Adynovi

Package leaflet: Information for the user

ADYNOVI 250 IU / 5 mL powder and solvent for solution for injection, 500 IU / 5 mL powder and solvent for solution for injection, 1,000 IU / 5 mL powder and solvent for solution for injection, 2,000 IU / 5 mL powder and solvent for solution for injection, 3,000 IU / 5 mL powder and solvent for solution for injection

rurioctocog alfa pegol (recombinant pegylated human coagulation factor VIII)
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• This medicine has been prescribed for you only. Never give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, contact your doctor. See section 4.

Contents of this leaflet:

1. What ADYNOVI is and what it is used for
2. What you need to know before using ADYNOVI
3. How to use ADYNOVI
4. Possible side effects
5. How to store ADYNOVI
6. Contents of the pack and other information

1. What ADYNOVI is and what it is used for

ADYNOVI contains the active substance rurioctocog alfa pegol, a pegylated human coagulation factor VIII. Human coagulation factor VIII has been modified to prolong its duration of action. Factor VIII is required for blood to clot and stop bleeding. In patients with haemophilia A (an inherited deficiency of factor VIII), it is either missing or does not function properly.
ADYNOVI is used for the treatment and prevention of bleeding in patients aged 12 years and older with haemophilia A (an inherited coagulation disorder caused by a lack of factor VIII).

2. What you should know before using ADYNOVI

Do not use ADYNOVI:

• if you are allergic to rurioctocog alfa pegol, octocog alfa, or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to mouse or hamster proteins.

If you have any doubts, consult your doctor.
Warnings and precautions
It is important to keep track of the batch number of ADYNOVI. Therefore, each time you receive a
new pack of ADYNOVI, record the date and the batch number (found on the packaging after
"Batch") and keep this information in a safe place.
Consult your doctor before using ADYNOVI.
There is a rare risk that you may develop an anaphylactic reaction (a sudden and severe allergic
reaction) to ADYNOVI. You should be aware of the early signs of allergic reactions, such as rash,
urticaria, wheals, generalized itching, swelling of the lips and tongue, difficulty breathing, wheezing,
chest tightness, feeling unwell, and dizziness.
These could be early symptoms of anaphylactic shock; other manifestations may include severe
dizziness, loss of consciousness, and extreme difficulty breathing.
If any of these symptoms occur, stop the infusion immediately and contact your doctor. Severe
symptoms, including difficulty breathing and fainting (or feeling faint), require immediate emergency
treatment.
If you have a heart condition, inform your doctor, as there is an increased risk of blood clotting
complications.
Patients who develop factor VIII inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during
treatment with all factor VIII medicines. Inhibitors, especially at high levels, prevent the treatment
from working properly, and you or your child will be closely monitored for the development of such
inhibitors. If ADYNOVI does not control bleeding in you or your child, inform your doctor
immediately.
Catheter-related complications
If you require a central venous access device (CVAD), the risk of CVAD-related complications
should be considered, including local infections, presence of bacteria in the blood, and catheter site
thrombosis.
Children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). The
warnings and precautions listed also apply to adolescents.
Other medicines and ADYNOVI
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding,
ask your doctor for advice before using this medicine. Haemophilia A occurs only rarely in women.
Therefore, there is no experience available on the use of ADYNOVI during pregnancy and
breastfeeding.
Driving and using machines
ADYNOVI has no effect or negligible effect on the ability to drive vehicles or operate machinery.
ADYNOVI contains sodium
This medicine contains up to 12.42 mg of sodium (a main component of table salt) per vial. This
corresponds to 0.62% of the maximum daily dietary intake recommended for an adult. Depending
on your body weight and the dose of ADYNOVI, you may be administered multiple vials. This should
be taken into account if you are on a low-salt diet.

3. How to use ADYNOVI

Treatment with ADYNOVI should be initiated and supervised by a physician experienced in the care of patients with haemophilia A.
Your doctor will calculate your ADYNOVI dose based on your condition, body weight, and the intended purpose—either prevention or treatment of bleeding. The frequency of administration will depend on how effective ADYNOVI is in your case. Replacement therapy with ADYNOVI is generally a lifelong treatment.

Use this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of ADYNOVI ranges from 40 to 50 IU per kg of body weight, administered twice weekly.

Treatment of bleeding
The ADYNOVI dose is calculated according to body weight and the factor VIII levels that need to be achieved. The required factor VIII levels depend on the severity and location of the bleeding.

If you feel that the effect of ADYNOVI is insufficient, consult your doctor.
Your doctor will perform the necessary laboratory tests to ensure your factor VIII levels are adequate. This is particularly important if you are undergoing major surgery.

Use in children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). In adolescents, the dose is also based on body weight and is the same as that used for adults.

How ADYNOVI is administered
ADYNOVI is usually injected into a vein (intravenous administration) by a doctor or nurse.
ADYNOVI may also be administered by you or another person via injection, but only after proper training has been received. Detailed instructions for self-administration are provided at the end of this leaflet.

If you use more ADYNOVI than you should
Always use ADYNOVI exactly as prescribed by your doctor. If you have any doubts, consult your doctor. If you inject more ADYNOVI than recommended, contact your doctor as soon as possible.

If you forget to use ADYNOVI
Do not inject a double dose to make up for the missed dose. Proceed with the next scheduled injection and continue as directed by your doctor.

If you stop using ADYNOVI
Do not discontinue treatment with ADYNOVI without consulting your doctor.
If you have any questions about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If a sudden and severe allergic reaction occurs (anaphylactic reaction), stop the injection immediately.
Contact your doctor immediately if you experience any of the following initial symptoms of allergic reactions:

• skin rash, hives, wheals, generalized itching,
• swelling of the lips and tongue,
• difficulty breathing, wheezing, chest tightness,
• feeling unwell,
• dizziness and loss of consciousness.

Severe symptoms, including breathing difficulties and fainting (or feeling faint), require immediate emergency treatment.
In patients who have previously received treatment with factor VIII (more than 150 days of treatment), inhibitory antibodies may develop with uncommon frequency (less than 1 in 100 patients) (see section 2). If this occurs, the medicine may no longer work properly and you may experience persistent bleeding. If this happens, contact your doctor immediately.

Very common side effects (may affect more than 1 in 10 people):
Headache

Common side effects (may affect up to 1 in 10 people):
Nausea
Diarrhea
Skin rash
Dizziness
Urticaria

Uncommon side effects (may affect up to 1 in 100 people):
Flushing, allergic reaction (hypersensitivity)
Factor VIII inhibitors (in patients who have previously received factor VIII treatment (more than 150 days of treatment))
Increase in certain types of white blood cells
Infusion-related reaction
Red eyes
Drug-related adverse skin reaction

Side effects with unknown frequency (frequency cannot be determined from available data):
Potentially life-threatening reactions (anaphylaxis)

Additional side effects in children
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of side effects
If you experience any side effect, contact your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store ADYNOVI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and on the carton after
Exp. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
During the shelf life, the powder vial may be stored at room temperature (up to a maximum of 30 °C) for a single period not exceeding 3 months. In this case, the medicine will expire at the end of this 3-month period or on the expiry date printed on the product vial, whichever comes first. Record the end of the 3-month room temperature storage period on the product carton. The product must not be returned to refrigerated storage once it has been stored at room temperature. Do not refrigerate the solution after reconstitution.
Use the product within 3 hours after complete dissolution of the powder.
The product is for single use only. Dispose of any unused solution appropriately.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What ADYNOVI contains

• The active substance is rurioctocog alfa pegol (pegylated recombinant human coagulation factor VIII produced using recombinant DNA technology). Each vial of powder contains nominally 250, 500, 1,000, 2,000, or 3,000 IU of rurioctocog alfa pegol.
• The solvent vial contains 5 mL of water for injections.
• The other ingredients are mannitol, trehalose dihydrate, histidine, glutathione, sodium chloride, calcium chloride dihydrate, tris(hydroxymethyl)aminomethane, and polysorbate 80. See section 2 “ADYNOVI contains sodium”.

