Consumer medicine information

Feiba-NF

Factor VIII inhibitor bypassing fraction

BRAND INFORMATION

Brand name

Feiba NF

Active ingredient

Factor VIII inhibitor bypassing fraction

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Feiba-NF.

SUMMARY CMI

FEIBA NF®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using FEIBA NF?

FEIBA NF contains the active ingredient factor VIII inhibitor bypassing fraction. FEIBA NF is used to treat and prevent bleeding in patients with haemophilia A and B who have developed inhibitors (antibodies) against coagulation factor VIII and factor IX, respectively. For more information, see Section 1. Why am I using FEIBA NF? in the full CMI.

2. What should I know before I use FEIBA NF?

Do not use if you are allergic to FEIBA NF or any of the ingredients listed at the end of the CMI. Do not use if you are suffering from a blood clotting condition called Disseminated Intravascular Coagulation. Talk to your doctor if you have or have had any other medical conditions, if you take any other medicines, if you are pregnant or plan to become pregnant or if you are breastfeeding or plan to breastfeed. If you are taking a medicine called emicizumab, it is very important you talk to your doctor before using FEIBA NF. For more information, see Section 2. What should I know before I use FEIBA NF? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FEIBA NF and how it works. Tell your doctor or Haemophilia Treatment Centre if you are taking or using any other medicines including any that you get without a prescription from your pharmacy, supermarket, or health food shop. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given FEIBA NF?

  • FEIBA NF injection is prepared and administered by a qualified healthcare professional who is experienced in the care of patients with haemophilia.
  • Your dose of FEIBA NF is dependent on your condition and body weight, and your dose may change during treatment.
  • The frequency of your infusions will depend on how well FEIBA NF is working for you.
  • FEIBA NF is given slowly by injection directly into your veins.
  • FEIBA NF is supplied as a dry powder and the powder must be dissolved with the diluent supplied in the pack before use.

More information can be found in Section 4. How do I use FEIBA NF? in the full CMI.

5. What should I know while using FEIBA NF?

Things you should do
  • Tell your doctor or Haemophilia Treatment Centre immediately if you notice any sudden signs and symptoms of a severe, sudden allergic reaction.
  • If you are on emicizumab before or while using FEIBA NF, seek urgent medical attention if you notice any symptoms of thrombotic microangiopathy or blood clots.
  • Tell your doctor or Haemophilia Treatment Centre immediately if FEIBA NF is no longer helping your condition (e.g., if you noticed an increase in bleeds).
  • Tell any doctors, dentists, or pharmacists you visit that you are using FEIBA NF.
  • Keep all your appointments with your doctor and any blood tests.
Things you should not do
  • Do not give your medicine to anyone else, even if they appear to have the same condition as you.
  • Do not stop using your medicine or change the dosage without checking with your doctor.
Looking after your medicine
  • Store FEIBA NF below 25°C.
  • Keep FEIBA NF in the pack until it is time to use it so that it is protected from light.

For more information, see Section 5. What should I know while using FEIBA NF? in the full CMI.

6. Are there any side effects?

Common side effects include headache, dizziness, light-headedness, rash, allergies, hepatitis B surface antibody positive. Serious side effects include a condition called disseminated intravascular coagulation, blood clots in the veins or lungs, heart attack, stroke, severe sudden allergic reaction which may progress to difficulty in breathing, chest pain and fainting. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FEIBA NF®

Active ingredient(s): factor VIII inhibitor bypassing fraction

Consumer Medicine Information (CMI)

This leaflet provides important information about using FEIBA NF.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FEIBA NF.

Where to find information in this leaflet:

1. Why am I using FEIBA NF?
2. What should I know before I use FEIBA NF?
3. What if I am taking other medicines?
4. How do I use FEIBA NF?
5. What should I know while using FEIBA NF?
6. Are there any side effects?
7. Product details
8. Instructions for use

1. Why am I using FEIBA NF?

FEIBA NF contains the active ingredient factor VIII inhibitor bypassing fraction (a human, plasma-derived protein with factor VIII inhibitor bypassing activity expressed).

FEIBA NF is used to help clotting in patients with haemophilia A or B who have developed inhibitors (antibodies) against the blood clotting factor VIII and factor IX, respectively.

FEIBA NF is used:

  • to treat bleeding episodes in haemophilia A or B patients with inhibitors,
  • to prevent bleeding episodes in haemophilia A or B patients with inhibitors,
  • in haemophilia A or B patients with inhibitors to prevent or reduce bleeding before, during and after surgery.

The blood clotting factor VIII and factor IX are essential for the blood to form clots and stop bleedings. Patients with haemophilia A have lower factor VIII levels than normal. Patients with haemophilia B have lower factor IX levels than normal. During the course of treatment with replacement therapy, some haemophilia A and haemophilia B patients can develop antibodies against factor VIII and factor IX, respectively. This results in the replacement therapy from working properly and blood will not clot properly.

