrhages 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.

Prophylaxis of bleeding in patients with a high inhibitor titer during an immune tolerance induction (ITI):

FEIBA may be administered concomitantly with factor VIII administration, in a dosage range of 50 – 100 U/kg body weight, twice per day, until the factor VIII inhibitor titer has decreased to < 2 B.U.*

*1 Bethesda Unit is defined as the amount of antibodies which inhibits 50% factor VIII activity in incubated plasma (2 h at 37 ºC).

4) Use of FEIBA in special patient groups

See Section 5.1 for information in relation to hemophilia B patients with factor IX inhibitor.

In combination with factor VIII concentrate, FEIBA was also used for long term therapy to achieve complete and permanent elimination of the factor VIII inhibitor.

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 the whole blood coagulation time (WBCT), the thromboelastogram (TEG, r-value) and the aPTT usually show only little reduction and do not necessarily correlate with the clinical efficacy. Therefore, these tests have little significance in the monitoring of the therapy with FEIBA. See section 4.4.

Method of administration

Reconstitute the product as described in section 6.6 and slow infusion via the intravenous route. FEIBA should be infused at an infusion rate of 2 U/kg body weight per minute. In patients who have tolerated the infusion rate of 2 U/kg body weight per minute well, in subsequent infusions the rate may be increased up to a maximum of 10 U/kg body weight per minute. See section 5.1.

FEIBA must not be used in the following situations if therapeutic alternatives to FEIBA are available:

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Disseminated Intravascular Coagulation (DIC).

• Acute thrombosis or embolism (including myocardial infarction).

See section 4.4.

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 septicemia) for thromboembolic events. Concomitant treatment with recombinant Factor VIIa 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 hemophilia.

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 (see clinical discussion in the European Public Assessment Report (EPAR) of emicizumab; see also Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017:377:809-818). 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 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 ischemia 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 hemorrhage.

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 hemophilia or with acquired inhibitors to factors VIII, IX and/or XI, the aPTT is prolonged by the underlying disease.

Patients with inhibitor hemophilia 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 titer and a life-threatening hemorrhage 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 ischemia, and signs and symptoms of other thrombotic or thromboembolic events. At the first signs or symptoms of thrombotic and thromboembolic events, the infusion 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 hemophilia B patients with inhibitors

Due to the rarity of the disease, only limited clinical data is available for the prophylaxis of bleeding in hemophilia B patients (literature case reports, n = 4, and clinical data in prophylaxis study 090701, 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 (fetal 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

500 U

FEIBA contains approximately 40 mg sodium per vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

1 000 U

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.

2 500 U

FEIBA contains approximately 200 mg sodium per vial, equivalent to 10% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No adequate and well-controlled studies of the combined or sequential use of FEIBA NF 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 aminocaproic 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 a potential drug interaction cannot be excluded according to available in vitro data and clinical observations (potentially resulting in adverse events such as a thromboembolic event).

Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab when FEIBA was used as part of a treatment regimen for breakthrough bleeding which may result in thromboembolic events and thrombotic microangiopathy (see section 4.4).

Pregnancy

There are no adequate data from the use of FEIBA in pregnant women. 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.

Lactation

There are no adequate data from the use of FEIBA in lactating women. 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.

Fertility

No animal reproduction studies have been conducted with FEIBA, and the effects of FEIBA on fertility have not been established in controlled clinical trials.

See section 4.4 for information on parvovirus B19 infection.

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

FEIBA can precipitate allergic-type hypersensitivity reactions that have included urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and a drop in blood pressure; these reactions can be severe and can be systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). See also section 4.4 Hypersensitivity Reactions.

The adverse reactions presented in this section have been reported from post marketing surveillance as well as from studies with FEIBA for the treatment of bleeding episodes in paediatric 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). The adverse reactions from a third study comparing prophylaxis with on-demand treatment have been added.

Frequency categories are defined according to the following convention:

^* A precise estimate of the rate of these adverse reactions is not possible from the available data.

^a Increase of inhibitor titer (anamnestic response) [not a MedDRA PT] is the rise of previously existing inhibitor titers occurring after the administration of FEIBA. See section 4.4.

^b ADR reported in the original and prophylaxis studies. Frequency shown is from the prophylaxis study only.