Description of the appearance of ADYNOVI and package contents
ADYNOVI is supplied as a powder and solvent for injectable solution (powder for injectable solution). The powder is a white to off-white friable powder. The solvent is a clear, colourless solution. After reconstitution, the solution appears clear, colourless, and free of foreign particles.
Each pack contains one vial of powder, one vial of solvent, and one reconstitution device (BAXJECT II Hi-Flow).

Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Manufacturer
Baxalta Belgium Manufacturing SA
Boulevard René Branquart 80
B-7860 Lessines
Belgium

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Takeda Belgium NV Takeda, UAB
Tél/Tel: +32 2 464 06 11 Tel: +370 521 09 070
[email protected] [email protected]

България Luxembourg/Luxemburg
Такеда България ЕООД Takeda Belgium NV
Тел.: +359 2 958 27 36 Tél/Tel: +32 2 464 06 11
[email protected] [email protected]

Česká republika Magyarország
Takeda Pharmaceuticals Czech Republic s.r.o. Takeda Pharma Kft.
Tel: +420 234 722 722 Tel.: +36 1 270 7030
[email protected] [email protected]

Danmark Malta
Takeda Pharma A/S Τakeda HELLAS S.A.
Tlf: +45 46 77 10 10 Tel: +30 210 6387800
[email protected] [email protected]

Deutschland Nederland
Takeda GmbH Takeda Nederland B.V.
Tel: +49 (0)800 825 3325 Tel: +31 20 203 5492
[email protected] [email protected]

Eesti Norge
Takeda Pharma AS Takeda AS
Tel: +372 6177 669 Tlf: +47 800 800 30
[email protected] [email protected]

Ελλάδα Österreich
Takeda ΕΛΛΑΣ Α.Ε. Takeda Pharma Ges.m.b.H.
Tηλ: +30 210 6387800 Tel: +43 (0) 800-20 80 50
[email protected] [email protected]

España Polska
Takeda Farmacéutica España S.A. Takeda Pharma Sp. z o.o.
Tel: +34 917 90 42 22 Tel.: +48223062447
[email protected] [email protected]

France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tél: +33 1 40 67 33 00 Tel: +351 21 120 1457
[email protected] [email protected]

Hrvatska România
Takeda Pharmaceuticals Croatia d.o.o. Takeda Pharmaceuticals SRL
Tel: +385 1 377 88 96 Tel: +40 21 335 03 91
[email protected] [email protected]

Ireland Slovenija
Takeda Products Ireland Ltd Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: 1800 937 970 Tel: +386 (0) 59 082 480
[email protected] [email protected]

Ísland Slovenská republika
Vistor hf. Takeda Pharmaceuticals Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 (2) 20 602 600
[email protected] [email protected]

Italia Suomi/Finland
Takeda Italia S.p.A. Takeda Oy
Tel: +39 06 502601 Puh/Tel: 0800 774 051
[email protected] [email protected]

Κύπρος Sverige
Proton Medical (Cyprus) Ltd Takeda Pharma AB
Τηλ: +357 22866000 Tel: 020 795 079
[email protected] [email protected]

Latvija United Kingdom (Northern Ireland)
Takeda Latvia SIA Takeda UK Ltd
Tel: +371 67840082 Tel: +44 (0) 2830 640 902
[email protected] [email protected]

More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/

Instructions for preparation and administration
For reconstitution, use only the solvent and reconstitution device supplied with each pack of ADYNOVI. The powder must not be mixed with other medicines or solvents or used with other reconstitution devices.
Each time ADYNOVI is administered, it is strongly recommended to record the product name and batch number. The powder vial is supplied with detachable labels.

Instructions for reconstitution

• Do not use after the expiry date stated on the label and outer carton.
• Do not use if the BAXJECT II Hi-Flow device, its sterile barrier, or its packaging are damaged or show signs of deterioration.
  1. During the reconstitution procedure, use an aseptic technique (clean conditions with very low germ content) and work on a flat surface.
  2. Before use, allow all vials of powder and solvent to reach room temperature (between 15 °C and 25 °C).
  3. Remove the plastic closure caps from the powder and solvent vials.
  4. Clean the rubber stoppers with an alcohol swab and allow them to dry before use.
  5. Open the BAXJECT II Hi-Flow device package by removing the top cover without touching the inside (Figure A). Do not remove the device from its packaging.
  6. Invert the package. Press vertically downwards to fully insert the transparent plastic tip through the solvent vial stopper (Figure B).
  7. Grasp the edge of the BAXJECT II Hi-Flow package and pull the package away from the device (Figure C). Do not remove the blue closure cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic tip.
  8. Invert the system so that the solvent vial is on top. Quickly and fully insert the purple plastic tip into the powder vial stopper by pressing vertically downwards (Figure D). The vacuum will draw the solvent into the powder vial.
  9. Gently swirl until the powder is completely dissolved. Do not refrigerate after reconstitution.

Figure A Figure B Figure C

Figure D Figure E Figure F

Instructions for injection
Important note:

• Before administration, inspect the prepared solution for particulate matter and discoloration (the solution should be clear, colourless, and free of particles).

Do not use ADYNOVI if the solution is not completely clear or fully dissolved.

1. Remove the blue closure cap from the BAXJECT II Hi-Flow device (Figure E). Do not draw air into the syringe. Attach the syringe to the BAXJECT II Hi-Flow device. Use of a Luer-lock syringe is recommended.
2. Invert the system (the powder vial is now on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger (Figure F).
3. Disconnect the syringe; attach a suitable needle and administer intravenously. If a patient is to receive more than one vial of ADYNOVI, the contents of multiple vials may be drawn into the same syringe. A separate BAXJECT II Hi-Flow device must be used to reconstitute each vial of ADYNOVI with solvent.
4. Administer over a period not exceeding 5 minutes (maximum infusion rate 10 mL/min).
5. Dispose of any unused solution appropriately.

The following information is intended exclusively for healthcare professionals:

On-demand treatment
In the event of the following bleeding episodes, factor VIII activity should not fall below the plasma activity level determined (in % of normal value or in IU/dL) for the corresponding period. The following table can be used as a guide for dosing during bleeding episodes and surgical procedures.
Table 1: Dosing guidance for bleeding episodes and surgical procedures

Prophylaxis
For long-term prophylaxis, the recommended dose is 40 – 50 IU of ADYNOVI per
kilogram of body weight, administered twice weekly with intervals of 3 – 4 days.
Dose adjustments and modifications of administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency.

Paediatric population
The on-demand treatment dose in paediatric patients (12 to 18 years of age) is the same as in adults. Prophylactic treatment in patients aged 12 to < 18 years is the same as in adults. The long-term safety of ADYNOVI in children below 12 years of age has not yet been established.
Dose adjustments and modifications of administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency.