FEIBA NF is a concentrate of blood factors normally present in your blood which can bypass the effects of these antibodies to make sure that your blood clots properly.

This medicine helps to control your condition but does not cure it.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use FEIBA NF?

Warnings

Do not use FEIBA NF if:

  • you are allergic to factor VIII inhibitor bypassing fraction, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are suffering from Disseminated Intravascular Coagulation (a blood clotting condition that can cause blood clots, bleeding and sudden bruising). This condition usually occurs after a serious disease, injury, or after a major operation, diagnosed by a blood test.

Check with your doctor if:

  • you have suffered from a heart attack.
  • you have a blood clot.
  • you have liver problems.
  • your immune system is not working properly.
  • you have or have had any other medical conditions.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. There is no information on the use of FEIBA NF during pregnancy. Your doctor will discuss the risks and benefits of using FEIBA NF if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if FEIBA NF passes into your milk and if it can harm your baby. Your doctor will discuss the risks and benefits of using FEIBA NF if you are breast-feeding.

3. What if I am taking other medicines?

Tell your doctor or Haemophilia Treatment Centre if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with FEIBA NF and affect how it works. These include:

  • anti-fibrinolytics (medicines which help make blood clots more stable and last longer), for example aminocarproic acid, tranexamic acid, recombinant activated factor VII.
  • emicizumab (a medicine used to prevent bleeding in haemophilia A patients).

If you are taking any of the above medicines while receiving FEIBA NF, be aware of the possibility of serious side effects. Your doctor will need to monitor you closely.

Your doctor or Haemophilia Treatment Centre have more information on medicines to be careful with or avoid if you have concerns.

4. How do I use FEIBA NF?

Treatment with FEIBA NF should be started in a hospital or Haemophilia Treatment Centre and supervised by your doctor who is experienced in the care of patients with haemophilia.

Each time you use FEIBA NF, record the name and batch number of the medicine.

How much to use

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor will decide how much FEIBA NF you use, how often and at what intervals you need to have it.

Your dose will depend on:

  • your body weight,
  • how much, how often and where you are bleeding.

A dose of 50 to 100 Units per kilogram of body weight (U/kg) is recommended.

The maximum single dose should not be more than 100 U/kg.

The maximum daily dose should not be more than 200 U/kg.

How to use FEIBA NF

FEIBA NF is given by slow injection or infusion directly into your vein.

Some individuals may be trained to use FEIBA NF at home.

Do not attempt to inject FEIBA NF by yourself unless you have received proper training by your doctor or Haemophilia Treatment Centre on how to use the product.

Preparing FEIBA NF

FEIBA NF is supplied as a powder and must be mixed with water for injections (diluent supplied in the pack) to form a clear solution before use.

  • Follow carefully the step-by-step instructions at the end of this leaflet or in the pack insert on how to prepare and inject FEIBA NF.
  • Do not mix FEIBA NF with any other medicines or solvent other than the water for injections diluent supplied with the pack.
  • Use only the reconstitution device provided with each pack to prepare the solution for injection.
  • After mixing the powder and the diluent, use the solution immediately. If the solution is not used straight way, you can keep the solution for a maximum of 3 hours when stored at room temperature.
  • Do not refrigerate the solution after it is prepared.
  • FEIBA NF is for single use in one patient only.
  • Dispose of all unused solution, empty vials, and used needles and syringes into a sharps bin.

The step-by-step instructions can be found under Section 8. Instructions for use.

If you are unsure about how to prepare the medicine for use, contact your doctor or Haemophilia Treatment Centre.

Inspecting FEIBA NF

  • Always inspect FEIBA NF before use and after it has been mixed.
  • After mixing, the solution should be clear to colourless, and free from foreign particles.
  • Do not inject the solution if it is discoloured, or cloudy, or contains particles.

How often to use FEIBA NF

Your doctor will tell you how often or at what intervals you will receive the injection.

The frequency of injections you receive, and how long you will use FEIBA NF for, will depend on how well FEIBA NF is working for you.

Continue using FEIBA NF for as long as your doctor tells you. Usually, the replacement therapy with FEIBA NF is a life-long treatment.

If you forget to use FEIBA NF

If you forget your scheduled injection, do not inject a double dose to make up for the dose your missed.

If you inject a double dose, this may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or Haemophilia Treatment Centre.

If you use too much FEIBA NF

If you think that you have used too much FEIBA NF, you may need urgent medical attention.

You should immediately:

  • contact your doctor or Haemophilia Treatment Centre, or
  • go to the Emergency Department at your nearest hospital, or
  • phone the Poisons Information Centre by calling
    13 1126 (if you are in Australia), or by calling 0800 764 766 (if you are in New Zealand).

