Feiba 100 U/ml powder and solvent for solution for infusion: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

FEIBA 100U/ml powder and solvent for solution for infusion

anti-inhibitor coagulant complex

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

Keep this leaflet, as you may need to read it again.
If you have any questions, consult your doctor or pharmacist.
This medicine has been prescribed for you only, and you should not give it to others, even if they have the same symptoms as you, because it could harm them.
If you experience any adverse reactions, consult your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

What FEIBA is and what it is used for
What you need to know before using FEIBA
How to use FEIBA
Possible side effects
How to store FEIBA
Contents of the pack and other information

1. What FEIBA is and what it is used for

FEIBA is a preparation derived from human plasma that promotes hemostasis, even when levels of specific coagulation factors are reduced or absent.

FEIBA is used for the treatment and prophylaxis of bleeding episodes in patients with hemophilia A who have inhibitors.

FEIBA is used for the treatment of bleeding episodes in patients with hemophilia B who have inhibitors.

FEIBA can be used for the treatment and prophylaxis of bleeding episodes in non-hemophilic patients with acquired factor VIII inhibitors.

In addition, FEIBA is used for prophylaxis during surgical procedures in patients with hemophilia A who have inhibitors.

FEIBA can be used in all age groups.

2. What you need to know before using FEIBA

Inform your doctor if you have any known allergies.

Inform your doctor if you are on a low-sodium diet.

Do not use FEIBA

FEIBA should only be used under the following circumstances, for example, if due to very high inhibitor titers, no response to treatment with the appropriate coagulation factor concentrate is expected:

if you are allergic (hypersensitive) to anti-inhibitor coagulant complex or to any of the other components of this medicine (listed in section 6).
if you have disseminated intravascular coagulation (DIC). (DIC = consumption coagulopathy, a potentially life-threatening condition characterized by excessive blood clotting, with pronounced formation of blood clots in blood vessels. This leads to systemic consumption of coagulation factors.)
in cases of acute myocardial infarction, thrombosis, and/or acute embolism: FEIBA should only be used in life-threatening hemorrhagic episodes.

Warnings and precautions

Talk to your doctor before starting to use FEIBA, as hypersensitivity reactions may occur, as with all plasma-derived products administered intravenously. To recognize an allergic reaction as early as possible, you should be aware that potential initial symptoms of a hypersensitivity reaction may include:

erythema (skin redness)
skin rash
appearance of hives on the skin (urticaria)
itching all over the body
swelling of the lips and tongue
difficulty breathing/dyspnea
chest tightness
general malaise
dizziness
drop in blood pressure

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

If you experience any of these symptoms, you must stop administration immediately and contact your doctor right away. The symptoms described may indicate anaphylactic shock. Severe symptoms require early emergency treatment.

Your doctor will only re-administer FEIBA to patients suspected of hypersensitivity to the product or any of its components after carefully weighing the expected benefit against the risk of re-exposure and/or lack of response to another preventive treatment or alternative therapy.

If you experience significant changes in blood pressure or pulse rate, breathing difficulties, cough, or chest pain, stop administration immediately and contact your doctor. Your doctor will initiate appropriate diagnostic and therapeutic measures.
In patients with hemophilia with inhibitors or acquired inhibitors to coagulation factors: during treatment with FEIBA, these patients may experience an increased tendency to bleed and an increased risk of thrombosis simultaneously.

Thrombotic and thromboembolic events, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, have occurred during treatment with FEIBA. Concomitant use with recombinant factor VIIa may increase the risk of thromboembolic events. Some thromboembolic events have occurred with high-dose FEIBA treatment.

In a clinical trial conducted by another company to evaluate emicizumab (a medication to prevent bleeding in patients with hemophilia A), some patients who experienced breakthrough bleeding were treated with FEIBA to control bleeding, and some of these patients developed thrombotic microangiopathy (TMA). TMA is a serious and potentially life-threatening condition. When this condition occurs, vascular wall damage may occur, and clots may form in small blood vessels. In some cases, this can lead to kidney damage and damage to other organs. In the event of breakthrough bleeding while on emicizumab prophylaxis, contact your hematologist or Hemophilia Treatment Center immediately.

When medicines derived from human plasma or blood are administered, certain measures must be taken to prevent transmission of infections to patients. These measures include careful donor selection to exclude those at risk of carrying infectious diseases, testing of individual donations and plasma pools for specific markers of infection, and inclusion of steps in the manufacturing process to inactivate or remove viruses. Nevertheless, when medicines derived from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to emerging viruses or those of unknown origin, as well as other types of infections.

These measures are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, as well as against non-enveloped hepatitis A virus. However, the measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with weakened immune systems or in patients with certain types of anemia (e.g., sickle cell disease or hemolytic anemia).

Your doctor may recommend vaccination against hepatitis A and hepatitis B if you are receiving regular or repeated plasma-derived products for factor VIII inhibitors.

After administration of high doses of FEIBA, the transient increase in passively transferred hepatitis B surface antibodies may lead to misinterpretation of serological test results as positive.

FEIBA is a plasma-derived product and may contain substances that react when infused into patients, leading to the presence of isohemagglutinins (antibodies that cause agglutination of red blood cells from another person). This process may lead to misinterpretation of blood test results.

It is strongly recommended that each time a dose of FEIBA is administered, the name of the medicine and the batch number used should be recorded to maintain traceability of the batches used.

Children

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

Other medicines and FEIBA

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines.

Adequate and well-controlled studies on the combined or sequential use of FEIBA with recombinant factor VIIa, antifibrinolytics, or emicizumab have not been conducted. When systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used during treatment with FEIBA, the possibility of thromboembolic events should be considered. Therefore, antifibrinolytics should not be used until approximately 6 to 12 hours after administration of FEIBA.

Based on available in vitro data and clinical observations, a potential drug interaction cannot be excluded when FEIBA is used concomitantly with recombinant factor VIIa, which could potentially lead to a thromboembolic event. Inform your doctor if you are to be treated with FEIBA after receiving emicizumab (a medication to prevent bleeding in patients with hemophilia A), as specific warnings and precautions must be considered. Your doctor will need to closely monitor you.

As with all products used for blood coagulation, FEIBA must not be mixed with other medications prior to administration, as this may impair the product's efficacy and tolerability. It is advisable to flush the intravenous line with isotonic saline solution before and after administration of FEIBA.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Your doctor will decide whether FEIBA can be used during pregnancy and breastfeeding. Due to the increased risk of thrombosis during pregnancy, FEIBA should only be administered under close medical supervision and only if clearly indicated. For information on the risk of infection with parvovirus B19, see section Warnings and precautions.

Driving and use of machines

There are no signs that FEIBA may affect the ability to drive or use machines.

FEIBA contains sodium

500 U

This medicine contains approximately 40 mg of sodium (main component of table/cooking salt) per vial. This corresponds to 2% of the maximum daily recommended sodium intake for an adult.

1,000 U

This medicine contains approximately 80 mg of sodium (main component of table/cooking salt) per vial. This corresponds to 4% of the maximum daily recommended sodium intake for an adult.

2,500 U

This medicine contains approximately 200 mg of sodium (main component of table/cooking salt) per vial. This corresponds to 10% of the maximum daily recommended sodium intake for an adult.

3. How to use FEIBA

Reconstitute the lyophilized FEIBA powder with the solvent provided and administer the solution intravenously.

Follow exactly the administration instructions for this medicine given by your doctor. If in doubt, consult your doctor or pharmacist again.

Your doctor will determine the frequency and dose required for you personally, taking into account the severity of the blood coagulation disorder, the location and extent of bleeding, and your clinical condition and response to the preparation. Do not change the dosage prescribed by your doctor and do not stop administering the preparation.

If you feel that the effect of FEIBA is too strong or too weak, consult your doctor or pharmacist.

Warm the product to room temperature or body temperature before administration, if necessary.

FEIBA must be reconstituted immediately before use. The solution should be used immediately (as the preparation does not contain preservatives).

Gently swirl until all of the product is dissolved. Ensure that FEIBA is completely dissolved, otherwise fewer units of FEIBA will pass through the filter of the administration set.

Solutions that appear cloudy or contain deposits must be properly discarded.

Do not reuse opened containers.

Use only the water for injections and the reconstitution equipment supplied in the package.

If equipment other than that supplied is used, ensure that an appropriate filter with a pore size of at least 149 micrometers is used.

Do not use the product if its sterility barrier system or container is damaged or shows any signs of deterioration.

Do not refrigerate after reconstitution.

After complete reconstitution of FEIBA, injection or infusion must begin immediately and be completed within 3 hours of reconstitution.

Disposal of unused medicine and of all materials that have come into contact with it must be carried out in accordance with local regulations.

Reconstitution of the powder for preparation of a solution for infusion using the BAXJECT II Hi-Flow device:

Warm the unopened solvent vial (water for injections) to room temperature or up to a maximum of 37°C, if necessary, for example by using a water bath for several minutes.
Remove the protective caps from both the powder vial and the solvent vial, and disinfect the rubber stoppers of both vials. Place the vials on a flat surface.
Open the BAXJECT II Hi-Flow package by removing the protective foil without touching the contents of the package (Figure a). Do not remove the device from its packaging.
Turn the package over and insert the transparent plastic tip through the rubber stopper of the solvent vial (Figure b). Now remove the BAXJECT II Hi-Flow device from its packaging (Figure c). Do not remove the blue protective cap from the BAXJECT II Hi-Flow device.
With the BAXJECT II Hi-Flow device attached to the solvent vial, invert the system so that the solvent vial is on top of the device. Insert the purple plastic tip of the BAXJECT II Hi-Flow device through the stopper of the FEIBA vial. The vacuum will draw the solvent into the FEIBA vial (Figure d).
Gently swirl, without shaking, the entire system until all the powder is dissolved. Ensure that FEIBA is completely dissolved; otherwise, active ingredient may be retained in the filter of the device.

Figure a	Figure b	Figure c

Infusion

Use aseptic technique throughout the procedure!

Remove the blue protective cap from the BAXJECT II Hi-Flow device. Firmly connect the syringe to the BAXJECT II Hi-Flow device. DO NOT INTRODUCE AIR INTO THE SYRINGE. (Figure e). The use of a Luer Lock syringe is strongly recommended to ensure a secure connection between the syringe and the BAXJECT II Hi-Flow device (rotate the syringe clockwise until it stops).
Invert the system so that the dissolved product is at the top. Draw the dissolved product into the syringe by slowly pulling back the plunger, ensuring that the secure connection between the BAXJECT II Hi-Flow device and the syringe is maintained throughout the process while pulling back the syringe plunger (Figure f).
Disconnect the syringe.
If foam appears in the syringe, wait until the foam dissipates. Administer the solution slowly by intravenous infusion using the infusion set provided.

Figure d	Figure e	Figure f

Do not exceed an infusion rate of 10 IU of FEIBA/kg per minute.

If you use more FEIBA than you should

Inform your doctor immediately. Overdosing on FEIBA may increase the risk of adverse effects such as thromboembolism (formation of a blood clot with redness in blood vessels), disseminated intravascular coagulation (DIC), or myocardial infarction. Some of the reported thromboembolic events occurred with doses exceeding 200 IU/kg/day or in patients with other risk factors for thromboembolic events. If signs or symptoms of a thromboembolic event occur, the infusion must be stopped immediately and appropriate diagnostic and therapeutic measures should be taken.

In case of overdose or accidental ingestion, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number 91 562 04 20, indicating the medication and the amount ingested.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Frequent adverse effects (may affect up to 1 in 10 patients)

Hypersensitivity, headache, dizziness, hypotension, skin rash, positive hepatitis B surface antibodies.

Adverse effects with unknown frequency (cannot be estimated from available data)

Blood and lymphatic system disorders: disseminated intravascular coagulation (DIC), increased inhibitor titre.

Immune system disorders: anaphylactic reactions, generalized skin rash (urticaria).

Nervous system disorders: numbness sensation in limbs (hypoesthesia), abnormal or reduced sensation (paresthesia), stroke (thrombotic event, embolic event), somnolence, altered taste sensation (dysgeusia).

Cardiac disorders: heart attack (myocardial infarction), rapid heartbeat (tachycardia).

Vascular disorders: blood clot formation with redness of blood vessels (thromboembolic events, venous and arterial thrombosis), increased blood pressure (hypertension), flushing.

Respiratory, thoracic and mediastinal disorders: pulmonary artery blockage (pulmonary embolism), airway obstruction (bronchospasm), chest wheezing, cough, difficulty breathing (dyspnea).

Gastrointestinal disorders: vomiting, diarrhea, abdominal discomfort, feeling of illness (nausea).

Skin and subcutaneous tissue disorders: numbness sensation in the face, swelling of the face, tongue, and lips (angioedema), generalized skin rash (urticaria), itching (pruritus).

General disorders and administration site conditions: injection site pain, general malaise, feeling of warmth, chills, fever, chest pain, chest discomfort.

Investigations: drop in blood pressure, increased blood fibrin D-dimer levels.

Rapid intravenous infusion may cause sharp pain and numbness sensation in the face and limbs, as well as a decrease in blood pressure.

Cases of myocardial infarction have been reported after administration of doses exceeding the maximum daily dose and/or prolonged administration and/or in the presence of thromboembolic risk factors.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaram.es.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of FEIBA

Keep this medicine out of the sight and reach of children.

Do not store above 25 °C. Do not freeze.

Store in the original packaging to protect from light.

Do not use this medicine after the expiry date stated on the label and on the container. The expiry date refers to the last day of the month indicated.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of FEIBA

Powder

The active substance per vial is anti-inhibitor coagulant complex.
1 ml contains 100 U of anti-inhibitor coagulant complex.
FEIBA 100 U/ml is available in three presentations:
The 500 U presentation contains 500 U (units) of anti-inhibitor coagulant complex in 200–600 mg of human plasma protein.
The 1,000 U presentation contains 1,000 U (units) of anti-inhibitor coagulant complex in 400–1,200 mg of human plasma protein.
The 2,500 U presentation contains 2,500 U (units) of anti-inhibitor coagulant complex in 1,000–3,000 mg of human plasma protein.

FEIBA also contains factors II, IX, and X, primarily in non-activated form, as well as activated factor VII. Factor VIII coagulant antigen (FVIII C:Ag) and components of the kallikrein-kinin system are present only in trace amounts.

Other components are sodium chloride and sodium citrate.

Solvent

Water for injections.

Appearance of the Product and Contents of the Package

The product is presented as a lyophilized or friable solid powder, white to off-white or pale green in color. The reconstituted solution has a pH between 6.5 and 7.3.

The powder and solvent are supplied in glass vials closed with rubber stoppers.

Presentation: 1 x 500 U
1 x 1,000 U
1 x 2,500 U

Only certain package sizes may be commercially available.

Contents of the Package:

1 vial containing 500 U / 1,000 U / 2,500 U of FEIBA – powder for solution for infusion
1 vial containing 5 ml / 10 ml / 25 ml of water for injections
1 reconstitution set BAXJECT II Hi-Flow
1 disposable syringe
1 butterfly needle

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Baxalta Innovations GmbH
Industriestrasse, 67
1221 Vienna, Austria

Manufacturer:

Takeda Manufacturing Austria AG
Industriestrasse, 67
1221 Vienna, Austria

Local Representative of the Marketing Authorization Holder

Takeda Farmacéutica España, S.A.
Calle Albacete, 5, 9th floor
Edificio Los Cubos
28027 Madrid
Spain
Tel: +34 91 790 42 22

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Austria:
FEIBA 100 E./ml Pulver und Lösungsmittel zur Herstellung einer Infusionslösung

Bulgaria:
FEIBA 100 U/ml powder and solvent for solution for infusion

Croatia:
FEIBA 100 U/ml prašak i otapalo za otopinu za infuziju

Cyprus:
FEIBA 100 U/ml κόνις και διαλύτης για διάλυμα προς έγχυση

Czech Republic:
FEIBA

Denmark:
Feiba

Estonia:
FEIBA 100 Ü/ML

Finland:
Feiba

Germany:
FEIBA 500 E konzentriert
FEIBA 1000 E konzentriert
FEIBA 2500 E konzentriert

Greece:
FEIBA 100 U/ml κόνις και διαλύτης για διάλυμα προς έγχυση

Ireland:
FEIBA 100 U/ml powder and solvent for solution for infusion

Latvia:
Feiba 100 V/ml pulveris un šķidrinātājs infūziju šķīduma pagatavošanai

Lithuania:
Feiba 100 V/ml milteliai ir tirpiklis infuziniam tirpalui

Malta:
FEIBA 100 U/ml powder and solvent for solution for infusion

Netherlands:
FEIBA 100 E/ML, poeder en oplosmiddel voor oplossing voor injectie

Norway:
Feiba

Romania:
FEIBA 100 U/ml pulbere si solvent pentru solutie injectabila

Slovakia:
FEIBA 100 U/ml prášok a rozpúšťadlo na infúzny roztok

Slovenia:
FEIBA 100 e./ml prašek in vehikel za raztopino za infundiranje

Spain:
FEIBA 100 U/ml polvo y disolvente para solución para perfusión

Sweden:
Feiba 100 enheter/ml pulver och vätska till infusionsvätska, lösning

Date of the most recent review of this summary: 08/2024

Detailed information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended for healthcare professionals only:

Treatment must be initiated and monitored under the supervision of a physician experienced in the management of coagulation disorders.

Dosage

The dose and duration of therapy depend on the severity of the hemostatic dysfunction, the location and severity of bleeding, and the patient's clinical condition.

The dose and frequency of administration should always be determined based on clinical efficacy in each individual case.

As a general guideline, doses of 50–100 U/kg of FEIBA are recommended; a single dose should not exceed 100 U/kg and the maximum daily dose should not exceed 200 U/kg, unless the severity of bleeding requires and justifies higher doses.

Due to patient-specific factors, response to a bypassing agent may vary, and in a given bleeding situation, patients who respond inadequately to one agent may respond to another. If there is an inadequate response to a bypassing agent, consideration should be given to using an alternative agent.

Paediatric population

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

Spontaneous bleeding

Bleeding into joints, muscles, and soft tissue

For mild to moderate bleeding, a dose of 50–75 U/kg every 12 hours is recommended. Treatment should continue until clear signs of clinical improvement are evident, such as reduced pain, decreased swelling, or improved joint mobility.

For severe bleeding into muscles and soft tissue, e.g., retroperitoneal hemorrhage, a dose of 100 U/kg every 12 hours is recommended.

Mucosal membrane bleeding

A dose of 50 U/kg every 6 hours is recommended, with strict patient monitoring (visual control of bleeding, repeated hematocrit measurements). If bleeding is not controlled, the dose may be increased to 100 U/kg; however, doses exceeding 200 U/kg should not be administered.

Other severe bleeding

In severe bleeding, such as CNS bleeding, a dose of 100 U/kg every 12 hours is recommended. In specific cases, FEIBA may be administered every 6 hours until clear signs of clinical improvement are observed (the maximum daily dose of 200 U/kg must not be exceeded).

Surgery

For surgical procedures, an initial dose of 100 U/kg may be administered before surgery, followed by another dose of 50–100 U/kg between 6 and 12 hours postoperatively. Postoperative maintenance doses of 50–100 U/kg every 6–12 hours may be given; the dose, dosing intervals, and duration of peri- and postoperative treatment depend on the type of surgery, the patient's general condition, and clinical efficacy in each individual case (the maximum daily dose of 200 U/kg must not be exceeded).

Prophylaxis in patients with inhibitor-positive hemophilia A

Prophylaxis of bleeding in patients with high inhibitor titers and frequent bleeding episodes, after failed immune tolerance induction (ITI) or when ITI is not considered:

A dose of 70–100 U/kg on alternate days is recommended. If necessary, the dose may be increased to 100 U/kg daily or gradually reduced.

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

FEIBA may be administered in combination with factor VIII, at a dosing interval of 50–100 U/kg twice daily, until the factor VIII inhibitor titer has decreased to < 2 U.B.*

*1 Bethesda Unit is defined as the amount of antibody that inhibits 50% of factor VIII activity in plasma incubated (2 hours at 37°C).

Use of FEIBA in special patient populations

FEIBA has also been used in combination with a factor VIII concentrate as long-term treatment for complete and permanent elimination of factor VIII inhibitors.

Monitoring

In case of inadequate response to treatment with this product, platelet count should be performed, as a sufficient number of functionally intact platelets is considered necessary for effective treatment with FEIBA.

Due to its complex mechanism of action, direct monitoring of the active substances is not available. Coagulation tests such as whole blood clotting time (WBCT), thromboelastography (TEG, r value), and activated partial thromboplastin time (aPTT) generally show only minor shortening and do not necessarily correlate with clinical improvement. Therefore, the utility of these assays for monitoring FEIBA treatment is very limited.

Method of Administration

FEIBA must be administered slowly by intravenous infusion. FEIBA should be infused at an infusion rate of 2 U/kg/min. In patients who have tolerated an infusion rate of 2 U/kg/min well, the infusion rate may be increased up to a maximum of 10 U/kg/min.

FEIBA must be reconstituted immediately before administration. The solution should be used immediately (as the preparation contains no preservatives). Do not use solutions that are cloudy or contain deposits. Disposal of unused medication and all materials that have come into contact with it must be carried out in accordance with local regulations.

Monitoring of Therapy

Single doses exceeding 100 U/kg and daily doses exceeding 200 U/kg should not be administered. Patients receiving more than 100 U/kg must be monitored for the development of DIC and/or acute coronary ischemia, as well as for symptoms of thrombotic or thromboembolic events. High doses of FEIBA should only be administered for the shortest time necessary to control bleeding.

If clinically significant changes in blood pressure or pulse rate, respiratory distress, cough, or chest pain occur, the infusion must be stopped immediately and appropriate diagnostic and therapeutic measures should be initiated. Laboratory parameters characteristic of DIC include decreased fibrinogen, decreased platelet count, and/or presence of fibrin or fibrinogen degradation products (FDP). Other parameters indicating DIC development are marked prolongation of thrombin time, prothrombin time, or activated partial thromboplastin time (aPTT). In patients with inhibitor-positive hemophilia or acquired inhibitors of factors VIII, IX, and/or XI, aPTT is prolonged due to the underlying disease.

Administration of FEIBA in inhibitor-positive patients may cause an initial "anamnestic" rise in inhibitor levels. During continued administration of FEIBA, inhibitor levels may decrease over time. Both clinical and published data suggest that the efficacy of FEIBA is not reduced.

Patients with inhibitor-positive hemophilia or acquired inhibitors of coagulation factors receiving FEIBA treatment may be more prone to bleeding while simultaneously having an increased risk of thrombosis.

Laboratory Tests and Clinical Efficacy

In vitro assays used to monitor efficacy, such as aPTT, whole blood clotting time (WBCT), and thromboelastography (TEG), do not necessarily correlate with clinical improvement. Therefore, normalization of these values should not be pursued by increasing the FEIBA dose and is strongly discouraged due to the potential risk of DIC from overdosing.

Importance of Platelet Count

In case of inadequate response to FEIBA treatment, platelet count is recommended, as a sufficient number of functionally intact platelets is considered necessary for effective FEIBA therapy.

Treatment of Patients with Inhibitor-Positive Hemophilia B

Experience in patients with hemophilia B and factor IX inhibitors is limited due to the rarity of the disease. Five patients with hemophilia B and inhibitors were treated with FEIBA in clinical trials, either on-demand, prophylactically, or perioperatively:

In a prospective, open-label, randomized, parallel-group clinical study in patients with hemophilia A or B and persistently elevated inhibitor titers (090701, PROOF), 36 patients were randomized to receive either prophylactic or on-demand treatment for 12 months ± 14 days. The 17 patients in the prophylactic group received 85 ± 15 U/kg of FEIBA administered on alternate days, and the 19 patients in the on-demand group received individualized treatment determined by the physician. Two patients with hemophilia B and inhibitors received on-demand treatment, and one patient with hemophilia B received prophylactic treatment. The median Annual Bleeding Rate (ABR) for all types of bleeding episodes in the prophylactic group (median ABR = 7.9) was lower than in the on-demand group (median ABR = 28.7), representing a 72.5% reduction in median ABR between treatment groups.