Package leaflet: Information for the user

ADYNOVI 250 IU / 5 mL powder and solvent for injectable solution, 500 IU / 5 mL powder and solvent for injectable solution, 1,000 IU / 5 mL powder and solvent for injectable solution, 2,000 IU / 5 mL powder and solvent for injectable solution, 3,000 IU / 5 mL powder and solvent for injectable solution

rurioctocog alfa pegol (recombinant pegylated human coagulation factor VIII)
This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• This medicine has been prescribed for you only. Never give it to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effect, contact your doctor. See section 4.

Contents of this leaflet

1. What ADYNOVI is and what it is used for
2. What you should know before using ADYNOVI
3. How to use ADYNOVI
4. Possible side effects
5. How to store ADYNOVI
6. Contents of the pack and other information

1. What ADYNOVI is and what it is used for

ADYNOVI contains the active substance rurioctocog alfa pegol, which is pegylated human coagulation factor VIII. Human coagulation factor VIII has been modified to prolong its duration of action. Factor VIII is necessary for blood to clot and stop bleeding. In patients with haemophilia A (congenital deficiency of factor VIII), this factor is either missing or does not function properly.
ADYNOVI is used for the treatment and prevention of bleeding in patients aged 12 years and older with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).

2. What you need to know before using ADYNOVI

Do not use ADYNOVI

• if you are allergic to rurioctocog alfa pegol, octocog alfa, or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to mouse or hamster proteins.

If you have any doubts about this, consult your doctor.
Warnings and precautions
It is important to keep track of the batch number of ADYNOVI. Therefore, each time you open a
new pack of ADYNOVI, record the date and the batch number (found on the packaging after
"Batch") and keep this information in a safe place.
Talk to your doctor before using ADYNOVI.
There is a rare risk that you may develop an anaphylactic reaction (a sudden and severe allergic
reaction) to ADYNOVI. You should be aware of the early signs of allergic reactions, such as rash,
urticaria, hives, generalized itching, swelling of the lips and tongue, difficulty breathing, wheezing,
chest tightness, feeling unwell, and dizziness.
These could be initial symptoms of anaphylactic shock; other manifestations may include severe
dizziness, loss of consciousness, and extreme difficulty breathing.
If you experience any of these symptoms, stop the injection immediately and contact your doctor.
Severe symptoms, including difficulty breathing and fainting (or feeling faint), require immediate
emergency treatment.
If you have a heart condition, inform your doctor, as there is an increased risk of blood clotting
complications.
Patients who develop factor VIII inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during
treatment with all factor VIII-containing medicines. Inhibitors, especially at high levels, may
prevent the treatment from working properly, and you or your child will be closely monitored for
the development of such inhibitors. If ADYNOVI does not control the bleeding in you or your
child, inform your doctor immediately.
Catheter-related complications
If you require a central venous access device (CVAD), the risk of CVAD-related complications
should be considered, including local infections, presence of bacteria in the blood, and catheter site
thrombosis.
Children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). The
warnings and precautions listed above also apply to adolescents.
Other medicines and ADYNOVI
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or are breastfeeding,
consult your doctor before using this medicine. Haemophilia A occurs only rarely in women.
Therefore, there is no experience with the use of ADYNOVI during pregnancy and breastfeeding.
Driving and using machines
ADYNOVI has no or negligible influence on the ability to drive or use machinery.
ADYNOVI contains sodium
This medicine contains up to 12.42 mg of sodium (a main component of table salt) per vial. This
is equivalent to 0.62% of the maximum recommended daily dietary intake of sodium for an adult.
Depending on your body weight and the dose of ADYNOVI, you may receive multiple vials. This
should be taken into account if you are on a low-salt diet.

3. How to use ADYNOVI

Treatment with ADYNOVI should be initiated and supervised by a physician experienced in the care of patients with haemophilia A.
Your doctor will calculate your ADYNOVI dose based on your condition, body weight, and the intended purpose—either prevention or treatment of bleeding. The frequency of administration will depend on how effective ADYNOVI is in your case. Generally, replacement therapy with ADYNOVI is a lifelong treatment.
Always use this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of ADYNOVI ranges from 40 to 50 IU per kg of body weight, administered twice weekly.

Treatment of bleeding
The ADYNOVI dose is calculated according to body weight and the factor VIII levels that need to be achieved. The required factor VIII levels depend on the severity and location of the bleeding.
If you feel that the effect of ADYNOVI is insufficient, consult your doctor.
Your doctor will perform the necessary laboratory tests to verify that your factor VIII levels are adequate. This is particularly important if you are undergoing major surgery.

Use in children and adolescents
ADYNOVI can only be used in adolescents and adults (from age 12 onwards). In adolescents, the dose is also calculated based on body weight and is the same as that used in adults.

How ADYNOVI is administered
ADYNOVI is usually injected into a vein (intravenous route) by a doctor or nurse.
ADYNOVI may also be administered by you or another person via injection, but only after proper training. Detailed instructions for self-administration are provided at the end of this leaflet.

If you use more ADYNOVI than you should
Always use ADYNOVI exactly as instructed by your doctor. If you have any doubts, consult your doctor. If you inject more ADYNOVI than recommended, contact your doctor as soon as possible.

If you forget to use ADYNOVI
Do not inject a double dose to make up for a missed dose. Proceed with the next scheduled injection and continue as directed by your doctor.

If you stop treatment with ADYNOVI
Do not stop using ADYNOVI without consulting your doctor.
If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience a sudden and severe allergic reaction (anaphylactic reaction), stop the injection
immediately. Contact your doctor immediately if you develop any of the following initial
symptoms of allergic reactions:

• skin rash, urticaria, wheals, generalized itching,
• swelling of the lips and tongue,
• difficulty breathing, wheezing, chest tightness,
• feeling unwell,
• dizziness and loss of consciousness.

Severe symptoms, including breathing difficulties and fainting (or feeling like fainting), require
immediate emergency treatment.
In patients who have received prior treatment with factor VIII (more than 150 days of treatment),
inhibitor antibodies may develop at an uncommon frequency (less than 1 in 100 patients) (see section 2).
If this occurs, the medicine may stop working properly and you may experience persistent bleeding. If
this happens, you must contact your doctor immediately.

Very common side effects (may affect more than 1 in 10 people)
Headache

Common side effects (may affect up to 1 in 10 people)
Nausea
Diarrhea
Skin rash
Dizziness
Urticaria

Uncommon side effects (may affect up to 1 in 100 people)
Flushing, allergic reaction (hypersensitivity)
Factor VIII inhibitors (in patients who have received prior treatment with factor VIII (more than 150
days of treatment))
Increase in certain types of white blood cells
Infusion-related reaction
Red eyes
Adverse drug skin reaction

Side effects with unknown frequency (frequency cannot be estimated from the available data)
Potentially life-threatening reactions (anaphylaxis)

Additional side effects in children
The frequency, type, and severity of adverse reactions in children are expected to be the same as in
adults.

Reporting of side effects
If you experience any side effect, talk to your doctor or nurse. You can also report side effects directly
through the national reporting system listed in Annex V. By reporting side effects, you can help provide
more information on the safety of this medicine.