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using FEIBA NF?

Things you should do

  • Tell you other doctors, dentists and pharmacists you are using this medicine.
  • If you are about to have any blood tests, tell your doctor that you are using FEIBA NF.
  • Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests before you start your treatment and from time to time during your treatment to monitor your progress.
  • Follow all instructions from your doctor. Your doctor may change the dose you use using your treatment.

Tell your doctor and/or Haemophilia Treatment Centre straight away if you notice:

  • any sudden signs and symptoms of a severe allergic response.
  • your bleeding is not controlled or worsens after using FEIBA NF.

See additional information under Section 6. Are there any side effects?

Things you should not do:

  • Do not give your medicine to anyone else, even if they appear to have the same condition as you.
  • Do not use FEIBA NF to treat any other complaints unless your doctor tells you to.
  • Do not stop using FEIBA NF unless advised by your doctor or healthcare professional or unless you have an allergic reaction.
  • Do not change the dosage without checking with your doctor.
  • Do not use FEIBA NF after the expiry date which is printed on the label after the word 'EXP'. The expiry date refers to the last day of the month.

Driving or using machines

FEIBA NF is not expected to have an influence on your ability to drive and use machines.

Be careful before you drive or use any machines or tools until you know how FEIBA NF affects you.

Looking after your medicine

  • Keep FEIBA NF in the pack until it is time to use it. This will protect the medicine from light.
  • Store FEIBA NF below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep FEIBA NF out of reach of children.

Getting rid of any unwanted medicine

Medicines should not be disposed of via wastewater or household waste.

If your doctor tells you to stop using this medicine, or if the medicine is out of date, or if the medicine has not been stored properly, ask your doctor or Haemophilia Treatment Centre what to do with any unwanted medicine that is left over.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Common:
  • headache
  • dizziness
  • light-headedness (or any other sign of low blood pressure)
  • rash
  • allergies
  • hepatitis B surface antibody positive (shown in blood tests)
Speak to your doctor or Haemophilia Treatment Centre if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
These serious side effects have been reported in post-marketing experience:
  • a blood clotting condition called disseminated intravascular coagulation (DIC) - shown in blood tests, causing blood clots, bleeding and sudden bruising
  • blood clots in the veins or lungs, signs may include pain or swelling in the legs, difficulty in breathing
  • heart attack
  • stroke
  • severe, sudden allergic reaction which may progress to anaphylaxis including shock
Stop the injection immediately.
Call your doctor or Haemophilia Treatment Centre straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Signs or symptoms of a severe sudden allergic response include:

  • rash, hives, wheals, or generalised itching
  • swelling of face, lips and tongue which may cause difficulty in swallowing,
  • shortness of breath, wheezing, difficulty in breathing,
  • tightness or discomfort in the chest, dizziness and fainting

Your body can make antibodies (also called "inhibitors") against FEIBA NF. If this happens, FEIBA NF may stop working properly, signs or symptoms include easily bruising or bleeding, swelling and pain or tightness in joints. This is a very common side effect in patients who have not been previously treated with factor VIII medicines. In patients who have not been previously treated with factor VIII medicines, this side effect is uncommon.

Tell your doctor, Haemophilia Treatment Centre, or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems (if you are in Australia), or to Medsafe online at pophealth.my.site.com/carmreportnz/s/ (if you are in New Zealand).

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

Always make sure you speak to your doctor, Haemophilia Treatment Centre, or pharmacist before you decide to stop using any of your medicines.

7. Product details

What FEIBA NF contains

Powder in a vial

Active ingredient 
(main ingredient)		Factor VIII inhibitor bypassing fraction*
Other ingredients
(inactive ingredients)		sodium chloride
sodium citrate dihydrate

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

Diluent in a vial

Other ingredients
(inactive ingredients)		water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What FEIBA NF looks like

FEIBA NF is a white to cream powder supplied in a single-dose glass vial.

Each pack of FEIBA NF contains:

  • 1 drug powder vial containing 500 U, 1000 U or 2500 U of FEIBA NF
  • 1 diluent vial containing 10 mL, 20 mL or 50 mL of water for injections
  • 1 BAXJECT II Hi-Flow reconstitution device

FEIBA NF is available in the following strengths:

  • FEIBA NF 500 U - AUST R 104896
  • FEIBA NF 1000 U - AUST R 104911
  • FEIBA NF 2500 U - AUST R 172236

Not all presentations may be marketed.

Who distributes FEIBA NF

FEIBA NF is supplied in Australia by:

Takeda Pharmaceuticals Australia Pty Ltd
Level 39, 225 George Street
Sydney NSW 2000
Australia
Telephone: 1800 012 612
www.takeda.com/en-au

FEIBA NF is supplied in New Zealand by:

Takeda New Zealand Pty Limited
Level 10, 21 Queen Street
Auckland 1010
New Zealand
Telephone: 0508 169 077
www.takeda.com/en-au

This leaflet was prepared in January 2024.

8. Instructions for use

IMPORTANT

  • Contact your doctor or Haemophilia Treatment Centre if you have any questions or if you experience any problems following this instruction guide.
  • These instructions are intended only as a visual aid for those patients who have been trained by their doctor or Haemophilia Treatment Centre on the proper way to self-inject the medicine.
  • Do not attempt to inject FEIBA NF by yourself unless you have been trained by your doctor or Haemophilia Treatment Centre on how to use the product.
  • Use only the water for injections (diluent) and the reconstitution device provided in the pack to prepare the solution for injection.
  • If more than one vial of FEIBA NF is needed for the dose, mix each vial of FEIBA NF using a separate reconstitution device supplied in each pack.
  • Follow the step-by-step instructions specific to the reconstitution device supplied with your FEIBA NF.
  • After preparing FEIBA NF, use the solution as soon as possible, within 3 hours after mixing.
  • Always inspect FEIBA NF before use and after it has been mixed. After mixing, the solution should be clear to colourless.
  • Do not use the solution if it is discoloured, or cloudy, or contains particles.

Preparing FEIBA NF using aseptic technique

In a quiet place, prepare a clean surface and gather all the materials you will need for the injection.

Remove FEIBA NF from the refrigerator and check the expiry date on the package.

Wash your hands and put on clean exam gloves. If you are self-injecting at home the use of gloves is optional.

Using the BAXJECT II device

Use aseptic technique (clean and germ free) and a flat work surface during the reconstitution procedure.

  1. Allow the FEIBA NF powder and diluent vials to reach room temperature before use.
  2. Remove plastic caps from the FEIBA NF powder and diluent vials.
  3. Cleanse rubber stoppers with an alcohol wipe and allow to dry before use.
    Open the BAXJECT II device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package.

Figure A

  1. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).

Figure B

  1. Grip the BAXJECT II package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II device. Do not touch the exposed white plastic spike.

Figure C

  1. Turn the system over so that the diluent vial is on top. Quickly insert the white plastic spike fully into the FEIBA NF powder vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the FEIBA NF powder vial.

Figure D

  1. Swirl gently until the FEIBA NF powder is completely dissolved. DO NOT SHAKE.

Administration

  1. Remove the blue cap from the BAXJECT II device. Connect the syringe to the BAXJECT II (Figure E). DO NOT INJECT AIR into the BAXJECT II device.

Figure E

  1. Turn the system upside down (FEIBA NF powder vial now on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly (Figure F).

Figure F

  1. Disconnect the syringe; attached a suitable needle and inject slowly into the vein over a period of up to 5 minutes (maximum infusion rate of 10 mL per minute).
  2. If more than one vial of FEIBA NF is to be used, the contents of multiple vials may be drawn into the same syringe.

FEIBA NF® and BAXJECT® are registered trademarks of Baxalta Incorporated.

TAKEDA and the TAKEDA Logo are registered trademarks of Takeda Pharmaceutical Company Limited.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Feiba NF

Active ingredient

Factor VIII inhibitor bypassing fraction

Schedule

Unscheduled

 

1 Name of Medicine

Factor VIII inhibitor bypassing fraction.

2 Qualitative and Quantitative Composition

Description.

Feiba NF is a sterile lyophilised powder containing a complex of coagulation Factors. It is intended for intravenous administration after reconstitution.
The potency of Feiba NF is expressed in arbitrary units of factor VIII bypassing activity. One Unit of activity is defined as that amount of Feiba NF that shortens the activated partial thromboplastin time (aPTT) of a high titre Factor VIII inhibitor reference plasma to 50% of the blank value.
Feiba NF contains Factors II, IX and X, mainly non-activated, and Factor VII mainly in the activated form. In addition, 1-6 units of Factor VIII coagulation antigen (FVIII C: Ag) per mL are present.
Feiba NF is prepared from pooled human plasma. During manufacture, the product is subjected to two dedicated viral inactivation steps - vapour heat treatment and nanofiltration.
Feiba NF is available in three strengths with each vial containing 500 U, 1000 U or 2500 U of factor VIII bypassing activity as contained in human plasma protein.
Following reconstitution with the diluent vial provided, the Feiba activity in each vial is: 50 Feiba units/mL (2500 U/50 mL, 1000 U/20 mL and 500 U/10 mL) or 25 Feiba units/mL (500 U/20 mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and diluent for injection.

Appearance.

Feiba NF is formulated as a sterile, nonpyrogenic, off-white, lyophilised powder, for intravenous injection. It is supplied in single-dose glass vials.
Each Feiba NF 500 U pack contains: 1 powder vial of 500 Feiba-units as contained in 200-600 mg human plasma protein, 1 diluent vial of either 10 mL or 20 mL water for injections, 1 Baxject II Hi-Flow - Needleless transfer device intended for transferring and mixing drugs contained in two vials into a syringe.
Each Feiba NF 1000 U pack contains: 1 powder vial of 1000 Feiba-units as contained in 400-1200 mg human plasma protein, 1 diluent vial of 20 mL water for injections, 1 Baxject II Hi-Flow - Needleless transfer device intended for transferring and mixing drugs contained in two vials into a syringe.
Each Feiba NF 2500 U pack contains: 1 powder vial of 2500 Feiba-units as contained in 1000-3000 mg human plasma protein, 1 diluent vial of 50 mL water for injections, 1 Baxject II Hi-Flow - Needleless transfer device intended for transferring and mixing drugs contained in two vials into a syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Feiba NF is indicated for routine prophylaxis, control of spontaneous bleeding episodes and use in surgery in haemophilia A or B patients with inhibitors.

4.2 Dose and Method of Administration

Dosage.

As a general rule a dose of 50 to 100 units of Feiba NF per kg body weight, is recommended. However, total daily dose should not exceed 200 U/kg body weight.
Treatment should be initiated and continued for a period of time under the supervision of a physician experienced in the treatment of coagulation disorders.
Dosage is independent of patient's inhibitor titre. Since the response to treatment may differ from patient to patient, the dosage recommendations are only guidelines. Coagulation tests such as the whole blood clotting time (WBCT), the thromboelastogram (TEG, r-value), and aPTT usually show only a minor shortening and need not correlate with clinical improvement. For these reasons, these tests have only a very limited value in monitoring Feiba NF therapy. See Section 4.4 Special Warnings and Precautions for Use.
Table 1 outlines the dosing recommendations for the administration of Feiba NF.

Rate of administration.

Do not exceed an injection/infusion rate of 2 units Feiba NF per kg of body weight per minute.

Reconstitution.

General: use aseptic technique.

Feiba NF is to be reconstituted immediately before use. It should then be used not more than 3 hours after reconstitution, as it does not contain antimicrobial preservative. Do not refrigerate the reconstituted solution. Do not use solutions, which are turbid or have deposits. Any unused solution must be discarded appropriately.

Reconstitution of the powder for injection.

1. Warm diluent (Water for Injections) vial to room temperature (15°C-25°C), for example by using a water bath for several minutes (max. 37°C).
2. Remove the protective caps from the Feiba NF vial and diluent vial and cleanse the rubber stoppers of both. Place the vials on a flat surface.
3. Open the Baxject II Hi-Flow device package by peeling away the paper lid without touching the inside. Do not remove the device from the package.
4. Turn the package over and insert the clear plastic spike through the diluent stopper. Grip the package at its edge and pull the package off Baxject II Hi-Flow. Do not remove the blue cap from Baxject II Hi-Flow device.
5. With Baxject II Hi-Flow attached to the diluent vial, invert the system so that the diluent vial is on top of the device. Insert the purple plastic spike through the Feiba NF vial stopper. The vacuum will draw the diluent into the Feiba NF vial.
6. Swirl gently until all material is dissolved. Ensure that Feiba NF is completely dissolved; otherwise active material will not pass through the device filter.

Injection/infusion.

1. Remove the blue cap from Baxject II Hi-Flow. Take the syringe and connect it to Baxject II Hi-Flow (do not draw air into the syringe).
2. Invert the system (with Feiba NF vial on top). Draw the Feiba NF solution into the syringe by pulling the plunger back slowly.
3. Disconnect the syringe.
4. Slowly inject the solution intravenously with a winged set for injection (or a disposable needle).

4.3 Contraindications

The use of Feiba NF is contraindicated in patients who are known to have a normal coagulation mechanism. It should not be given to patients with significant signs of disseminated intravascular coagulation (DIC) or fibrinolysis. In patients with tentative or definite diagnosis of coronary heart disease as well as in patients with acute thrombosis and/or embolism (including myocardial infarction), the use of Feiba NF is only indicated in life-threatening bleeding events.
Feiba NF is contraindicated in cardiac surgery involving cardiopulmonary bypass and procedures involving extracorporeal membrane oxygenation (ECMO) due to the high risk of thrombotic adverse events.
Feiba NF must not be used in patients with hypersensitivity to the product if therapeutic alternatives to Feiba NF are available.
See Section 4.4 Special Warnings and Precautions For Use.

4.4 Special Warnings and Precautions for Use

Thromboembolic adverse events.