In another completed prospective, non-interventional safety surveillance study of perioperative FEIBA use (PASS-INT-003, SURF), a total of 34 surgical procedures were performed in 23 patients. The majority of patients (18) had congenital hemophilia A with inhibitors, two were patients with hemophilia B with inhibitors, and three were patients with acquired hemophilia A with inhibitors. Exposure to FEIBA 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. In patients with hemophilia B and inhibitors, the longest FEIBA exposure was 21 days, and the maximum dose administered was 7,324 U.

In addition, 48 patients have been reported in the literature in whom FEIBA was used for the treatment and prevention of bleeding episodes in patients with hemophilia B and factor IX inhibitors (34 patients with hemophilia B and inhibitors received on-demand treatment, six received prophylactic treatment, and eight received treatment for surgical procedures).

In a prospective, open-label, randomized crossover study (091501), the tolerability and safety of FEIBA reconstituted with a regular or 50% reduced volume and administered at faster infusion rates were evaluated in patients with hemophilia and inhibitors. Thirty-three patients were treated, and 28 completed the study. During the study, FEIBA was reconstituted with a 50% reduced volume (concentration of 100 U/ml) and infused intravenously at rates of 2, 4, and 10 U/kg/min at the indicated dose of 85 U/kg ± 15 U/kg for all patients. Primary endpoints were tolerability and safety with the 50% reduced volume (higher concentration) and with standard and increased infusion rates. The study demonstrated that both the higher concentration (100 U/ml) and increased infusion rates (4 and 10 U/kg/min) were well tolerated, with a safety profile comparable to that of the indicated dose of 85 U/kg ± 15 U/kg. Patients receiving the 50% reduced volume (higher concentration) at the standard infusion rate of 2 U/kg/min had similar rates of treatment-emergent adverse events (TEAEs) as those receiving the standard volume (concentration of 50 U/ml) at the same infusion rate. No TEAEs were reported at the 4 U/kg/min infusion rate. Patients receiving the 50% reduced volume (100 U/ml) at the 10 U/kg/min infusion rate experienced one related TEAE that was not serious. Furthermore, patients receiving the 50% reduced volume (higher concentration) at infusion rates of 4 and 10 U/kg/min experienced no serious TEAEs, hypersensitivity reactions, infusion site reactions, thrombotic TEAEs, or TEAEs leading to drug discontinuation or study withdrawal. Overall, the TEAEs observed in the study were consistent with the known safety profile of FEIBA in patients with hemophilia and inhibitors.

In an observational, post-authorization, open-label, uncontrolled, non-interventional safety study of FEIBA (PASS-EU-006), 75 patients (median age 34.8 years, 70 males and 5 females) were treated with FEIBA, of whom 73 had hemophilia A with inhibitors or hemophilia B with inhibitors. 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 as prophylactic treatment and 32 as on-demand treatment. Infusion rates greater than 2 U/kg/min were used in 6 pediatric patients (ages 11 months to 11 years) and in 5 adolescent patients (ages 13 to 16 years). Of the 320 infusions performed at available infusion rates in 7 pediatric and 6 adolescent patients, there were 129 infusions (40.3%) in 2 patients (both pediatric) at an infusion rate >10 U/kg/min, 26 infusions (8.1%) in 7 patients (4 pediatric; 3 adolescent) at rates >4 and ≤10 U/kg/min, 135 infusions (42.2%) in 7 patients (3 pediatric; 4 adolescent) at rates >2 and ≤4 U/kg/min, and 30 infusions (9.4%) in 3 patients (1 pediatric; 2 adolescent) at a rate ≤2 U/kg/min.

Additionally, isolated reports are available on the use of FEIBA in the treatment of patients with acquired inhibitors against factors IX, X, XI, and XIII.

In rare cases, FEIBA has also been used in patients with von Willebrand factor inhibitor.