5. How to store ADYNOVI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and on the carton after
Exp. The expiry date refers to the last day of that month.
Store in the refrigerator (2 °C – 8 °C).
Do not freeze.
Keep the blister in the outer packaging to protect the medicine from light.
During the shelf life, the powder vial may be stored at room temperature (up to a maximum of 30 °C) for a single period not exceeding 3 months. In this case, the medicine will expire at the end of this 3-month period or on the expiry date printed on the product vial, whichever comes first. Record the end of the 3-month period at room temperature on the product carton. The product must not be returned to refrigerated storage once it has been stored at room temperature. Do not refrigerate the solution after reconstitution.
Use the product within 3 hours after complete dissolution of the powder.
The product is for single use only. Dispose of any unused solution appropriately.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What ADYNOVI contains

• The active substance is rurioctocog alfa pegol (pegylated human coagulation factor VIII produced by recombinant DNA technology). Each vial of powder contains nominally 250, 500, 1,000, 2,000, or 3,000 IU of rurioctocog alfa pegol.
• The solvent vial contains 5 mL of water for injections.
• The other ingredients are mannitol, trehalose dihydrate, histidine, glutathione, sodium chloride, calcium chloride dihydrate, tris(hydroxymethyl)aminomethane, and polysorbate 80. See section 2, “ADYNOVI contains sodium”.

Description of the appearance of ADYNOVI and contents of the pack
ADYNOVI is supplied as a powder and solvent for solution for injection (powder for
solution for injection). The powder is a white to off-white, friable powder. The solvent is a
clear, colourless solution. After reconstitution, the solution appears clear, colourless, and free from
foreign particles.
Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Manufacturer
Baxalta Belgium Manufacturing SA
Boulevard René Branquart 80
B-7860 Lessines
Belgium
For further information about this medicinal product, please contact the local representative of the marketing authorisation holder:
België/Belgique/Belgien Lietuva
Takeda Belgium NV Takeda, UAB
Tél/Tel: +32 2 464 06 11 Tel: +370 521 09 070
[email protected] [email protected]
България Luxembourg/Luxemburg
Такеда България ЕООД Takeda Belgium NV
Тел.: +359 2 958 27 36 Tél/Tel: +32 2 464 06 11
[email protected] [email protected]
Česká republika Magyarország
Takeda Pharmaceuticals Czech Republic s.r.o. Takeda Pharma Kft.
Tel: +420 234 722 722 Tel.: +36 1 270 7030
[email protected] [email protected]
Danmark Malta
Takeda Pharma A/S Τakeda HELLAS S.A.
Tlf: +45 46 77 10 10 Tel: +30 210 6387800
[email protected] [email protected]
Deutschland Nederland
Takeda GmbH Takeda Nederland B.V.
Tel: +49 (0)800 825 3325 Tel: +31 20 203 5492
[email protected] [email protected]
Eesti Norge
Takeda Pharma AS Takeda AS
Tel: +372 6177 669 Tlf: +47 800 800 30
[email protected] [email protected]
Ελλάδα Österreich
Τakeda ΕΛΛΑΣ Α.Ε. Takeda Pharma Ges.m.b.H.
Tηλ: +30 210 6387800 Tel: +43 (0) 800-20 80 50
[email protected] [email protected]
España Polska
Takeda Farmacéutica España S.A. Takeda Pharma Sp. z o.o.
Tel: +34 917 90 42 22 Tel.: +48223062447
[email protected] [email protected]
France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tél: + 33 1 40 67 33 00 Tel: + 351 21 120 1457
[email protected] [email protected]
Hrvatska România
Takeda Pharmaceuticals Croatia d.o.o. Takeda Pharmaceuticals SRL
Tel: +385 1 377 88 96 Tel: +40 21 335 03 91
[email protected] [email protected]
Ireland Slovenija
Takeda Products Ireland Ltd Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: 1800 937 970 Tel: + 386 (0) 59 082 480
[email protected] [email protected]
Ísland Slovenská republika
Vistor hf. Takeda Pharmaceuticals Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 (2) 20 602 600
[email protected] [email protected]
Italia Suomi/Finland
Takeda Italia S.p.A. Takeda Oy
Tel: +39 06 502601 Puh/Tel: 0800 774 051
[email protected] [email protected]
Κύπρος Sverige
Proton Medical (Cyprus) Ltd Takeda Pharma AB
Τηλ: +357 22866000 Tel: 020 795 079
[email protected] [email protected]
Latvija United Kingdom (Northern Ireland)
Takeda Latvia SIA Takeda UK Ltd
Tel: +371 67840082 Tel: +44 (0) 2830 640 902
[email protected] [email protected]
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/
Instructions for preparation and administration
ADYNOVI must not be mixed with other medicinal products or solvents.
Each time ADYNOVI is administered, it is strongly recommended to record the name and batch number of the product. Detachable labels are provided on the blister.
Reconstitution instructions

• Do not use after the expiry date stated on the label and carton.
• Do not use if the top of the blister is not fully sealed.
• Do not refrigerate the solution after preparation.
  1. If the product is still stored in the refrigerator, remove the sealed blister (containing the powder and solvent vials pre-assembled with the reconstitution system) and allow it to reach room temperature (15 °C – 25 °C).
  2. Wash hands thoroughly with soap and warm water.
  3. Open the ADYNOVI blister by removing the top cover. Remove the BAXJECT III system from the blister.
  4. Place the powder vial on a flat surface with the solvent vial on top (Figure 1). There is a blue strip on the solvent vial. Do not remove the blue closure cap until instructed in a later step.
  5. Holding the powder vial in the BAXJECT III system with one hand, firmly press down the solvent vial with the other hand until the system is fully depressed and the solvent flows into the powder vial (Figure 2). Do not tilt the system until the transfer is complete.
  6. Check that the solvent transfer is complete. Gently swirl until the substance is completely dissolved (Figure 3). Ensure that the powder is fully dissolved, otherwise not all of the reconstituted solution will pass through the filter in the device. The product dissolves rapidly (usually within less than 1 minute). After reconstitution, the solution appears clear, colourless, and free from foreign particles.

Figure 1 Figure 2 Figure 3

Figure 4 Figure 5

Injection instructions
During administration, an aseptic technique (clean conditions and very low germ content) must be used.
Important note:

• Before administration, inspect the prepared solution for particulate matter and discoloration (the solution should be clear, colourless, and free from particles). Do not use if the solution is not completely clear or fully dissolved.

1. Remove the blue closure cap from the BAXJECT III device (Figure 4). Do not draw air into the syringe. Attach the syringe to the BAXJECT III device. Use of a Luer-lock syringe is recommended.
2. Invert the system (the powder vial is now on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger (Figure 5).
3. Disconnect the syringe; attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The solution should be administered slowly, at a rate determined by patient comfort, not exceeding 10 mL/min. (See section 4 “Possible side effects”.)
4. Dispose of any unused solution appropriately.

The following information is intended exclusively for healthcare professionals:

On-demand treatment
In the event of the following bleeding episodes, factor VIII activity should not fall below the determined plasma activity level (in % of normal or in IU/dL) corresponding to the relevant period. The following table can be used as a guide for dosing during bleeding episodes and surgical procedures.
Table 1: Dosing guide for bleeding episodes and surgical procedures

Prophylaxis
For long-term prophylaxis, the recommended dose is 40 – 50 IU of ADYNOVI per
kilogram of body weight administered twice weekly with intervals of 3 – 4 days.
Dose adjustments and changes in administration intervals may be considered based on
achieved FVIII levels and individual bleeding tendency.

Paediatric population
The on-demand treatment dose in paediatric patients (12 to 18 years of age) is the same as in adults.
Prophylactic treatment in patients aged 12 to < 18 years is the same as in adults. The long-term safety of ADYNOVI in children below 12 years of age has not yet been established.
Dose adjustments and changes in administration intervals may be considered based on
achieved FVIII levels and individual bleeding tendency.