Thromboembolic events, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, have occurred in the course of treatment with Feiba NF.
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 (rFVIIa) may increase the risk of developing a thromboembolic event. The possible presence of such risk factors should always be considered in patients with congenital and acquired haemophilia.
Feiba should be used with particular caution in patients at risk of DIC, arterial or venous thrombosis.
Thrombotic microangiopathy (TMA) has not been reported in Feiba NF 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects) in emicizumab Product Information1; see also Oldenburg et al., "Emicizumab Prophylaxis in Hemophilia A with Inhibitors". N Engl J Med 2017:377:809-8182). The safety and efficacy of Feiba NF for breakthrough bleeding in patients receiving emicizumab has not been established. Consider the benefits and risks if Feiba NF must be used in a patient receiving emicizumab prophylaxis. If treatment with Feiba NF is considered required for patients receiving emicizumab, patients must be closely monitored by their physicians.
At the first signs or symptoms of thromboembolic events, the infusion should be stopped immediately and appropriate diagnostic and therapeutic measures initiated.
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.

Allergic reactions.

Feiba NF can precipitate allergic-type hypersensitivity reactions that have included: urticarial, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic (e.g. anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions such as chills, pyrexia and hypertension have also been reported.
At the first sign or symptom of an infusion/ hypersensitivity reaction, Feiba NF administration should be stopped and medical care initiated as appropriate.
When considering re-exposure to Feiba in patients with known or suspected hypersensitivity to the product, the expected benefit and the risk of re-exposure must be carefully weighed, taking into account the known or suspected type of the patient's hypersensitivity (allergic or non-allergic), including potential remedial and/or preventative therapy or alternative therapeutic agents.

Viral safety.

Feiba NF is made from human plasma. Products made from human plasma may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jacob Disease (vCJD) agents and theoretically Creutzfeldt-Jacob Disease (CJD) agent.
Standard measures to prevent infections resulting from the use of plasma-derived products include:
selection of donors;
screening of individual donations and plasma pools for specific markers of infection; and
the inclusion of effective manufacturing steps for the inactivation/removal of viruses. The manufacturing process for Feiba NF includes two such steps (vapour heat treatment and nanofiltration).
Despite this, when plasma-derived products 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 for Feiba NF are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). They may be of limited value against non-enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients who receive regular/repeated treatment with Feiba NF.
It is recommended that every time Feiba NF is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Use in hepatic impairment.

The safety and efficacy of Feiba NF has not been established in patients with hepatic impairment. Caution should be exercised with such patients.

Sodium restriction.

The amount of sodium in the maximum daily dose may exceed the recommended daily allowance of dietary sodium for patients on a low sodium diet. In these patients, the amount of sodium from the product should be calculated and taken into account when determining dietary sodium intake.
Feiba 500 U/1000 U contains approximately 80 mg sodium (calculated) per vial.
Feiba 2500 U contains approximately 200 mg sodium (calculated) per vial.

Monitoring of therapy and clinical efficacy.

Single doses of 100 Units/kg body weight and daily doses of 200 Units/kg body weight should not be exceeded. Patients given single doses of 100 Units/kg body weight should be monitored for the development of DIC, acute coronary ischemia, and signs and symptoms of other thrombotic or thromboembolic events. High doses of Feiba NF should be given only for as long as necessary to stop the bleeding.
In case of significant clinical changes in blood pressure, pulse rate, respiratory distress, chest pain and cough, the infusion should be stopped promptly and appropriate diagnostic and therapeutic measures are to be initiated. Laboratory indications of DIC are decreased fibrinogen, decreased platelet count, and/or presence of fibrin-fibrinogen degradation product (FDP). Other indications of DIC include significantly prolonged thrombin time, prothrombin time, or partial thromboplastin time.
Due to patient-specific factors, the response to a bypassing agent can vary and, in a specific 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.
Due to the complex mechanism of action, no direct monitoring of active ingredients is available. In vitro coagulation tests to control efficacy such as aPPT, whole blood clotting time (WBCT), and thromboelastogram (TEG) may not correlate with clinical improvement. Thus, attempts to normalize these values by increasing the dose of Feiba NF may not be successful and are strongly discouraged, because of potential hazard of inducing DIC by overdosage.
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.
Administration of Feiba NF to patients with inhibitors may result in an initial "anamnestic" rise in inhibitor levels. Upon continued administration of Feiba NF, inhibitors may decrease over time.

Use in the elderly.

No data available.

Paediatric use.

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.

Effects on laboratory tests.

Feiba NF 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).
After administration of high doses of Feiba NF, the transitory rise of passively transferred Hepatitis B surface antibodies may result in misleading interpretation of positive results in serological testing.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The use of antifibrinolytic agents, such as, tranexamic acid and aminocaproic acid, in combination with Feiba NF, is not recommended, due to an increased risk of thromboembolic events. If treatment with both Feiba NF and an antifibrinolytic agent is indicated, the products should be administered at least 12 hours apart.
No adequate and well-controlled studies of the combined or sequential use of Feiba and recombinant Factor VIIa, antifibrinolytics, or emicizumab have been conducted.
In cases of concomitant or sequential rFVIIa use, according to available in vitro data and clinical observations a potential drug interaction may occur (potentially resulting in adverse events such as a thromboembolic event).
Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab when Feiba NF was used as part of a treatment regimen for breakthrough bleeding (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects) in emicizumab Product Information4).
There is a theoretical risk that active immunity from a live attenuated vaccine may not develop because of interference from circulating antibodies to the vaccine virus. Antibodies from any source (e.g. transplacental, transfusion) can interfere with replication of the vaccine organism and lead to poor response or no response to the vaccine (also known as vaccine failure). Whether this type of interference can occur with the levels of antibodies present in the passive transfer associated with the use of Feiba is not known. If the response to the vaccine is altered, additional testing and/or re-vaccination may be required.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been performed with Feiba NF.
(Category B2)
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
The effect of Feiba NF on reproduction and development has not been studied. Feiba NF should only be given in pregnancy 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.
 It is not known whether components from Feiba NF are excreted in human milk. The safe use of Feiba NF in lactation has not been established. Caution should be exercised in the administration of Feiba NF to breastfeeding women, 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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical trials.

The adverse reactions presented in Table 2 were reported in the original Feiba studies (Hilgartner 1983, 1990; Sjamsoedin LJ. et al.,1981) for the treatment of bleeding episodes in haemophilia A or B patients with inhibitors to Factors VIII or IX and the randomised, prospective prophylaxis study (090701) comparing prophylaxis with on-demand treatment.

Post-marketing adverse reactions.

The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible.

Blood and lymphatic system disorders.

Disseminated intravascular coagulation.

Immune system disorders.

Anaphylactic reaction.

Nervous system disorders.

Paraesthesia, thrombotic stroke, embolic stroke.

Cardiac disorders.

Myocardial infarction, tachycardia.

Vascular disorders.

Thrombosis, venous thrombosis, arterial thrombosis, hypertension, flushing.

Respiratory, thoracic, and mediastinal disorders.

Pulmonary embolism, bronchospasm, wheezing, cough.

Gastrointestinal disorders.

Vomiting, diarrhoea, abdominal discomfort.

Skin and subcutaneous tissue disorders.

Angioedema, urticaria, pruritus.

General disorders and administration site conditions.

Malaise, feeling hot, injection site pain.

Investigations.

Fibrin D-dimer increased.

Class reactions.

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

Other adverse reactions.

Other adverse events which have been observed in clinical trials or with post-marketing experience are listed below. In clinical trials, adverse events occurred with a frequency of up to 4% of infusions.

Body as a whole.

Myalgia.

Gastrointestinal system.

Elevated liver enzymes.

Central nervous system.

Seizure, speech disorder, anxiety.

Cardiovascular system.

Pulmonary oedema.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Some reported thromboembolic events have occurred with doses above 200 U/kg.
If signs and symptoms of thromboembolic events are observed, the infusion should be stopped immediately, and appropriate diagnostic and therapeutic measures initiated.
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Coagulation involves the activation of Factor X to form Xa, which with cofactor Va, catalyses the formation of thrombin from prothrombin. The production of sufficient quantities of Xa usually requires a complex of Factors VIIIa and IXa. People (often those with haemophilia A and B) can acquire inhibitors to Factor VIII or IX during the treatment with Factor VIII or IX replacement therapy, which prevent the formation of the complex that catalyses Xa production. Feiba NF results in the generation of Xa and thrombin without the help of Factor VIIIa-IXa complex, thereby bypassing the inhibitory action of Factor VIII (or Factor IX) inhibitors.

Clinical trials.

Data to support the efficacy and safety of Feiba NF come from three prospective clinical trials using earlier versions of Feiba. The bleeding sites were joint 117, muscle 29 and mucocutaneous 4.
The first study3 was a randomised, double-blind controlled trial comparing an early non-virally inactivated version of Feiba with a European non-activated prothrombin complex concentrate (Prothromblex). The median age of patients was 12 years, range 3-37 years. In Hilgartner 1983, three patients had haemophilia B with inhibitors and two patients had acquired Factor VIII inhibitors. Patients were aged greater than 4 years. A total of 15 patients with haemophilia A and inhibitors to Factor VIII were enrolled. For each patient, successive bleeds at a particular site were randomised to treatment with one of the two products. A total of 150 bleeds were treated. Feiba was administered at a dose of 88 U/kg (1-2 doses) and Prothromblex at a dose of 48 U Factor IX/kg (1-2 doses). According to the investigators' assessments, Feiba was effective or partially effective in 64% of episodes compared to 52% of episodes with Prothromblex.
Data from two other uncontrolled trials, in patients with haemophilia A or B with inhibitors, are summarised in Table 3.
In Hilgartner 1983, the bleeding sites were joint 102, muscle/soft tissue 33, mucus membrane 20, surgical 4, central nervous system 3, nose 1, chest wall 1 and auditory canal 1. In Hilgartner 1990, the bleeding sites were joint 73, muscle/soft tissue 16, mucous membrane 9, surgical 7, central nervous system 1 and excluded due to protocol violation 12. The majority of patients had haemophilia A with inhibitors: 44 in Hilgartner 1983 and all patients in Hilgartner 1990.
The use of Feiba prophylaxis was assessed in a global multicentre trial in haemophilia A or B subjects with high titre or low titre inhibitors refractory to FVIII or FIX treatment. The trial was a randomised, open-label, parallel-group study comparing prophylactic versus on-demand treatment with Feiba. Subjects randomised to prophylaxis received 70-100 U/kg every other day. If a bleeding episode occurred, Feiba was dosed at the discretion of the treating doctor in both treatments groups based on the protocol dosing guidance. The duration of the study was 12 months.
Thirty six subjects entered the study, 17 randomised to prophylaxis and 19 to on-demand. All were included in the intent-to-treat analysis. The two groups were similar in baseline demographic and disease characteristics. All subjects were male. The median age was 23.5 years, range 7-56 years.
The primary endpoint was reduction in annualised bleeding rate (ABR) in the prophylaxis arm compared to the on-demand arm. Prophylaxis with Feiba significantly reduced the annualised bleeding rate (see Table 4). The results were also confirmed in a negative binomial mixed effects model. Most (79%) of the bleeds were treated with 1-2 infusions of Feiba. Haemostatic efficacy was rated as excellent or good in 87% of bleeding episodes at 24 hours in both arms. The majority of bleeds in both groups involved the joints. Administration of Feiba prophylactically significantly reduced both joint and non-joint bleeds as well as spontaneous and traumatic bleeds.
Prophylaxis with Feiba also significantly increased the time between bleeds overall by a median of 9 days (Table 4). In the case of time between joint bleeds, the trend was in favour of prophylaxis.

5.2 Pharmacokinetic Properties

Not available.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity was observed using a bacterial reversion assay (Ames test).

Carcinogenicity.

No carcinogenicity studies have been performed with Feiba NF.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, sodium citrate dihydrate, water for injections (diluent).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.
The product is stable for the duration of the specified shelf life when stored in the specified temperature storage condition. Feiba NF should be administered at room temperature not more than 3 hours after reconstitution. For single use and for one patient only. Discard unused portion of the product.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light. Do not freeze.
Do not use beyond the expiration date printed on the label.

6.5 Nature and Contents of Container

Feiba NF is supplied in single pack and as a lyophilised powder, accompanied by a suitable volume of diluent and a needleless transfer device for reconstitution. For details of the diluent volume supplied with each available potency, see Section 3 Pharmaceutical Form.
The powder and diluent are supplied in clear glass vials, closed by butyl rubber stoppers and protective caps.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Feiba NF contains Factors II, IX and X, mainly non-activated, and Factor VII mainly in the activated form. In addition, 1-6 units of Factor VIII coagulation antigen (FVIII C: Ag) per mL are present.

CAS number.

Not available.

References

1 Australian approved Product Information for emicizumab.
2 Oldenburg J., Mahlangu J., Kim B., Schmitt C., et al, "Emicizumab Prophylaxis in Hemophilia A with Inhibitors", N Engl J Med (2017), 377, 809-818.
3 Sjamsoedin L.J.M., Heijnen L., Mauser-Bunschoten E.P. et al, "The Effect of Activated Prothrombin-Complex Concentrate (Feiba) on joint and muscle bleeding in patients with haemophilia A and antibodies to Factor VIII", New England J. Med. (1981), 305, 717-721.
4 Hilgartner M.W, Knatterud G.L., "Feiba Study Group, The use of Factor Eight Inhibitor By-Passing Activity (Feiba Immuno) Product for treatment of bleeding episodes in haemophiliacs with inhibitors", Blood, (1983), 61, 36-40.
5 Hilgartner M., Aledort L., Andes A., Gill J., The Members of the Feiba Study Group: "Efficacy and safety of vapour-heated anti-inhibitor coagulant complex in haemophilia patients", Transfusion, (1990), 30, 626-630.

7 Medicine Schedule (Poisons Standard)

Unscheduled (Exempted).

Summary Table of Changes