^c ADR reported in the prophylaxis study. Frequency shown is from the prophylaxis study.

Class Reactions

Other symptoms of hypersensitivity reactions to plasma-derived products include lethargy and restlessness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The risk of thrombotic and thromboembolic events (including DIC, myocardial infarction, venous thrombosis, and pulmonary embolism) may be increased with high doses of FEIBA. Some of the reported thromboembolic events occurred with doses above 200 U/kg or with patients with other risk factors for thromboembolic events. If signs or symptoms of thrombotic and thromboembolic events are observed, the infusion should be stopped immediately and appropriate diagnostic and therapeutic measures initiated. See section 4.4.

Pharmacotherapeutic group: antihemorrhagics, blood coagulation factors, ATC code: B02BD03.

Although FEIBA was developed in the early seventies and its factor VIII inhibitor bypassing activity has been proven in vitro as well as in vivo, its mode of action is still the subject of scientific discussion. FEIBA, as found with activity assays, is composed of prothrombin complex zymogens which are both procoagulant (prothrombin FVII, FIX, FX) and anticoagulant (protein C) in relatively equal quantities to the arbitrary FEIBA potency unit but its procoagulant enzyme content is relatively low. FEIBA, thus, contains the proenzymes of the prothrombin complex factors, but only very small amounts of their activation products, with the contents of FVIIa being the highest. [Turecek PL and Schwarz HP. Chapter 4: Factor Eight Inhibitor Bypassing Activity, in Production of Plasma Proteins for Therapeutic Use, eds. Joseph Bertolini, Neil Goss, John Curling, Wiley 2013, ISBN: 978-0-470-92431-0].

Current scientific works point to the role of specific components of the activated prothrombin complex, prothrombin (F II) and activated factor X (FXa) in the mode of action of FEIBA. [Turecek PL, Varadi K, Gritsch H, et al. Factor Xa and Prothrombin: Mechanism of Action of FEIBA. Vox Sang. 77: 72-79, 1999]

FEIBA controls bleeding by induction and facilitation of thrombin generation, a process for which the formation of the prothrombinase-complex is crucial. A number of biochemical in vitro and in vivo studies have shown that FXa and prothrombin play a critical role in the activity of FEIBA. The prothrombinase complex has been found to be a major target site for FEIBA. Apart from prothrombin and FXa, FEIBA contains other proteins of the prothrombin complex, which could also facilitate haemostasis in haemophilia patients with inhibitors.

Treatment of hemophilia B patients with inhibitors

The experience in hemophilia B patients with factor IX inhibitors is limited due to the rarity of the disease. Five hemophilia B patients with inhibitors were treated with FEIBA during clinical trials either on-demand, prophylactically or for surgical interventions:

In a prospective open-label, randomized, parallel clinical study in hemophilia A or B patients with persistent high-titer inhibitors (090701, PROOF), 36 patients were randomized to either 12 months ± 14 days of prophylactic or on-demand therapy. The 17 patients in the prophylaxis arm received 85 ± 15 U/kg FEIBA administered every other day and the 19 patients in the on-demand arm were treated individually determined by the physician. Two hemophilia B patients with inhibitors were treated in the on-demand arm and one hemophilia B patient was treated in the prophylactic arm. The median ABR (annualized bleeding rate) for all types of bleeding episodes in patients in the prophylaxis arm (median ABR = 7.9) was less than that of patients in the on-demand arm (median ABR = 28.7), which amounts to a 72.5% reduction in median ABRs between treatment arms.

In another completed prospective non-interventional surveillance study of the perioperative use of FEIBA (PASS-INT-003, SURF) a total of 34 surgical procedures were performed in 23 patients. The majority of patients (18) were congenital hemophilia A patients with inhibitors, two were hemophilia B patients with inhibitors and three were patients with acquired hemophilia A with inhibitors. The duration of FEIBA exposure ranged from 1 to 28 days, with a mean of 9 days and a median of 8 days. The mean cumulative dose was 88 347 U and the median dose was 59 000 U. For hemophilia B patients with inhibitors, the longest exposure to FEIBA was 21 days and the maximum dose applied was 7324 U. In addition, 36 case reports are available when FEIBA was used for treatment and prevention of bleeding episodes in hemophilia B patients with factor IX inhibitor (24 hemophilia B patients with inhibitors were treated on-demand, four hemophilia B patients with inhibitors were treated prophylactically and eight hemophilia B patients with inhibitors were treated for surgical procedures).

The tolerability and safety of FEIBA, reconstituted in regular or 50% reduced volume and of faster infusion rates in hemophilia patients with inhibitors was investigated in a prospective, open-labeled, and randomized crossover study (091501). Thirty-three patients were treated, and twenty-eight patients completed the study. In the study, FEIBA was reconstituted in 50% reduced volume (100 U/ml concentration) and infused IV at infusion rates of 2, 4 and 10 U/kg/min at the labelled dose of 85 U/kg ± 15 U/kg for all patients. The primary endpoints were tolerability and safety with the 50% reduced volume (increased concentration) at standard and increased infusion rates. The study demonstrated that both the higher concentration (100 U/ml) and the higher infusion rates (4 and 10 U/kg/min) were well tolerated and that the safety profile was comparable at the labelled dose of 85 U/kg ± 15 U/kg. The patients who received the 50% reduced volume (increased concentration) at the standard infusion rate of 2 U/kg/min had similar rates of related treatment emergent adverse events (TEAEs) compared to those who received the regular volume (50 U/ml concentration) with the same infusion rate. No related TEAEs were reported at the infusion rate of 4 U/kg/min. Patients who received the 50% reduced volume (100 U/ml) at the infusion rate of 10 U/kg/min experienced 1 related, non-serious TEAE In addition, the patients who received the 50% reduced volume (increased concentration) at the increased infusion rates of 4 and 10 U/kg/min did not experience any serious TEAE, any hypersensitivity reaction, any infusion site reaction, any thrombotic TEAE, or any TEAE leading to drug withdrawal or study discontinuation. Overall, the TEAEs seen in the study were consistent with the known safety profile of FEIBA in patients with hemophilia with inhibitors.

In an open, uncontrolled, non-interventional observational post-authorization safety study of FEIBA (PASS-EU-006), 75 patients (mean age 34.8 years, 70 males and 5 females), of which 73 had hemophilia A with inhibitors and 2 hemophilia B with inhibitors, were treated with FEIBA. Of the 65 patients with congenital hemophilia, 63 had congenital hemophilia A and 2 had congenital hemophilia B. At baseline, 43 patients were prescribed FEIBA for prophylaxis and 32 were prescribed FEIBA for on-demand treatment. Higher infusion rates (> 2 U/kg/min) were used in 6 paediatric patients with age between 11 months and 11 years and in 5 adolescents with age 13 to 16 years.

Out of 320 infusions with an available infusion rate in 7 paediatric and 6 adolescent patients, there were 129 infusions (40.3%) in 2 patients (both paediatric) with infusion rate > 10 U/kg/min, 26 infusions (8.1%) in 7 patients (4 paediatric; 3 adolescents) with infusion rate > 4 and ≤ 10 U/kg/min, 135 infusions (42.2%) in 7 patients (3 paediatric; 4 adolescents) with infusion rate > 2 and ≤ 4 U/kg/min, and 30 infusions (9.4%) in 3 patients (1 paediatric; 2 adolescents) with infusion rate ≤ 2 U/kg/min.

There are also isolated reports on the use of FEIBA in the treatment of patients with acquired inhibitors to factors X, XI and XIII.

As the mode of action of FEIBA is still being discussed, it is not possible to make a conclusive statement about the pharmacokinetic properties.

Based on acute toxicity studies in factor VIII knockout mice and in normal mice and in rats, with doses higher than the maximum daily dose in humans (> 200 U/kg body weight), it can be concluded that the side effects in connection with FEIBA are mainly the result of hypercoagulation due to the pharmacological properties.

Toxicity studies with repeated administration in animal experiments are practically unfeasible as interference occurs through the development of antibodies to heterologous proteins.

Since human blood coagulation factors are not seen as carcinogenic or mutagenic, experimental animal studies, especially in heterologous species, were not considered necessary.

This medicinal product must not be mixed with other medicinal products except the solvent mentioned in section 6.6.

As in all blood coagulation preparations, the efficacy and tolerance of the medicinal product may be impaired by being mixed with other medicinal products. It is advisable to rinse a common venous access with a suitable solution, e.g. with isotonic saline solution, before and after the administration 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 infusion devices may be used with FEIBA.

2 years.

Chemical and physical in-use stability has been demonstrated for 3 hours at room temperature (up to 25 ºC). From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination (controlled and validated aseptic conditions), the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Reconstituted product must not be refrigerated.

Do not store above 25 ºC. Do not freeze.

Store in the original package in order to protect from light. For storage conditions of the reconstituted medicinal product – see section 6.3.

The powder is supplied in a vial made of surface treated, colorless glass (hydrolytic type I for 500 U, and 2 500 U; hydrolytic type II for 1 000 U). The solvent is supplied in a vial made of surface treated, colorless glass (hydrolytic type I for 5 ml, 10 ml and 25 ml). The vials are closed by a stopper made of butyl rubber.

FEIBA 100 U/ml is available in the following presentations:

1 x 500 U

1 x 1 000 U

1 x 2 500 U

Presentation 500 U / 1 000 U / 2 500 U contains

1 vial with 500 U / 1 000 U / 2 500 U FEIBA powder for solution for infusion

1 vial with 5 ml / 10 ml / 25 ml Water for Injections

1 BAXJECT II Hi-Flow

1 disposable syringe

1 butterfly needle with clamp

Not all pack sizes may be marketed.

FEIBA is to be reconstituted immediately prior to administration. The solution should be used immediately (as the preparation does not contain preservatives).

Swirl gently until all material is dissolved. Ensure that FEIBA is completely dissolved; otherwise, less FEIBA Units will 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 cloudy or have deposits.

Open containers must not be re-used.

Do not use the product if its sterile barrier has been breached, its package damaged or if it shows signs of deterioration.

Use only the included Water for Injections and the included device set for reconstitution. If devices other than those enclosed are used, ensure the use of an adequate filter with a pore size of at least 149 µm.

Do not refrigerate after reconstitution.

After complete reconstitution of FEIBA, its injection or infusion should be commenced immediately and must be completed within three hours following reconstitution.

Any unused product or waste material should be disposed of in accordance with local requirements.

Reconstitution of the powder for preparing a solution for infusion with the BaxJect II Hi-Flow:

1. Warm the unopened solvent vial (Water for Injections) to room temperature (15 ºC to 25 ºC), for example by using a water bath for several minutes (max. 37 ºC) if necessary.

2. Remove the protective caps from the powder vial and solvent vial and disinfect the rubber stoppers of both vials. Place the vials on an even surface.

3. Open the packaging of the BAXJECT II Hi-Flow by pulling off the protective foil without touching the contents of the package (Fig. a). Do not remove the transfer system from the package at this point.

4. Turn the package around and press the transparent plastic pin through the rubber stopper of the solvent vial (Fig. b). Now remove the packaging from the BAXJECT II Hi-Flow (Fig. c). Do not remove the blue protective cap from the BAXJECT II Hi-Flow.

5. Now turn the system, consisting of the BAXJECT II Hi-Flow and the solvent vial, in such a way that the solvent vial is on top. Press the purple pin of the BAXJECT II Hi-Flow through the FEIBA vial. The solvent is drawn into the FEIBA vial by vacuum (Fig. d).

6. Swirl, but do not shake the entire system gently until the powder is dissolved. Make sure that the FEIBA has been dissolved completely, as active material may otherwise be retained by the filter in the system.

Infusion

1) Remove the blue protective cap from the BAXJECT II Hi-Flow. Tightly connect the syringe to the BAXJECT II Hi-Flow. DO NOT DRAW AIR INTO THE SYRINGE. (Fig. e). In order to ensure tight connection between syringe and BAXJECT II Hi-Flow, the use of a luer lock syringe is highly recommended (turn syringe in clockwise direction until stop position when mounting).

2) Invert the system so that the dissolved product is on top. Draw the dissolved product into the syringe by pulling the plunger back SLOWLY and ensure that the tight connection between BAXJECT II Hi-Flow and the syringe is maintained throughout the whole pulling process (Fig. f).

3) Disconnect the syringe.

4) If foaming of the product in the syringe occurs, wait until the foam is collapsed. Slowly administer the solution intravenously with the enclosed infusion set.

Do not exceed an infusion rate of 10 U FEIBA/kg body weight per minute.