Package leaflet: information for the user

ADYNOVI 250 IU / 2 mL powder and solvent for injectable solution, 500 IU / 2 mL powder and solvent for injectable solution, 1,000 IU / 2 mL powder and solvent for injectable solution

rurioctocog alfa pegol (recombinant pegylated human coagulation factor VIII)
This medicinal product is subject to additional monitoring. This will allow any new safety information to be identified quickly. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before using this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• This medicine has been prescribed for you only. Never give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, contact your doctor. See section 4.

Contents of this leaflet

1. What ADYNOVI is and what it is used for
2. What you need to know before using ADYNOVI
3. How to use ADYNOVI
4. Possible side effects
5. How to store ADYNOVI
6. Contents of the pack and other information

1. What ADYNOVI is and what it is used for

ADYNOVI contains the active substance rurioctocog alfa pegol, which is pegylated human coagulation factor VIII. Human coagulation factor VIII has been modified to prolong its duration of action. Factor VIII is required for blood to clot and stop bleeding. In patients with haemophilia A (an inherited deficiency of factor VIII), factor VIII is either missing or does not function properly.
ADYNOVI is used for the treatment and prevention of bleeding in patients aged 12 years and older with haemophilia A (an inherited bleeding disorder caused by a deficiency of factor VIII).

2. What you should know before using ADYNOVI

Do not use ADYNOVI

• if you are allergic to rurioctocog alfa pegol, octocog alfa, or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to mouse or hamster proteins.

If you have any doubts, consult your doctor.
Warnings and precautions
It is important to keep track of the batch number of ADYNOVI. Therefore, each time you open a
new pack of ADYNOVI, record the date and the batch number (found on the packaging after
“Batch”) and keep this information in a safe place.
Consult your doctor before using ADYNOVI.
There is a rare risk that you may develop an anaphylactic reaction (a sudden and severe allergic
reaction) to ADYNOVI. You should be aware of the early signs of allergic reactions, such as rash,
hives, wheals, generalized itching, swelling of the lips and tongue, difficulty breathing, wheezing,
chest tightness, feeling unwell, and dizziness.
These could be early symptoms of anaphylactic shock; other manifestations may include severe
dizziness, loss of consciousness, and extreme difficulty breathing.
If you experience any of these symptoms, stop the injection immediately and contact your
doctor. Severe symptoms, including difficulty breathing and fainting (or feeling faint), require
immediate emergency treatment.
If you have a heart condition, inform your doctor, as there is an increased risk of complications
related to blood clotting.
Patients who develop factor VIII inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during
treatment with all factor VIII-containing medicines. Inhibitors, especially at high levels, may
prevent the treatment from working properly, and you or your child will be closely monitored for
the development of such inhibitors. If ADYNOVI does not control bleeding in you or your child,
inform your doctor immediately.
Central venous access device (CVAD) complications
If you require a central venous access device (CVAD), the risk of CVAD-related complications
should be considered, including local infections, presence of bacteria in the blood, and catheter-site
thrombosis.
Children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). The
warnings and precautions listed also apply to adolescents.
Other medicines and ADYNOVI
Inform your doctor if you are currently using, have recently used, or might use any other
medicines.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding,
please consult your doctor before using this medicine. Haemophilia A occurs only rarely in women.
Therefore, there is no experience available regarding the use of ADYNOVI during pregnancy and
breastfeeding.
Driving and using machines
ADYNOVI has no or negligible influence on the ability to drive vehicles or use machines.
ADYNOVI contains sodium
This medicine contains up to 12.42 mg of sodium (a main component of table salt) per vial. This
corresponds to 0.62% of the maximum recommended daily dietary intake of sodium for an adult.
Depending on your body weight and the dose of ADYNOVI, you may be administered multiple
vials. This should be taken into account if you are on a low-salt diet.

3. How to use ADYNOVI

Treatment with ADYNOVI should be initiated and supervised by a physician experienced in the care of patients with haemophilia A.
Your doctor will calculate your ADYNOVI dose based on your condition, body weight, and the intended purpose—either prevention or treatment of bleeding. The frequency of administration will depend on how effective ADYNOVI is in your case. Generally, replacement therapy with ADYNOVI is a lifelong treatment.
Always use this medicine exactly as your doctor has instructed. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of ADYNOVI ranges from 40 to 50 IU per kg of body weight, administered twice weekly.

Treatment of bleeding
The dose of ADYNOVI is calculated according to body weight and the factor VIII levels that need to be achieved. The required factor VIII levels depend on the severity and location of the bleeding.
If you feel that the effect of ADYNOVI is insufficient, contact your doctor.
Your doctor will perform the necessary laboratory tests to verify that your factor VIII levels are adequate. This is particularly important if you are undergoing major surgery.

Use in children and adolescents
ADYNOVI can only be used in adolescents and adults (from 12 years of age onwards). In adolescents, the dose is also based on body weight and is the same as that used in adults.

How ADYNOVI is administered
ADYNOVI is usually administered intravenously (into a vein) by a doctor or nurse.
ADYNOVI may also be administered by you or another person via injection, but only after proper training has been received. Detailed instructions for self-administration are provided at the end of this leaflet.

If you use more ADYNOVI than you should
Always use ADYNOVI exactly as instructed by your doctor. If you have any doubts, consult your doctor. If you inject more ADYNOVI than recommended, contact your doctor as soon as possible.

If you forget to use ADYNOVI
Do not inject a double dose to make up for a missed dose. Proceed with the next scheduled injection and continue as instructed by your doctor.

If you stop using ADYNOVI
Do not stop using ADYNOVI without consulting your doctor.
If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience a sudden and severe allergic reaction (anaphylactic reaction), stop the injection immediately.
Contact your doctor immediately if you develop any of the following initial symptoms of allergic reactions:

• skin rash, hives, wheals, generalized itching,
• swelling of the lips and tongue,
• difficulty breathing, wheezing, chest tightness,
• feeling unwell,
• dizziness and loss of consciousness.

Severe symptoms, including breathing difficulties and fainting (or feeling faint), require immediate emergency treatment.
In patients who have previously received treatment with factor VIII (more than 150 days of treatment), inhibitory antibodies may develop with uncommon frequency (less than 1 in 100 patients) (see section 2). If this occurs, the medicine may stop working properly and you may experience persistent bleeding. If this happens, you must contact your doctor immediately.
Very common side effects (may affect more than 1 in 10 people)
Headache
Common side effects (may affect up to 1 in 10 people)
Nausea
Diarrhea
Rash
Dizziness
Urticaria
Uncommon side effects (may affect up to 1 in 100 people)
Flushing, allergic reaction (hypersensitivity)
Factor VIII inhibitors (in patients who have previously received factor VIII treatment (more than 150 days of treatment))
Increase in certain types of white blood cells
Infusion reaction
Red eyes
Drug-related adverse skin reaction
Side effects with unknown frequency (frequency cannot be estimated from the available data)
Potentially life-threatening reactions (anaphylaxis)
Additional side effects in children
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.
Reporting of side effects
If you experience any side effect, consult your doctor or nurse. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store ADYNOVI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and the carton after
Exp. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
During its shelf life, the powder vial may be stored at room temperature (up to a maximum of 30 °C) for a single period not exceeding 3 months. In this case, the medicine will expire at the end of this 3-month period or on the expiry date printed on the vial, whichever comes first. Record the end of the 3-month room temperature storage period on the product carton. The product must not be returned to the refrigerator after storage at room temperature. Do not refrigerate the solution after reconstitution.
Use the product within 3 hours after complete dissolution of the powder.
This product is for single use only. Dispose of any unused solution appropriately.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What ADYNOVI contains

• The active substance is rurioctocog alfa pegol (pegylated human coagulation factor VIII produced by recombinant DNA technology). Each vial of powder contains nominally 250, 500 or 1,000 IU of rurioctocog alfa pegol.
• The solvent vial contains 2 mL of water for injections.
• The other ingredients are mannitol, anhydrous trehalose, histidine, glutathione, sodium chloride, calcium chloride dihydrate, tris(hydroxymethyl)aminomethane and polysorbate 80. See section 2, “ADYNOVI contains sodium”.

