Label: information for the user

FEIBA 50 U/ml powder and solvent for solution for infusion

Anti-inhibitor coagulant complex

Read this label carefully before starting to use this medication, as it contains important information for you.

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

1. What is FEIBA and how it is used

2. What you need to know before starting to use FEIBA

3. How to use FEIBA

4. Possible adverse effects

5. Storage of FEIBA

6. Contents of the package and additional information

FEIBA is a preparation made from human plasma, which allows for hemostasis, even when the amount of specific coagulation factors is reduced or absent.

FEIBA is used for the treatment and prophylaxis of bleeding in patients with hemophilia A and inhibitor.

FEIBA is used for the treatment of bleeding in patients with hemophilia B and inhibitor.

FEIBA is used for the treatment and prophylaxis of bleeding in non-hemophiliac patients with acquired factor VIII inhibitor.

Additionally, FEIBA is used for prophylaxis in surgical interventions in patients with hemophilia A and inhibitor.

FEIBA can be used in all age groups.

Inform your doctor if you have any known allergy.

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

Do not use FEIBA.

FEIBA should only be used in the following circumstances if, for example, due to a very high level of inhibitors, no response to treatment with the appropriate coagulation factor concentrate is expected:

• If you are allergic (hypersensitive) to the anti-inhibitor coagulant complex or to any of the other components of this medication (including those listed in section 6).
• If there is disseminated intravascular coagulation (DIC). (DIC = consumptive coagulopathy, a potentially life-threatening condition in which there is excessive blood clotting, with pronounced formation of blood clots in blood vessels. This causes consumption of clotting factors throughout the body)

• In the case of acute myocardial infarction, thrombosis, and/or embolism: FEIBA should only be used in episodes of hemorrhage that pose a threat to life.

Warnings and precautions

Consult your doctor before starting to use FEIBA because hypersensitivity reactions may occur, as with all plasma-derived products administered intravenously. To recognize an allergic reaction as soon as possible, you should know that the first potential symptoms of a hypersensitivity reaction may be:

- 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 notice any of these symptoms, stop administration immediately and contact your doctor immediately. These symptoms may indicate anaphylactic shock. Severe symptoms require early emergency treatment.

Your doctor will only reuse FEIBA in patients suspected of hypersensitivity to the product or any of its components after carefully evaluating the expected benefit and risk of re-exposure and/or no response to other preventive or alternative therapy.

• If you experience significant changes in blood pressure or heart rate, difficulty breathing, 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 clotting factors. During FEIBA treatment, these patients may have an increased tendency to develop bleeding and an increased risk of thrombosis at the same time.

During FEIBA treatment, thrombotic and thromboembolic events, including disseminated intravascular coagulation (DIC), deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke, have occurred. The use of recombinant factor VIIa may increase the risk of developing a thromboembolic event. Some thromboembolic events have occurred with high-dose FEIBA treatment.

In a study conducted by another company to evaluate emicizumab (a medication to prevent bleeding in patients with hemophilia A), some patients who experienced intercurrent bleeding were treated with FEIBA to control bleeding, and some of these patients developed microangiopathic thrombosis (MAT). MAT is a serious and potentially life-threatening condition. When this condition occurs, the blood vessel wall can be damaged, and blood clots can form in small blood vessels. In some cases, this can cause damage to the kidneys and other organs. If you experience intercurrent bleeding while on emicizumab prophylaxis, contact your hematologist or Hemophilia Treatment Center immediately.

When plasma-derived or blood products are administered, certain measures must be taken to prevent the transmission of infections to patients. These measures include a careful selection of donors to exclude those at risk of being carriers of infectious diseases, analysis of specific infection markers in individual donations and plasma mixtures, and inclusion of steps in the manufacturing process to eliminate/inactivate viruses. Despite this, when plasma-derived or blood products are administered, the possibility of transmission of infectious agents cannot be ruled out entirely. This also applies to emerging or unknown viruses or other types of infections.

These measures are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for non-enveloped viruses such as hepatitis A virus. The measures taken may have limited value for non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection can be serious for a pregnant woman (fetal infection) and for individuals with a weakened immune system or patients with certain types of anemia (e.g., sickle cell disease or hemolytic anemia).

Your doctor may recommend that you be vaccinated against hepatitis A and hepatitis B if you are regularly or repeatedly administered plasma-derived products for Factor VIII inhibitors.

After administration of high doses of FEIBA, the transient increase in surface antibodies to hepatitis B transferred passively may cause a false-positive interpretation of serological test results.

FEIBA is a plasma derivative and may contain substances that react when administered to patients, causing the presence of isohemaglutinins (antibodies that cause red blood cells from another person to adhere). This process may lead to misinterpretation of blood test results.

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

Children

The experience in children under 6 years is limited; the same adult dosage regimen should be adapted for the child's clinical condition.

Use of FEIBA with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

No adequate and well-controlled studies have been conducted on the combined or sequential use of FEIBA and recombinant factor VIIa, antifibrinolytics, or emicizumab. When systemic antifibrinolytics, such as tranexamic acid and aminocaproic acid, are used during FEIBA treatment, the possibility of thromboembolic events should be considered. Therefore, antifibrinolytics should not be used until approximately 6 to 12 hours after FEIBA administration.

According to available in vitro data and clinical observations, a potential drug interaction cannot be ruled out with concomitant use of recombinant factor VIIa that may produce 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 some specific warnings and precautions need to be taken into account. Your doctor will need to closely monitor you.

As with all coagulation products, FEIBA should not be mixed with other medications before administration, as this may impair the efficacy and tolerance of the product. It is recommended to wash the venous access with isotonic saline solution before and after FEIBA administration.

Pregnancy, breastfeeding, and fertility

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

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 parvovirus B19 infection, see the Warnings and Precautions section.

Driving and operating machinery

There is no indication that FEIBA may affect the ability to drive and operate machinery.

FEIBA contains sodium

500 U

This medication contains approximately 40 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 2% of the recommended daily maximum sodium intake for an adult.

1000 U

This medication contains approximately 80 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 4% of the recommended daily maximum sodium intake for an adult.

2500 U

This medication contains approximately 200 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 10% of the recommended daily maximum sodium intake for an adult.

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

Follow exactly the administration instructions for this medication as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Your doctor will determine the frequency and required dose for you personally, taking into account the severity of the bleeding disorder, the location and magnitude of the hemorrhage, and your clinical condition and response to the preparation. Do not change the established dosage by your doctor and do not suspend the administration of 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 administration. The solution must be used immediately (since the preparation does not contain preservatives).

Agitate gently until all the product is dissolved. Ensure that FEIBA is completely dissolved, as otherwise fewer units of FEIBA will pass through the filter of the equipment.

Solutions with a turbid appearance or containing deposits must be properly discarded.

Do not reuse opened containers.

Use only the water for injectable preparations and the equipment for reconstitution included in the container.

If other equipment is used, ensure that a suitable filter with a pore size of at least 149 µm is used.

Do not use the product if your sterile barrier system or container is damaged or shows any sign of deterioration.

Do not refrigerate after reconstitution.

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

The elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

[For the prospectus for administration with needles]

Reconstitution of the powder for the preparation of a solution for infusion with needles:

Throughout the procedure, aseptic technique must be used.

1. Warm the vial of solvent without opening (water for injectable preparations) to room temperature or a maximum of +37 °C, if necessary.

2. Remove the protectors from the vial containing the powder and the vial containing the solvent (Figure A), and disinfect the rubber stoppers of both vials.

3. Rotate to open the protective cap of one end of the transfer needle included, remove it and insert the needle through the rubber stopper of the vial of solvent (Figures B and C).

4. Remove the protective cap from the other end of the transfer needle, being careful not to touch it.

5. Invert the vial of solvent and insert the free end of the transfer needle through the rubber stopper of the vial of powder (Figure D). The vacuum existing in this vial will aspirate the solvent.

6. Separate the two vials by removing the transfer needle from the vial of powder (Figure E). Gently agitate the vial of powder to accelerate dissolution.

7. Once the powder is completely dissolved, insert the air vent needle (Figure F) and the foam that may have formed will disappear. Remove the air vent needle.

Infusion:

Throughout the procedure, aseptic technique must be used.

1. Rotate to open one end of the protective cap of the included filter needle; remove and connect the needle to the sterile disposable syringe. Aspirate the solution into the syringe (Figure G).
2. Separate the filter needle from the syringe and administer the solution slowly intravenously, with the infusion equipment included (or the disposable needle included).

Figure A Figure B Figure C Figure D Figure E Figure F Figure G

[For the prospectus for administration with BAXJECT II-Hi-Flow]

Reconstitution of the powder for the preparation of a solution for infusion with the BAXJECT II Hi-Flow equipment:

1. Warm the vial of solvent without opening (water for injectable preparations) to room temperature or a maximum of 37°C, if necessary, for example, by using a water bath for several minutes.

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

3.Open the packaging of the BAXJECT II Hi-Flow equipment by removing the protective sheet without touching the contents of the package (Figure a). Do not remove the equipment from the packaging.

4.Turn the packaging over and insert the transparent plastic tip through the rubber stopper of the vial of solvent (Figure b). Now remove the BAXJECT II Hi-Flow equipment from its packaging (Figure c). Do not remove the blue protective cap from the BAXJECT II Hi-Flow equipment.

5.With the BAXJECT II Hi-Flow equipment attached to the vial of solvent, invert the system so that the vial of solvent is at the top of the equipment. Insert the purple plastic tip of the BAXJECT II Hi-Flow equipment through the stopper of the vial of FEIBA. The vacuum will cause the solvent to penetrate the vial of FEIBA (Figure d).

6.Agitate gently, without shaking, the entire system until all the powder is dissolved. Ensure that FEIBA is completely dissolved, otherwise the active ingredient may be retained in the filter of the equipment.

Infusion

Use aseptic technique throughout the procedure!

1. Remove the blue protective cap from the BAXJECT II Hi-Flow equipment. Connect the syringe firmly to the BAXJECT II Hi-Flow equipment. DO NOT INTRODUCE AIR INTO THE SYRINGE. (Figure e). It is strongly recommended to use a Luer Lock syringe in order to ensure a firm connection between the syringe and the BAXJECT II Hi-Flow equipment (rotate the syringe clockwise until it stops when it reaches the top).

1. Invert the system so that the dissolved product is at the top. Insert the dissolved product into the syringe, pulling the plunger back slowly and ensuring that the firm connection between the BAXJECT II Hi-Flow device and the syringe is maintained throughout the process while pulling the syringe plunger back (Figure f).

1. Disconnect the syringe.

1. If foam forms in the syringe, wait for the foam to compact. Administer the solution slowly intravenously with the infusion equipment provided (or a disposable needle).

Do not exceed a perfusion rate of 2 U of FEIBA/kg per minute.

If you use more FEIBA than you should

Inform your doctor immediately. Excessive use of FEIBA may increase the risk of adverse effects, such as thromboembolism (formation of a blood clot with redness in the blood vessels), disseminated intravascular coagulation (DIC) or myocardial infarction. Some thromboembolic events reported occurred with doses above 200 U/kg/day or in patients with other risk factors for thromboembolic events.

If signs or symptoms of thromboembolic events are observed, the infusion must be stopped immediately and the necessary diagnostic and therapeutic measures must be taken.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

Frequent side effects(may affect up to1in every10patients)

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

Side effects of unknown frequency(cannot be estimated from available data)

Blood and lymphatic system disorders:disseminated intravascular coagulation (DIC), increase in inhibitor titer

Immune system disorders:anaphylactic reactions, skin rash all over the body (urticaria)

Nervous system disorders:numbness sensation in the extremities (hypoesthesia), abnormal or reduced sensitivity (paresthesia), stroke (thrombotic accident, embolic accident), drowsiness, altered taste sensation (dysgeusia).

Cardiac disorders:heart attack (myocardial infarction), heart palpitations (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 embolism, airway obstruction (bronchospasm), chest sounds, cough, shortness of breath (dyspnea).

Gastrointestinal disorders:vomiting, diarrhea, abdominal discomfort, nausea.

Skin and subcutaneous tissue disorders:numbness sensation in the face, facial swelling, tongue, and lip swelling (angioedema), skin rash all over the body (urticaria), itching (pruritus).

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

Complementary examinations: hypotension, increase in fibrinogen D-dimer level in blood.

The rapid intravenous infusion may cause a stinging pain and a numbness sensation in the face and extremities, 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 presence of thromboembolic risk factors.

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this prospectus. You can also report them directlythrough the Spanish System for Pharmacovigilance of Medicines for Human Use: www.notificaram.es

By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

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

Store in the original packaging to protect it from light.

Do not use this medication after the expiration date shown on the label and packaging. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and unused medications. This will help protect the environment.

Composition of FEIBA

Dry Powder

• The active ingredient per vial is a complex anti-inhibitor coagulant.
• 1 ml contains 50 U of anti-inhibitor coagulant complex.
• FEIBA 50 U/ml is available in three presentations:
• The 500 U FEIBA presentation contains 500 U (units) of anti-inhibitor coagulant complex in 200 – 600 mg of human plasma protein.

- The 1000 U FEIBA presentation contains 1000 U (units) of anti-inhibitor coagulant complex in 400 – 1200 mg of human plasma protein.

- The 2500 U FEIBA presentation contains 2500 U (units) of anti-inhibitor coagulant complex in 1000 – 3000 mg of human plasma protein.

• FEIBA also contains factors II, IX, and X, mainly non-activated, as well as activated factor VII. The factor VIII coagulant antigen (F VIII C:Ag) and the factors of the kallikrein-kinin system are present only in trace amounts.
• The other components are sodium chloride and sodium citrate.

Vehicle

– Sterile Water for Injection

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 6.8 and 7.6.

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

Presentation:1 x 500 U

1 x 1000 U

1 x 2500 U

Only certain package sizes may be commercially available.

[For the prospectus for administration with needles]

Contents of the package:

-1 vial with 500 U / 1000 U of FEIBA - dry powder for solution for infusion

- 1 vial with 10 ml / 20 ml of sterile water for injection

- 1 disposable syringe

- 1 disposable needle

- 1 butterfly needle

- 1 filter needle

- 1 transfer needle

- 1 air needle

[For the prospectus for administration with BAXJECT II-Hi-Flow]

Contents of the package:

-1 vial with 500 U/1000 U/2500 U of FEIBA - dry powder for solution for infusion

- 1 vial with 10 ml/20 ml/50 ml of sterile water for injection

- 1 BAXJECT II Hi-Flow reconstitution device

- 1 disposable syringe

- 1 disposable needle

- 1 butterfly needle

Marketing Authorization Holder and Responsible Manufacturer

Marketing Authorization Holder

Baxalta Innovations GmbH

Industriestrasse, 67

1221 Vienna, Austria

Responsible Manufacturer

Takeda Manufacturing Austria AGIndustriestrasse, 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

Phone: +34 91 790 42 22

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

Austria:

FEIBA 50 E./ml Powder and Vehicle for the Preparation of an Infusion Solution

Croatia:

FEIBA 50 U/ml Powder and Vehicle for the Preparation of an Infusion Solution

Cyprus:

FEIBA 50 U/mlκ?νιςandδιαλ?τηςγιαδι?λυμαπρος?γχυση

Czech Republic: FEIBA NF

Denmark:

Feiba

Estonia:

FEIBA

Finland:

Feiba

Germany: FEIBA 500 E, FEIBA 1000 E, FEIBA 2500 E

Greece:

FEIBA 50 U/mlκ?νιςandδιαλ?τηςγιαδι?λυμαπρος?γχυση

Ireland:

FEIBA50U/ml powder and solvent for solution for infusion

Latvia:

Feiba 50 V/ml pulveris un ški din a tājs infūziju

Lithuania:

Feiba 50 V/ml milteliai ir tirpiklis infuziniam tirpalui

Malta:

FEIBA 50 U/ml powder and solvent for solution for infusion

Netherlands:

FEIBA 50 E./ML, poeder en oplosmidel voor oplossing voor injectie

Norway:

Feiba

Romania:

FEIBA 50 U/ml pulbere si solvent pentru solutie injectabila

Slovakia:

FEIBA 50 U/ml prášok a rozpúštadlo na infúzny roztok

Slovenia:

FEIBA 50 e./ml prašek in vehikel za raztopino za infundiranje

Spain:

FEIBA 50 U/ml powder and vehicle for solution for perfusion

Sweden:

Feiba 50 enheter/ml pulver och vätska till infusionsvätska, lösning

Last review date of this prospectus:August 2024

The detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

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This information is intended solely for healthcare professionals:

The treatment should be initiated and monitored under the supervision of a doctor with experience in the treatment of bleeding disorders.

Dosage

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

The dose and frequency of administration will be established based on clinical efficacy in each case.

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

Due to specific factors in patients, the response to a bypass agent may vary, and in a given bleeding situation, patients who have an insufficient response to one agent may respond to another agent. In the event of an insufficient response to a bypass agent, the use of another agent should be considered.

Pediatric population

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

1) Spontaneous bleeding

Bleeding in joints, muscles, and soft tissue

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

For severe bleeding in muscles and soft tissue, such as retroperitoneal bleeding, a dose of 100 U/kg every 12 hours is recommended.

Bleeding in mucous membranes

A dose of 50 U/kg every 6 hours, under strict patient supervision (visual control of bleeding, repeated hematocrit), is recommended. If bleeding does not stop, the dose may be increased to 100 U/kg; however, the dose should not exceed 200 U/kg.

Other severe bleeding

In severe bleeding, such as central nervous system bleeding, a dose of 100 U/kg every 12 hours is recommended. In individual cases, FEIBA may be administered every 6 hours, until clear signs of clinical improvement appear (the daily dose should not exceed 200 U/kg).

2) Surgery

In surgical interventions, an initial dose of 100 U/kg may be administered before surgery, and between 6 to 12 hours post-surgery, another dose of 50 – 100 U/kg may be administered. As a postoperative maintenance dose, 50 – 100 U/kg may be administered every 6 – 12 hours; the dose, dosing interval, and duration of peri- and postoperative treatment depend on the surgical intervention, the patient's general condition, and clinical efficacy in each individual case (the daily dose should not exceed 200 U/kg).

3) Prophylaxis in patients with hemophilia A and inhibitor

• Prophylaxis of bleeding in patients with high inhibitor titer and frequent bleeding, after a failed response to immunotolerance induction (ITI) or when such induction is not considered:

A dose of 70 to 100 U/kg every other day is recommended. If necessary, the dose may be increased to 100 U/kg per day or gradually reduced.

• Prophylaxis of bleeding in patients with high inhibitor titer during immunotolerance induction (ITI):

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

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

4) Use of FEIBA in special patient groups

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

Monitoring

In the event of an inadequate response to treatment with the product, a platelet count should be performed, as a sufficient number of intact platelets is considered necessary for the product to be effective.

Due to the complex mechanism of action, there is no direct monitoring of the active principles. The coagulation tests, such as prothrombin time (PT), thromboelastogram (TEG, value r), and activated partial thromboplastin time (aPTT), generally show only small shortening, which does not necessarily correlate with clinical improvement. For these reasons, the utility of these tests for monitoring treatment with FEIBA is very limited.

Administration

FEIBA should be administered slowly, by intravenous route. The infusion rate should not exceed 2 U/kg per minute.

FEIBA should be reconstituted immediately before administration. The solution should be used immediately (since the preparation does not contain preservatives). Do not use solutions that appear turbid or contain deposits. The elimination of unused medication and all materials that have come into contact with it should be carried out in accordance with local regulations.

Monitoring of therapy

The individual dose should not exceed 100 U/kg, and the daily dose should not exceed 200 U/kg. Patients receiving more than 100 U/kg should be monitored for the development of CIDs and/or acute coronary ischemia and for symptoms of thrombotic or thromboembolic events. To stop bleeding, high doses of FEIBA should only be administered for the time strictly necessary.

If clinically significant changes in blood pressure or pulse rate, respiratory difficulty, cough, or chest pain occur, the infusion should be stopped immediately, and diagnostic and therapeutic measures should be taken. The characteristic analytical parameters of CID are a decrease in fibrinogen, a decrease in platelet count, and/or the presence of degradation products of fibrin or fibrinogen (PDF). Other parameters for the development of CID are a clear prolongation of thrombin time, prothrombin time, or activated partial thromboplastin time (aPTT). In patients with hemophilia and inhibitor or acquired inhibitors against factors VIII, IX, and/or XI, aPTT is prolonged due to the underlying disease.

The administration of FEIBA in patients with inhibitor may produce an initial "anamnestic" increase 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 hemophilia and inhibitor or acquired inhibitors against coagulation factors who receive treatment with FEIBA may be more prone to bleeding, and the risk of thrombosis may increase.

Laboratory tests and clinical efficacy

In vitro tests to control efficacy, such as aPTT, prothrombin time (PT), and thromboelastogram (TEG), do not necessarily correlate with clinical improvement. For this reason, normalization of these values by increasing doses of FEIBA should not be sought, and they are strongly rejected due to the possible risk of CID by overdose.

Importance of platelet count

In the event of an inadequate response to treatment with FEIBA, a platelet count should be performed, as a sufficient number of intact platelets is considered necessary for FEIBA to be effective.

Treatment of patients with hemophilia B and inhibitor

The experience in patients with hemophilia B and inhibitor is limited due to the rarity of the disease. Five patients with hemophilia B and inhibitor were treated with FEIBA during clinical trials, or on demand, or as prophylaxis, or for surgical interventions:

In a prospective, open, randomized, and parallel clinical trial in patients with hemophilia A or B with consistently high inhibitor titer (090701, PROOF), 36 patients were randomized to receive 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 every other day, and the 19 patients in the on-demand group received individualized treatment, determined by the doctor. Two patients with hemophilia B and inhibitor 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 patients in the prophylactic group (median ABR = 7.9) was lower than that of patients in the on-demand group (median ABR = 28.7), representing a 72.5% reduction in median ABR between treatment groups.

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

Forty-eight patients have also been described in the literature in whom FEIBA was used for the treatment and prevention of bleeding episodes in patients with hemophilia B and inhibitor against factor IX (34 patients with hemophilia B and inhibitor received on-demand treatment, six patients with hemophilia B and inhibitor received prophylactic treatment, and eight patients with hemophilia B and inhibitor received treatment for surgical interventions).

Additionally, there are isolated reports of 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.