Description of the appearance of ADYNOVI and contents of the pack
ADYNOVI is supplied as a powder and solvent for solution for injection (powder for solution for injection). The powder is a white to off-white, friable powder. The solvent is a clear, colourless solution. After reconstitution, the solution appears clear, colourless and free from foreign particles.
Each pack contains one vial of powder, one vial of solvent and one reconstitution device (BAXJECT II Hi-Flow).

Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Austria

Manufacturer
Baxalta Belgium Manufacturing SA
Boulevard René Branquart 80
B-7860 Lessines
Belgium

For further information about this medicinal product, contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Takeda Belgium NV Takeda, UAB
Tél/Tel: +32 2 464 06 11 Tel: +370 521 09 070
[email protected] [email protected]

България Luxembourg/Luxemburg
Такеда България ЕООД Takeda Belgium NV
Тел.: +359 2 958 27 36 Tél/Tel: +32 2 464 06 11
[email protected] [email protected]

Česká republika Magyarország
Takeda Pharmaceuticals Czech Republic s.r.o. Takeda Pharma Kft.
Tel: +420 234 722 722 Tel.: +36 1 270 7030
[email protected] [email protected]

Danmark Malta
Takeda Pharma A/S Τakeda HELLAS S.A.
Tlf: +45 46 77 10 10 Tel: +30 210 6387800
[email protected] [email protected]

Deutschland Nederland
Takeda GmbH Takeda Nederland B.V.
Tel: +49 (0)800 825 3325 Tel: +31 20 203 5492
[email protected] [email protected]

Eesti Norge
Takeda Pharma AS Takeda AS
Tel: +372 6177 669 Tlf: +47 800 800 30
[email protected] [email protected]

Ελλάδα Österreich
Τakeda ΕΛΛΑΣ Α.Ε. Takeda Pharma Ges.m.b.H.
Tηλ: +30 210 6387800 Tel: +43 (0) 800-20 80 50
[email protected] [email protected]

España Polska
Takeda Farmacéutica España S.A. Takeda Pharma Sp. z o.o.
Tel: +34 917 90 42 22 Tel. +48223062447
[email protected] [email protected]

France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tél: +33 1 40 67 33 00 Tel: +351 21 120 1457
[email protected] [email protected]

Hrvatska România
Takeda Pharmaceuticals Croatia d.o.o. Takeda Pharmaceuticals SRL
Tel: +385 1 377 88 96 Tel: +40 21 335 03 91
[email protected] [email protected]

Ireland Slovenija
Takeda Products Ireland Ltd Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: 1800 937 970 Tel: +386 (0) 59 082 480
[email protected] [email protected]

Ísland Slovenská republika
Vistor hf. Takeda Pharmaceuticals Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 (2) 20 602 600
[email protected] [email protected]

Italia Suomi/Finland
Takeda Italia S.p.A. Takeda Oy
Tel: +39 06 502601 Puh/Tel: 0800 774 051
[email protected] [email protected]

Κύπρος Sverige
Proton Medical (Cyprus) Ltd Takeda Pharma AB
Τηλ: +357 22866000 Tel: 020 795 079
[email protected] [email protected]

Latvija United Kingdom (Northern Ireland)
Takeda Latvia SIA Takeda UK Ltd
Tel: +371 67840082 Tel: +44 (0) 2830 640 902
[email protected] [email protected]

More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/

Instructions for preparation and administration
Only use the solvent and reconstitution device supplied with each pack of ADYNOVI for preparing the solution. The powder must not be mixed with other medicines or solvents or used with other reconstitution devices.
Every time ADYNOVI is administered, it is strongly recommended to record the name and batch number of the product. Removable labels are provided on the vial of powder.

Instructions for reconstitution

• Do not use after the expiry date stated on the label and carton.
• Do not use if the BAXJECT II Hi-Flow device, its sterile barrier or its packaging are damaged or show signs of deterioration.
  1. During the reconstitution procedure, use an aseptic technique (clean conditions with very low germ content) and a flat working surface.
  2. Before use, allow all vials of powder and solvent to reach room temperature (between 15 °C and 25 °C).
  3. Remove the plastic closure caps from the vials of powder and solvent.
  4. Clean the rubber stoppers with an alcohol swab and allow them to dry before use.
  5. Open the BAXJECT II Hi-Flow device packaging by removing the top cover without touching the inside (Figure A). Do not remove the device from its packaging.
  6. Invert the packaging. Press vertically downwards to fully insert the transparent plastic tip through the solvent vial stopper (Figure B).
  7. Grasp the edge of the BAXJECT II Hi-Flow packaging and pull the packaging away from the device (Figure C). Do not remove the blue closure cap from the BAXJECT II Hi-Flow device. Do not touch the exposed purple plastic tip.
  8. Invert the system so that the solvent vial is on top. Quickly and completely insert the purple plastic tip into the powder vial stopper by pressing vertically downwards (Figure D). The vacuum will draw the solvent into the powder vial.
  9. Gently swirl until the powder is completely dissolved. Do not refrigerate after reconstitution.

Figure A Figure B Figure C

Figure D Figure E Figure F

Instructions for injection
Important note:

• Before administration, inspect the prepared solution for the presence of particulate matter or discoloration (the solution should be clear, colourless and free from particles).

Do not use ADYNOVI if the solution is not completely clear or fully dissolved.

1. Remove the blue closure cap from the BAXJECT II Hi-Flow device (Figure E). Do not draw air into the syringe. Attach the syringe to the BAXJECT II Hi-Flow device. The use of a Luer-lock syringe is recommended.
2. Invert the system (the powder vial is now on top). Draw the reconstituted solution into the syringe by slowly pulling back the plunger (Figure F).
3. Disconnect the syringe; attach a suitable needle and administer intravenously. If a patient is to receive more than one vial of ADYNOVI, the contents of multiple vials may be drawn into the same syringe. However, a separate BAXJECT II Hi-Flow device must be used to reconstitute each vial of ADYNOVI with the solvent.
4. Administer over a period not exceeding 5 minutes (maximum infusion rate 10 mL/min).
5. Dispose of any unused solution appropriately.

---

The following information is intended for healthcare professionals only:

On-demand treatment
In the event of the following hemorrhagic episodes, factor VIII activity should not fall below the determined level of plasma activity (as % of normal value or in IU/dL) corresponding to the period. The following table can be used as a guide for dosing during bleeding episodes and surgical procedures.
Table 1: Dosing guide for bleeding episodes and surgical procedures

Prophylaxis
For long-term prophylaxis, the recommended dose is 40 – 50 IU of ADYNOVI per
kilogram of body weight administered twice weekly with intervals of 3 – 4 days.
Dose and dosing interval adjustments may be considered based on achieved FVIII levels and individual bleeding tendency.

Paediatric population
The on-demand treatment dose in paediatric patients (12 to 18 years of age) is the same as in adults. Prophylactic treatment in patients aged 12 to < 18 years is the same as in adults. The long-term safety of ADYNOVI in children below 12 years of age has not yet been established.
Dose and dosing interval adjustments may be considered based on achieved FVIII levels and individual bleeding tendency.

Package leaflet: information for the user

ADYNOVI 250 IU / 2 mL powder and solvent for injectable solution, 500 IU / 2 mL powder and solvent for injectable solution, 1,000 IU / 2 mL powder and solvent for injectable solution

rurioctocog alfa pegol (recombinant pegylated human coagulation factor VIII)
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before using this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• This medicine has been prescribed for you only. Never give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, contact your doctor. See section 4.

Contents of this leaflet

1. What ADYNOVI is and what it is used for
2. What you need to know before using ADYNOVI
3. How to use ADYNOVI
4. Possible side effects
5. How to store ADYNOVI
6. Contents of the pack and other information

1. What ADYNOVI is and what it is used for

ADYNOVI contains the active substance rurioctocog alfa pegol, a pegylated human coagulation factor VIII. Human coagulation factor VIII has been modified to prolong its duration of action. Factor VIII is required for blood to clot and stop bleeding. In patients with haemophilia A (a congenital deficiency of factor VIII), this factor is either missing or does not function properly.
ADYNOVI is used for the treatment and prevention of bleeding in patients aged 12 years and older with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).

2. What you need to know before using ADYNOVI

Do not use ADYNOVI

• if you are allergic to rurioctocog alfa pegol, octocog alfa, or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to mouse or hamster proteins.

If you have any doubts, consult your doctor.
Warnings and precautions
It is important to keep track of the batch number of ADYNOVI. Therefore, each time you start a
new pack of ADYNOVI, record the date and the batch number (found on the packaging after
“Batch”) and keep this information in a safe place.
Consult your doctor before using ADYNOVI.
There is a rare risk that you may develop an anaphylactic reaction (a sudden and severe allergic
reaction) to ADYNOVI. You should be aware of the early signs of allergic reactions, such as rash,
hives, wheals, generalized itching, swelling of the lips and tongue, breathing difficulties, wheezing,
chest tightness, feeling unwell, and dizziness.
These could be early symptoms of anaphylactic shock; other manifestations may include severe
dizziness, loss of consciousness, and extreme difficulty in breathing.
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe
symptoms, including difficulty breathing and fainting (or feeling faint), require immediate emergency
treatment.
If you have a heart condition, inform your doctor, as there is an increased risk of complications
related to blood clotting.
Patients who develop factor VIII inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during
treatment with all factor VIII-containing medicines. Inhibitors, especially at high levels, may prevent
the treatment from working properly, and you or your child will be closely monitored for the
development of such inhibitors. If ADYNOVI does not control bleeding in you or your child, inform
your doctor immediately.
Catheter-related complications
If you require a central venous access device (CVAD), the risk of CVAD-related complications
should be considered, including local infections, presence of bacteria in the blood, and catheter site
thrombosis.
Children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). The
warnings and precautions listed above also apply to adolescents.
Other medicines and ADYNOVI
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding,
consult your doctor before using this medicine. Haemophilia A occurs only rarely in women. Therefore,
there is no experience available regarding the use of ADYNOVI during pregnancy and breastfeeding.
Driving and using machines
ADYNOVI has no effect or a negligible effect on your ability to drive or operate machinery.
ADYNOVI contains sodium
This medicine contains up to 12.42 mg of sodium (a key component of table salt) per vial. This
corresponds to 0.62% of the maximum daily recommended dietary intake for an adult. Depending on
your body weight and the dose of ADYNOVI, you may be administered more than one vial. This
should be taken into account if you are on a low-salt diet.

3. How to use ADYNOVI

Treatment with ADYNOVI should be initiated and supervised by a physician experienced in the care of patients with haemophilia A.
Your doctor will calculate your ADYNOVI dose based on your condition, body weight, and the purpose of treatment—either prevention or treatment of bleeding. The frequency of administration will depend on how effective ADYNOVI is in your case. In general, replacement therapy with ADYNOVI is a lifelong treatment.
Use this medicine exactly as your doctor has told you. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of ADYNOVI ranges from 40 to 50 IU per kg of body weight, administered twice weekly.

Treatment of bleeding
The dose of ADYNOVI is calculated based on body weight and the factor VIII levels that need to be achieved. The required factor VIII levels depend on the severity and location of the bleeding.
If you think that the effect of ADYNOVI is too weak, contact your doctor.
Your doctor will perform the necessary laboratory tests to check whether your factor VIII levels are adequate. This is particularly important if you are undergoing major surgery.

Use in children and adolescents
ADYNOVI may only be used in adolescents and adults (from 12 years of age onwards). In adolescents, the dose is also calculated according to body weight and is the same as that used in adults.

How ADYNOVI is administered
ADYNOVI is usually administered intravenously (into a vein) by a doctor or nurse.
ADYNOVI may also be administered by you or another person by injection, but only after proper training has been received. Detailed instructions for self-administration are provided at the end of this package leaflet.

If you use more ADYNOVI than you should
Always use ADYNOVI exactly as your doctor has instructed. If you have any doubts, consult your doctor. If you inject more ADYNOVI than recommended, contact your doctor as soon as possible.

If you forget to use ADYNOVI
Do not inject a double dose to make up for a forgotten dose. Continue with the next scheduled injection and follow your doctor’s instructions.

If you stop using ADYNOVI
Do not stop using ADYNOVI without consulting your doctor.
If you have any doubts about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience a sudden and severe allergic reaction (anaphylactic reaction), stop the injection
immediately. Contact your doctor immediately if you experience any of the following initial
symptoms of allergic reactions:

• skin rash, hives, wheals, widespread itching,
• swelling of the lips and tongue,
• difficulty breathing, wheezing, chest tightness,
• feeling unwell,
• dizziness and loss of consciousness.

Severe symptoms, including breathing difficulties and fainting (or feeling like fainting), require immediate emergency treatment.
In patients who have received prior treatment with factor VIII (more than 150 days of treatment), inhibitor antibodies may develop with uncommon frequency (less than 1 in 100 patients) (see section 2). If this occurs, the medicine may stop working properly and you may experience persistent bleeding. If this happens, you must contact your doctor immediately.
Very common side effects (may affect more than 1 in 10 people)
Headache
Common side effects (may affect up to 1 in 10 people)
Nausea
Diarrhea
Skin rash
Dizziness
Hives
Uncommon side effects (may affect up to 1 in 100 people)
Flushing, allergic reaction (hypersensitivity)
Factor VIII inhibitors (in patients who have received prior treatment with factor VIII (more than 150 days of treatment))
Increase in certain types of white blood cells
Infusion-related reaction
Red eyes
Adverse drug reaction affecting the skin
Side effects with unknown frequency (frequency cannot be estimated from the available data)
Potentially life-threatening reactions (anaphylaxis)
Additional side effects in children
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.
Reporting of side effects
If you experience any side effect, contact your doctor or nurse. You may also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store ADYNOVI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and on the carton after
Exp. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Keep the blister pack in the outer packaging to protect the medicine from light.
During its shelf life, the powder vial may be stored at room temperature (up to a maximum of 30 °C) for a single period not exceeding 3 months. In this case, the medicine will expire at the end of this 3-month period or on the expiry date printed on the product vial, whichever comes first. Record the end of the 3-month period at room temperature on the product carton. The product must not be returned to refrigerated storage once it has been stored at room temperature. Do not refrigerate the solution after reconstitution.
Use the product within 3 hours after complete dissolution of the powder.
The product is for single use only. Dispose of any unused solution appropriately.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What ADYNOVI contains

• The active substance is rurioctocog alfa pegol (pegylated human coagulation factor VIII produced by recombinant DNA technology). Each vial of powder contains nominally 250, 500 or 1,000 IU of rurioctocog alfa pegol.
• The solvent vial contains 2 mL of water for injections.
• The other ingredients are mannitol, trehalose dihydrate, histidine, glutathione, sodium chloride, calcium chloride dihydrate, tris(hydroxymethyl)aminomethane and polysorbate 80. See section 2, “ADYNOVI contains sodium”.

Description of the appearance of ADYNOVI and contents of the pack
ADYNOVI is supplied as a powder and solvent for solution for injection (powder for solution for injection). The powder is a white to off-white, friable powder. The solvent is a clear, colourless solution. After reconstitution, the solution appears clear, colourless and free from foreign particles.
Marketing Authorisation Holder
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
Manufacturer
Baxalta Belgium Manufacturing SA
Boulevard René Branquart 80
B-7860 Lessines
Belgium
For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
Takeda Belgium NV Takeda, UAB
Tél/Tel: +32 2 464 06 11 Tel: +370 521 09 070
[email protected] [email protected]
България Luxembourg/Luxemburg
Takeda Bulgaria EOOD Takeda Belgium NV
Tel.: +359 2 958 27 36 Tél/Tel: +32 2 464 06 11
[email protected] [email protected]
Česká republika Magyarország
Takeda Pharmaceuticals Czech Republic s.r.o. Takeda Pharma Kft.
Tel: +420 234 722 722 Tel.: +36 1 270 7030
[email protected] [email protected]
Danmark Malta
Takeda Pharma A/S Takeda HELLAS S.A.
Tlf: +45 46 77 10 10 Tel: +30 210 6387800
[email protected] [email protected]
Deutschland Nederland
Takeda GmbH Takeda Nederland B.V.
Tel: +49 (0)800 825 3325 Tel: +31 20 203 5492
[email protected] [email protected]
Eesti Norge
Takeda Pharma AS Takeda AS
Tel: +372 6177 669 Tlf: +47 800 800 30
[email protected] [email protected]
Ελλάδα Österreich
Takeda ELLAS A.E. Takeda Pharma Ges.m.b.H.
Tηλ: +30 210 6387800 Tel: +43 (0) 800-20 80 50
[email protected] [email protected]
España Polska
Takeda Farmacéutica España S.A. Takeda Pharma Sp. z o.o.
Tel: +34 917 90 42 22 Tel.: +48223062447
[email protected] [email protected]
France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tél: +33 1 40 67 33 00 Tel: +351 21 120 1457
[email protected] [email protected]
Hrvatska România
Takeda Pharmaceuticals Croatia d.o.o. Takeda Pharmaceuticals SRL
Tel: +385 1 377 88 96 Tel: +40 21 335 03 91
[email protected] [email protected]
Ireland Slovenija
Takeda Products Ireland Ltd Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: 1800 937 970 Tel: +386 (0) 59 082 480
[email protected] [email protected]
Ísland Slovenská republika
Vistor hf. Takeda Pharmaceuticals Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 (2) 20 602 600
[email protected] [email protected]
Italia Suomi/Finland
Takeda Italia S.p.A. Takeda Oy
Tel: +39 06 502601 Puh/Tel: 0800 774 051
[email protected] [email protected]
Κύπρος Sverige
Proton Medical (Cyprus) Ltd Takeda Pharma AB
Τηλ: +357 22866000 Tel: 020 795 079
[email protected] [email protected]
Latvija United Kingdom (Northern Ireland)
Takeda Latvia SIA Takeda UK Ltd
Tel: +371 67840082 Tel: +44 (0) 2830 640 902
[email protected] [email protected]
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/
Instructions for preparation and administration
ADYNOVI must not be mixed with other medicinal products or solvents.
Each time ADYNOVI is administered, it is strongly recommended to record the name and batch number of the product. The blister pack is supplied with detachable labels.
Reconstitution instructions

• Do not use after the expiry date stated on the label and carton.
• Do not use if the top part of the blister is not fully sealed.
• Do not refrigerate the solution after preparation.
  1. If the product is still stored in the refrigerator, remove the sealed blister (containing the vials of powder and solvent pre-assembled with the reconstitution system) and allow it to reach room temperature (15 °C – 25 °C).
  2. Wash hands thoroughly with soap and warm water.
  3. Open the ADYNOVI blister by removing the top cover. Remove the BAXJECT III system from the blister.
  4. Place the vial of powder on a flat surface with the solvent vial on top (Figure 1). There is a blue strip on the solvent vial. Do not remove the blue closure cap until instructed in a later step.
  5. Holding the powder vial in the BAXJECT III system with one hand, firmly press the solvent vial with the other hand until the system is fully depressed and the solvent flows into the powder vial (Figure 2). Do not tilt the system until the transfer is complete.
  6. Confirm that the transfer of solvent is complete. Gently swirl until the substance is completely dissolved (Figure 3). Ensure that the powder is completely dissolved; otherwise, not all of the reconstituted solution may pass through the filter in the device. The product dissolves rapidly (usually within less than 1 minute). After reconstitution, the solution appears clear, colourless and free from foreign particles.

Figure 1 Figure 2 Figure 3

Figure 4 Figure 5

Injection instructions
During administration, an aseptic technique (clean conditions and minimal germ presence) must be used.
Important note:

• Before administration, inspect the prepared solution for the presence of particulate matter and discoloration (the solution should be clear, colourless and free from particles). Do not use if the solution is not completely clear or fully dissolved.

1. Remove the blue closure cap from the BAXJECT III device (Figure 4). Do not draw air into the syringe. Attach the syringe to the BAXJECT III device. The use of a Luer-lock syringe is recommended.
2. Invert the system (the powder vial is now on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger slowly (Figure 5).
3. Disconnect the syringe; attach a butterfly needle to the syringe and inject the reconstituted solution into a vein. The solution should be administered slowly, at a rate determined by the patient's comfort level, not exceeding 10 mL/min. (See section 4 “Possible side effects”.)
4. Dispose of any unused solution appropriately.

The following information is intended for healthcare professionals only:

On-demand treatment
In the event of the following bleeding episodes, factor VIII activity must not fall below the determined plasma activity level (expressed as % of normal or in IU/dL) during the corresponding period. The following table can be used as a guide for dosing during bleeding episodes and surgical procedures.
Table 1: Dosing guide for bleeding episodes and surgical procedures

Prophylaxis
For long-term prophylaxis, the recommended dose is 40 – 50 IU of ADYNOVI per
kilogram of body weight twice weekly, with intervals of 3 – 4 days. Dose adjustments and adjustments of administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency.

Paediatric population
The on-demand treatment dosage in paediatric patients (12 to 18 years of age) is the same as in adult patients. Prophylactic treatment for patients aged 12 to < 18 years is the same as in adults. The long-term safety of ADYNOVI in children below 12 years of age has not yet been established. Dose adjustments and adjustments of administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency.