Advate

Package leaflet: Information for the user

ADVATE 250 IU Powder and solvent for solution for injection, 500 IU Powder and solvent for solution for injection, 1000 IU Powder and solvent for solution for injection, 1500 IU Powder and solvent for solution for injection, 2000 IU Powder and solvent for solution for injection, 3000 IU Powder and solvent for solution for injection

octocog alfa (recombinant human coagulation factor VIII)
Please read all of this leaflet carefully before you start 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, ask your doctor.
• This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

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

1. WHAT ADVATE IS AND WHAT IT IS USED FOR

ADVATE contains the active substance octocog alfa, recombinant human coagulation factor VIII produced using recombinant DNA technology. Factor VIII is necessary for blood to form clots and to stop bleeding. In patients with haemophilia A (congenital factor VIII deficiency), this factor is missing or does not function properly.
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).
ADVATE is manufactured without the addition of any human or animal proteins during the entire production process.

2. WHAT YOU NEED TO KNOW BEFORE USING ADVATE

Do not use ADVATE

• if you are allergic to 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 in doubt, consult your doctor.
Warnings and precautions
Talk to your doctor before using ADVATE. You must inform your doctor if you have previously been
treated with factor VIII-containing medicines, especially if you have developed inhibitors, as there may
be an increased risk of this happening again. Inhibitors are neutralizing antibodies against factor VIII
that reduce the effectiveness of ADVATE in preventing and controlling bleeding. The development of
inhibitors is a well-known complication in the treatment of haemophilia A. If bleeding is not controlled
with ADVATE, inform your doctor immediately.
There is a risk, although rare, that you may develop an anaphylactic reaction (a severe and sudden
allergic reaction) to ADVATE. You should be aware of the early signs of such allergic reactions, which
include: skin rash, hives, blisters (wheals), generalized itching, swelling of the lips and tongue,
breathing difficulties, shortness of breath, chest tightness, feeling unwell and dizziness. These symptoms
may be early signs of anaphylactic shock, which may also include extreme dizziness, loss of
consciousness, and severe breathing difficulties.
If any of these symptoms occur, stop the injection/infusion of the medicine immediately and consult
your doctor. In case of severe symptoms, including difficulty breathing and fainting (or feeling faint),
immediate emergency treatment is required.
Patients who develop factor VIII inhibitors
The formation 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 ADVATE fails to control bleeding in you or your child, inform your doctor immediately.
Children and adolescents
The warnings and precautions mentioned above apply to both adults and children (from 0 to 18 years of
age).
Inform your doctor if you are currently using, have recently used, or might use any other medicines.
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding,
please seek medical advice before using this medicine.
Driving and using machines
ADVATE does not affect the ability to drive or operate machinery.
ADVATE contains sodium
This medicine contains 10 mg of sodium (a main component of table salt) per vial. This corresponds to
0.5% of the maximum daily recommended dietary intake of sodium for an adult.

3. HOW TO USE ADVATE

Treatment with ADVATE should be initiated by a physician experienced in managing patients with haemophilia A.
The physician will determine the dose of ADVATE (in International Units or IU) based on your physical condition, body weight, and whether it is being used for prevention or treatment of bleeding.
The frequency of administration will depend on the assessment of ADVATE's effectiveness in your individual case. Generally, replacement therapy with ADVATE lasts for life.
Always use this medicinal product exactly as your doctor has instructed. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of octocog alfa is between 20 IU and 40 IU per kg of body weight, administered every 2–3 days. However, in some cases, especially in younger patients, more frequent injections or higher doses may be required.

Treatment of bleeding
The dose of octocog alfa is calculated based on body weight and the desired factor VIII levels to be achieved. The optimal factor VIII levels will depend on the severity and location of the bleeding.

DOSE (IU) = body weight (kg) × desired increase in factor VIII (% of normal) × 0.5

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

Use in children and adolescents (aged 0 to 18 years)
For treatment of bleeding, the dose in children does not differ from that in adult patients. For prevention of bleeding in children under 6 years of age, doses of 20 to 50 IU per kg of body weight, administered 3–4 times per week, are recommended. Administration of ADVATE in children (intravenously) does not differ from administration in adults. To allow frequent infusions of factor VIII products, a central venous access device (CVAD) may become necessary.

How to administer ADVATE
ADVATE is generally administered intravenously by a physician or nurse. You or another person may administer ADVATE by injection, but only after receiving adequate training. Detailed instructions for self-administration are provided at the end of this leaflet.

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

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

If you stop treatment with ADVATE
Do not stop using ADVATE without first consulting your doctor.
If you have any questions about the use of this medicinal product, consult your doctor.

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
In case of severe and sudden allergic (anaphylactic) reactions, you must immediately stop the injection.
You must contact your doctor immediately if you experience any of the following early symptoms of allergic reactions:

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

Severe symptoms such as difficulty breathing and fainting (feeling of passing out) require immediate emergency treatment.
In children who have not previously been treated with factor VIII-containing medicines, the development of
inhibitor antibodies (see section 2) can be very common (more than 1 in 10 people); however, in patients who have
previously received treatment with factor VIII (more than 150 days of treatment), the risk is uncommon (less than 1 in 100).
If this occurs, the medicine may no longer work properly and you or your child may experience persistent bleeding.
If this happens, you must contact your doctor immediately.

Very common adverse reactions (may affect more than 1 in 10 people)
Factor VIII inhibitors (in children not previously treated with factor VIII-containing medicines).

Common adverse reactions (may affect up to 1 in 10 people)
Headache and fever.

Uncommon adverse reactions (may affect up to 1 in 100 people)
Factor VIII inhibitors (in patients previously treated with factor VIII (more than 150 days of treatment)), dizziness, influenza, fainting, abnormal heartbeat, red, swollen, and itchy skin patches, chest discomfort, bruising at injection site, injection site reaction, itching, increased sweating, unusual taste in mouth, hot flushes, migraine, memory impairment, chills, diarrhea, nausea, vomiting, shortness of breath, laryngitis, lymphatic vessel infection, skin pallor, eye inflammation, rash, excessive sweating, swelling of feet and legs, decrease in blood cellular component (hematocrit), increase in a type of white blood cells (monocytes), and pain in the upper abdomen or lower chest.

Surgery-related
Catheter-related infection, decreased hematocrit, limb and joint edema, prolonged bleeding after drain removal, decreased factor VIII levels, and postoperative hematoma.

Related to central venous access devices (CVAD)
Catheter-related infection, systemic infection, and local blood clot at catheter site.

Adverse reactions with unknown frequency (frequency cannot be estimated from available data)
Potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional adverse reactions in children
In addition to inhibitor development in previously untreated pediatric patients (PUP) and catheter-related complications, no age-specific differences in adverse reactions were observed in clinical studies.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor. You may also report adverse reactions directly through the national reporting system listed in Annex V. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. HOW TO STORE ADVATE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
During the shelf life, the vial of powder may be stored at room temperature (not above 25 °C) for a single period not exceeding 6 months. In this case, the medicine expires at the end of this 6-month period or on the expiry date printed on the product vial, whichever comes first. Record the end of the 6-month room temperature storage period on the outer label. The medicine must not be refrigerated again after storage at room temperature.
Keep the vial in the outer packaging to protect the medicine from light.
This medicine is for single use only. Dispose of any unused residue properly.
Use the product immediately after complete reconstitution of the lyophilized powder.
Do not refrigerate the solution after preparation.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. CONTENTS OF THE PACKAGE AND OTHER INFORMATION

What ADVATE contains

• The active substance is octocog alfa (recombinant human coagulation Factor VIII). Each vial of powder contains nominally 250, 500, 1000, 1500, 2000 or 3000 IU of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trehalose, calcium chloride, tromethamine, polysorbate 80 and reduced glutathione.

Solvent vial: Water for injections 5 mL

Description of the appearance of ADVATE and contents of the pack
ADVATE is a white or almost white, friable powder.
After reconstitution, the solution is clear, colourless and free from foreign particles.
Each pack contains one reconstitution device (BAXJECT II).

Marketing Authorisation Holder
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna
Tel: +800 66838470
e-mail: [email protected]

Manufacturers
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
Tel/Tél: +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 Tel/Tél: +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 Drugsales Ltd
Tlf: +45 46 77 10 10 Tel: +356 21419070
[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 ΑΕ 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.
Tel: +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]

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

During preparation of the solution and administration, an aseptic technique must be used.
Use only water for injections and the reconstitution and preparation devices supplied in each pack of ADVATE. ADVATE must not be mixed with other medicinal products or solvents.
It is strongly recommended that each time ADVATE is administered, the name and batch number of the product are recorded.

Instructions for reconstitution of the solution

• Do not use the product after the expiry date stated on the labels and carton.

• Do not use the product if the BAXJECT II device, its sterile barrier system or its packaging are damaged or show any signs of deterioration, as indicated by the symbol: .

• Do not refrigerate the solution after preparation.

1. If the product is still stored in the refrigerator, remove both the lyophilised ADVATE powder and the solvent vial and allow them to reach room temperature (between 15–25 °C).
2. Wash hands thoroughly with soap and warm water.
3. Remove the caps from the lyophilised powder and solvent vials.
4. Clean the stoppers with alcohol-impregnated cotton swabs. Place the vials on a clean, flat surface.
5. Open the BAXJECT II package by removing the top cover, taking care not to touch the inside (Fig. a). Do not remove the device from the package. Do not use the product if the BAXJECT II device, its sterile barrier system or its packaging are damaged or show any signs of deterioration.
6. Turn the package upside down and insert the transparent plastic spike through the solvent vial stopper. Hold the edge of the package and pull it away to release the BAXJECT II device (Fig. b). Do not remove the blue cap from the BAXJECT II device. Only use the sterile water for injections and the reconstitution device supplied in the pack for reconstitution. While keeping the BAXJECT II attached to the solvent vial, invert the system so that the solvent vial is positioned above the device. Insert the white plastic spike through the stopper of the ADVATE powder vial. The solvent will be drawn into the ADVATE powder vial (Fig. c).
7. Gently swirl until the powder is completely dissolved. Ensure that all the ADVATE 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 a Figure b Figure c

Instructions for injection
Use a luer-lock syringe for administration.

Important note:

• Do not attempt to administer the injection unless you have received specific instructions from medical or nursing personnel.
• Check the solution for undissolved particles or abnormal discolouration (the solution must be clear, colourless and free from foreign particles). Do not use ADVATE if the solution is not completely clear or not fully dissolved.

1. Remove the blue cap from the BAXJECT II. Do not allow air into the syringe. Attach the syringe to the BAXJECT II (Fig. d).
2. Invert the system (the vial with the reconstituted solution should be above). Slowly draw the reconstituted solution into the syringe by pulling back the plunger (Fig. e).
3. Disconnect the syringe. Attach the 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 per minute. (See section 4 "Possible side effects").
4. Dispose of unused residues appropriately.

Figure d Figure e

---

The following information is intended for healthcare professionals only:

Treatment
In the event of the following bleeding episodes, factor VIII activity must not fall below the determined plasma activity levels (in % or in IU/dL) relative to normal levels during the corresponding period. The following table can be used as a guide for dosing in bleeding episodes and surgery.
The dose and frequency of administration should be adjusted according to the individual clinical response. In certain circumstances (e.g., presence of a low-titer inhibitor), doses higher than those calculated using the formula may be required.

Package leaflet: Information for the user

ADVATE 250 IU Powder and solvent for solution for injection, 500 IU Powder and solvent for solution for injection, 1000 IU Powder and solvent for solution for injection, 1500 IU Powder and solvent for solution for injection, 2000 IU Powder and solvent for solution for injection, 3000 IU Powder and solvent for solution for injection

octocog alfa (recombinant human coagulation factor VIII)
Please read this leaflet carefully before 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. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

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

1. WHAT ADVATE IS AND WHAT IT IS USED FOR

ADVATE contains the active substance octocog alfa, recombinant human coagulation factor VIII produced using recombinant DNA technology. Factor VIII is necessary for blood to form clots and to stop bleeding. In patients with haemophilia A (congenital factor VIII deficiency), this factor is missing or does not function properly.
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).
ADVATE is manufactured without the addition of any human or animal proteins during the entire production process.

2. WHAT YOU NEED TO KNOW BEFORE USING ADVATE

Do not use ADVATE

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

If in doubt, consult your doctor.
Warnings and precautions
Talk to your doctor before using ADVATE. You must inform your doctor if you have previously been
treated with factor VIII-containing medicines, especially if you have developed inhibitors, as there may
be an increased risk of this occurring again. Inhibitors are neutralizing antibodies against factor VIII that reduce the effectiveness of ADVATE in preventing and controlling bleeding. The development of inhibitors is a well-known complication in the treatment of haemophilia A. If bleeding is not controlled with ADVATE, inform your doctor immediately.
There is a risk, although rare, that you may develop an anaphylactic reaction (a severe and sudden allergic reaction) to ADVATE. You should be aware of the early signs of such allergic reactions, which include: skin rash, urticaria, blisters (wheals), generalized itching, swelling of the lips and tongue, breathing difficulties, shortness of breath, chest tightness, feeling unwell and dizziness. These symptoms may be early signs of anaphylactic shock, which may also include extreme dizziness, loss of consciousness and severe breathing difficulties.
If any of these symptoms occur, stop the injection/infusion of the medicine immediately and consult your doctor. In case of severe symptoms, including difficulty breathing and fainting (or feeling faint), emergency medical treatment is required.
Patients who develop factor VIII inhibitors
The formation of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII-containing 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 these inhibitors. If ADVATE does not control bleeding in you or your child, inform your doctor immediately.
Children and adolescents
The warnings and precautions listed above apply to both adults and children (from 0 to 18 years of age).
Inform your doctor if you are currently taking, have recently taken, or might take any other medicines.
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, seek advice from your doctor before using this medicinal product.
Driving and operating machinery
ADVATE does not affect the ability to drive or operate machinery.
ADVATE contains sodium
This medicinal product contains 10 mg of sodium (the main component of table salt) per vial. This corresponds to 0.5% of the maximum recommended daily dietary intake of sodium for an adult.

3. HOW TO USE ADVATE

Treatment with ADVATE should be initiated by a physician experienced in the treatment of patients
with haemophilia A.
Your doctor will determine the dose of ADVATE (in International Units or IU) based on your physical
condition and body weight, and whether it is being used for prevention or treatment of bleeding.
The frequency of administration will depend on the assessment of ADVATE's effectiveness in your
case. Generally, replacement therapy with ADVATE lasts for life.
Use this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor.

Prevention of bleeding
The usual dose of octocog alfa is between 20 IU and 40 IU per kg of body weight, administered every
2–3 days. However, in some cases, especially in younger patients, more frequent injections or higher
doses may be required.

Treatment of bleeding
The dose of octocog alfa is calculated based on body weight and the desired factor VIII levels to be
achieved. Optimal factor VIII levels will depend on the severity and location of the bleeding.

DOSE (IU) = body weight (kg) × desired increase in factor VIII (% of normal) × 0.5

If you feel that the effect of ADVATE is insufficient, consult your doctor.
Your doctor will perform appropriate laboratory tests to ensure that you have adequate levels of Factor VIII.
This is particularly important if you are undergoing major surgical procedures.

Use in children and adolescents (aged 0 to 18 years)
For treatment of bleeding, the dose in children does not differ from that in adult patients. For prevention
of bleeding in children under 6 years of age, doses of 20 to 50 IU per kg of body weight, 3–4 times per
week, are recommended. Administration of ADVATE in children (intravenously) does not differ from
administration in adults. To allow frequent infusions of factor VIII products, a central venous access
device (CVAD) may become necessary.

How to administer ADVATE
ADVATE is generally administered intravenously by a doctor or nurse.
You or another person may administer ADVATE by injection, but only after receiving adequate
training. Detailed instructions for self-administration are provided at the end of this leaflet.

If you use more ADVATE than you should
Always use ADVATE exactly as directed by your doctor. If you have any doubts, consult your doctor.
If you take more ADVATE than recommended, inform your doctor as soon as possible.

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

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

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
In case of severe and sudden allergic (anaphylactic) reactions , you must stop the infusion immediately . You must contact your doctor immediately if you experience any of the following early symptoms of allergic reactions:

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

Severe symptoms such as difficulty breathing and fainting (feeling of passing out) require immediate emergency treatment.
For children who have not previously been treated with factor VIII-containing medicines, the development of inhibitory antibodies (see section 2) may be very common (more than 1 in 10 people); however, in patients who have previously received treatment with factor VIII (more than 150 days of treatment), the risk is uncommon (less than 1 in 100). If this occurs, the medicine may no longer work properly and you or your child may experience persistent bleeding. If this happens, you must contact your doctor immediately.

Very common adverse reactions (may affect more than 1 in 10 people):
Factor VIII inhibitors (in children not previously treated with factor VIII-containing medicines).

Common adverse reactions (may affect up to 1 in 10 people):
Headache and fever.

Uncommon adverse reactions (may affect up to 1 in 100 people):
Factor VIII inhibitors (in patients previously treated with factor VIII (more than 150 days of treatment)), dizziness, influenza-like illness, fainting, abnormal heartbeat, red, swollen, itchy skin patches, chest discomfort, bruising at injection site, injection site reaction, itching, increased sweating, unusual taste in mouth, hot flushes, migraine, memory impairment, chills, diarrhea, nausea, vomiting, shortness of breath, laryngitis, lymphatic vessel infection, skin pallor, eye inflammation, rash, excessive sweating, swelling of feet and legs, decreased blood cell mass (hematocrit), increase in a type of white blood cells (monocytes), and pain in the upper abdomen or lower chest.

Surgery-related:
Catheter-related infection, decreased hematocrit, swelling of limbs and joints, prolonged bleeding after drain removal, decreased factor VIII levels, and postoperative hematoma.

Related to central venous access devices (CVAD):
Catheter-related infection, systemic infection, and local blood clot at catheter site.

Adverse reactions with unknown frequency (frequency cannot be estimated from available data):
Potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional adverse reactions in children
In addition to inhibitor development in previously untreated pediatric patients (PUP) and catheter-related complications, no age-specific differences in adverse reactions were observed in clinical studies.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor. You can also report adverse reactions directly via the national reporting system listed in Annex V. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. HOW TO STORE ADVATE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
During the shelf life, the product blister may be stored at room temperature (not above 25 °C) for a single period not exceeding 6 months. In this case, the medicine expires at the end of this 6-month period or on the expiry date printed on the blister, whichever comes first. Record the end of the 6-month room temperature storage period on the outer label. The medicine cannot be stored in the refrigerator again after being kept at room temperature.
Keep the product blister in the outer packaging to protect the medicine from light.
The medicine is for single use only. Dispose of any unused residues properly.
Use the product immediately after complete reconstitution of the lyophilized powder.
Do not refrigerate the solution after preparation.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. PACK CONTENTS AND OTHER INFORMATION

What ADVATE contains

• The active substance is octocog alfa (recombinant human coagulation Factor VIII). Each vial of powder nominally contains 250, 500, 1000, 1500, 2000, or 3000 IU of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trehalose, calcium chloride, tromethamine, polysorbate 80, and glutathione (reduced).

Solvent vial: Water for injections 5 mL

Description of the appearance of ADVATE and pack contents
ADVATE is a white or almost white, friable powder.
After reconstitution, the solution is clear, colourless, and free from foreign particles.

Marketing Authorisation Holder
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna
Tel: +800 66838470
e-mail: [email protected]

Manufacturers
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
Tel/Tél: +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 Tel/Tél: +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 Drugsales Ltd
Tlf: +45 46 77 10 10 Tel: +356 21419070
[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 ΑΕ 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.
Tel: +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]

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

ADVATE must not be mixed with other medicinal products or solvents.
It is strongly recommended that each time ADVATE is administered, the product name and batch number are recorded.

Instructions for reconstitution of the solution

• Do not use the product after the expiry date stated on the labels and carton.
• Do not use the product 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 (between 15 °C and 25 °C).

2. Wash hands thoroughly with soap and warm water.

3. Open the ADVATE packaging by removing the top cover. Remove the BAXJECT III system from the blister.

4. Place ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a blue strip. Do not remove the blue cap until instructed to do so in a later step.

5. Holding the BAXJECT III system in one hand, firmly press down on the solvent vial with the other hand until the system is fully depressed and the solvent flows into the ADVATE vial (Fig. 2). Do not invert the system until the transfer is complete.

6. Ensure that the solvent transfer is complete. Gently swirl to dissolve the powder. Make sure that the ADVATE powder is completely 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 should be clear, colourless, and free from foreign particles.

Figure 1 Figure 2 Figure 3

Instructions for injection
An aseptic technique must be used during administration.
Use a luer-lock syringe for administration.

Important note:

• Do not attempt to perform the injection unless specific instructions have been received from medical or nursing personnel.
• Check the solution for undissolved particles or abnormal discolouration (the solution must be clear, colourless, and free from foreign particles). Do not use ADVATE if the solution is not completely clear or not fully dissolved.

1. Remove the blue cap from the BAXJECT III system. Do not allow air into the syringe. Attach the syringe to the BAXJECT III system.
2. Invert the system (the vial with the reconstituted solution should now be on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger gently.
3. Disconnect the syringe. Attach the 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 per minute. (See section 4 "Possible side effects").
4. Dispose of any unused residues appropriately.

The following information is intended exclusively for healthcare professionals:

Treatment
In the event of the following haemorrhagic episodes, factor VIII activity must not fall below the required plasma activity levels (expressed as % or IU/dL) relative to normal levels during the corresponding period. The following table may be used as a guide for dosing in haemorrhagic episodes and surgery.
The dose and frequency of administration should be adjusted according to the individual clinical response. In certain circumstances (e.g. presence of a low-titre inhibitor), higher doses than those calculated using the formula may be required.

Package leaflet: information for the user

ADVATE 250 IU Powder and solvent for injectable solution, 500 IU Powder and solvent for injectable solution, 1000 IU Powder and solvent for injectable solution, 1500 IU Powder and solvent for injectable solution

octocog alfa (recombinant human coagulation factor VIII)
Please read this leaflet carefully before 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. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet:

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

1. WHAT ADVATE IS AND WHAT IT IS USED FOR

ADVATE contains the active substance octocog alfa, recombinant human coagulation factor VIII produced using recombinant DNA technology. Factor VIII is necessary for blood to form clots and to stop bleeding. In patients with haemophilia A (congenital factor VIII deficiency), this factor is missing or does not function properly.
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).
ADVATE is manufactured without the addition of any human or animal proteins during the entire production process.

2. WHAT YOU SHOULD KNOW BEFORE USING ADVATE

Do not use ADVATE

• if you are allergic to 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 in doubt, consult your doctor.
Warnings and precautions
Talk to your doctor before using ADVATE. You must inform your doctor if you have previously been
treated with factor VIII-containing medicines, especially if you have developed inhibitors, as there
may be an increased risk that this will happen again. Inhibitors are antibodies against factor VIII that reduce the effectiveness of ADVATE in preventing and controlling bleeding. The development of inhibitors is a well-known complication in the treatment of haemophilia A. If bleeding is not controlled with the use of ADVATE, inform your doctor immediately.
There is a risk, although rare, that you may develop an anaphylactic reaction (a severe and sudden allergic reaction) to ADVATE. You should be aware of the early signs of such allergic reactions, which include: skin rash, urticaria, blisters (wheals), generalized itching, swelling of the lips and tongue, breathing difficulties, shortness of breath, chest tightness, feeling unwell, and dizziness. These symptoms may be early signs of anaphylactic shock, which may also include extreme dizziness, loss of consciousness, and severe breathing difficulties.
If any of these symptoms occur, stop the injection/infusion of the medicine immediately and consult your doctor. In case of severe symptoms, including difficulty breathing and fainting (or feeling faint), emergency medical treatment is required.
Patients who develop factor VIII inhibitors
The formation of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII-containing 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 these inhibitors. If ADVATE does not control bleeding in you or your child, inform your doctor immediately.
Children and adolescents
The warnings and precautions described above apply to both adults and children (from 0 to 18 years of age).
Inform your doctor if you are currently using, have recently used, or might use any other medicines.
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.
Driving and operating machinery
ADVATE does not affect the ability to drive or operate machinery.
ADVATE contains sodium
This medicine contains 10 mg of sodium (the main component of table salt) per vial. This corresponds to 0.5% of the maximum daily recommended dietary intake of sodium for an adult.
Incorrect administration of ADVATE
Incorrect administration (injection into an artery or outside a vein) must be avoided, as it may cause mild, short-term reactions at the injection site, such as bruising and redness.

3. HOW TO USE ADVATE

Treatment with ADVATE should be initiated by a physician experienced in the management of patients with haemophilia A.
The physician will determine the dose of ADVATE (in International Units or IU) based on your physical condition, body weight, and whether it is being used for prevention or treatment of bleeding episodes.
The frequency of administration will depend on the assessment of ADVATE's effectiveness in your case. Generally, replacement therapy with ADVATE lasts for life.
Use this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.

Prevention of bleeding episodes
The usual dose of octocog alfa is between 20 IU and 40 IU per kg of body weight, administered every 2–3 days. However, in some cases, especially in younger patients, more frequent injections or higher doses may be required.

Treatment of bleeding episodes
The dose of octocog alfa is calculated based on body weight and the required factor VIII levels. Optimal factor VIII levels will depend on the severity and location of the bleeding.

DOSE (IU) = body weight (kg) × desired increase in factor VIII (%) × 0.5

If you feel that the effect of ADVATE is insufficient, consult your doctor.
Your doctor will perform appropriate laboratory tests to ensure that you have adequate levels of Factor VIII.
This is particularly important if you are undergoing major surgical procedures.

Use in children and adolescents (from 0 to 18 years of age)
For the treatment of bleeding episodes, the dose in children does not differ from that in adult patients. For prophylaxis in children under 6 years of age, doses of 20 to 50 IU per kg of body weight, 3–4 times per week, are recommended. The administration of ADVATE in children (intravenously) does not differ from that in adults. To allow frequent infusions of factor VIII products, a central venous access device (CVAD) may become necessary.
Due to the reduced reconstitution volume of ADVATE to 2 mL, the time available to respond to hypersensitivity reactions during injection is further shortened. Therefore, particular caution is advised during the injection of ADVATE reconstituted to 2 mL, especially in paediatric patients.

How to administer ADVATE
ADVATE is generally administered intravenously by a physician or nurse. You or another person may administer the injection of ADVATE, but only after proper training. Detailed instructions for self-administration are provided at the end of this leaflet.

If you use more ADVATE than you should
Always use ADVATE exactly as prescribed by your doctor. If you have any doubts, consult your doctor.
If you receive a dose of ADVATE higher than recommended, inform your doctor as soon as possible.

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

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

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
In the case of severe and sudden allergic (anaphylactic) reactions, you must stop the infusion immediately. You must contact your doctor immediately if you experience any of the following early symptoms of allergic reactions:

• skin rash, hives, blisters (wheals), and generalized itching,
• swelling of the lips and tongue,
• breathing difficulties, wheezing, chest tightness,
• general feeling of illness,
• dizziness, loss of consciousness.

Severe symptoms such as difficulty breathing and fainting (feeling of passing out) require immediate emergency treatment.
For children who have not previously been treated with factor VIII-containing medicines, the development of inhibitory antibodies (see section 2) can be very common (more than 1 in 10 people); however, in patients who have previously received treatment with factor VIII (more than 150 days of treatment), the risk is uncommon (less than 1 in 100 people). If this occurs, the medicine may no longer work properly, and you or your child may experience persistent bleeding. If this happens, you must contact your doctor immediately.

Very common adverse reactions (may affect more than 1 in 10 people):
Factor VIII inhibitors (in children not previously treated with factor VIII-containing medicines).

Common adverse reactions (may affect up to 1 in 10 people):
Headache and fever.

Uncommon adverse reactions (may affect up to 1 in 100 people):
Factor VIII inhibitors (in patients who have previously received factor VIII treatment (more than 150 days of treatment)), dizziness, influenza, fainting, abnormal heartbeat, red, itchy swellings on the skin, chest discomfort, bruising at the injection site, injection site reaction, itching, increased sweating, unusual taste in the mouth, hot flushes, migraine, memory impairment, chills, diarrhea, nausea, vomiting, shortness of breath, laryngitis, lymphatic vessel infection, skin pallor, eye inflammation, rash, excessive sweating, swelling of feet and legs, decrease in blood cellular component (hematocrit), increase in a type of white blood cells (monocytes), and pain in the upper abdominal quadrants or lower part of the chest.

Surgery-related
Catheter infection, decreased hematocrit, limb and joint edema, prolonged bleeding after drain removal, decreased factor VIII levels, and postoperative hematoma.

Related to central venous access devices (CVAD)
Catheter infection, systemic infection, and local blood clot at the catheter site.

Adverse reactions with unknown frequency (frequency cannot be estimated from the available data):
Potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional adverse reactions in children
In addition to the development of inhibitors in previously untreated pediatric patients (PUP) and catheter-related complications, no age-specific differences in adverse reactions were observed in clinical studies.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor. You may also report adverse reactions directly via the national reporting system listed in Annex V. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. HOW TO STORE ADVATE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
During its shelf life, the vial of powder may be stored at room temperature (not above 25 °C) for a single period not exceeding 6 months. In this case, the medicine expires at the end of this 6-month period or on the expiry date printed on the product vial, whichever comes first. Record the end of this 6-month room temperature storage period on the outer label. Once stored at room temperature, the medicine must no longer be refrigerated.
Keep the vial in the outer packaging to protect the medicine from light.
This medicine is for single use only. Dispose of any unused residues properly.
Use the product immediately after complete reconstitution of the lyophilized powder.
Do not refrigerate the solution after preparation.
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. PACK CONTENTS AND OTHER INFORMATION

What ADVATE contains

• The active substance is octocog alfa (recombinant human coagulation Factor VIII). Each vial of powder contains nominally 250, 500, 1000, or 1500 IU of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trehalose, calcium chloride, tromethamine, polysorbate 80, and reduced glutathione.

Solvent vial: Water for injections 2 mL

Description of the appearance of ADVATE and pack contents
ADVATE is a white or almost white, friable powder.
After reconstitution, the solution is clear, colourless, and free from foreign particles.
Each pack contains a reconstitution device (BAXJECT II).

Marketing Authorisation Holder
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna
Tel: +800 66838470
e-mail: [email protected]

Manufacturers
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
Tel/Tél: +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 Tel/Tél: +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 Drugsales Ltd
Tlf: +45 46 77 10 10 Tel: +356 21419070
[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 ΑΕ 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.
Tel: +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]

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

Aseptic technique must be used during solution preparation and administration.
Only use water for injections and the reconstitution and preparation devices supplied in each ADVATE pack. ADVATE must not be mixed with other medicinal products or solvents.
It is strongly recommended that each time ADVATE is administered, the product name and batch number are recorded.

Instructions for reconstitution of the solution

• Do not use the product after the expiry date stated on the labels and carton.

• Do not use the product if the BAXJECT II device, its sterile barrier system, or its packaging are damaged or show any signs of deterioration, as indicated by the symbol: .

• Do not refrigerate the solution after preparation.

1. If the product is still refrigerated, remove both the lyophilised ADVATE powder and the solvent vial from the refrigerator and allow them to reach room temperature (15–25 °C).
2. Wash hands thoroughly with soap and warm water.
3. Remove the caps from the lyophilised powder and solvent vials.
4. Clean the vial stoppers with alcohol swabs. Place the vials on a clean, flat surface.
5. Open the BAXJECT II package by removing the top cover, taking care not to touch the inside (Fig. a). Do not remove the device from the package. Do not use the product if the BAXJECT II device, its sterile barrier system, or its packaging are damaged or show any signs of deterioration.
6. Turn the package upside down and insert the transparent plastic spike through the solvent vial stopper. Hold the edges of the package and pull it away to release the BAXJECT II device (Fig. b). Do not remove the blue cap from the BAXJECT II device. Only use the sterile water for injections and the reconstitution device supplied in the pack for reconstitution. Holding the BAXJECT II attached to the solvent vial, invert the system so that the solvent vial is above the device. Insert the white plastic spike through the stopper of the ADVATE powder vial. The solvent will be drawn into the ADVATE powder vial (Fig. c).
7. Gently swirl until the powder is completely dissolved. Ensure that all ADVATE powder is fully dissolved, otherwise not all of the reconstituted solution will pass through the device filter. The product dissolves rapidly (usually within less than 1 minute). After reconstitution, the solution appears clear, colourless, and free from foreign particles.

Fig. a Fig. b Fig. c

Instructions for injection

For administration, use a luer-lock syringe.

Important note:

• Do not attempt to administer the injection unless specific instructions have been received from medical or nursing personnel.
• Check the solution for undissolved particles or abnormal discolouration (the solution should be clear, colourless, and free from foreign particles). Do not use ADVATE if the solution is not completely clear or not fully dissolved.

1. Remove the blue cap from BAXJECT II. Do not allow air into the syringe. Attach the syringe to BAXJECT II (Fig. d).
2. Invert the system (the vial with reconstituted solution should be above). Slowly draw the reconstituted solution into the syringe by pulling back the plunger (Fig. e).
3. Disconnect the syringe.
4. Attach the 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 per minute. (See section 4 "Possible side effects").
5. Dispose of unused residues appropriately.

Figure d Figure e

---

The following information is intended for healthcare professionals only:

Treatment
In the event of the following bleeding episodes, factor VIII activity should not fall below the determined plasma activity levels (in % or in IU/dL) relative to normal levels during the corresponding period. The following table can be used as a guide for dosing in bleeding episodes and surgery.
The dose and frequency of administration should be adjusted according to the individual clinical response. In certain circumstances (e.g., presence of a low-titer inhibitor), higher doses than those calculated using the formula may be required.

Package leaflet: Information for the user

ADVATE 250 IU Powder and solvent for injectable solution, 500 IU Powder and solvent for injectable solution, 1000 IU Powder and solvent for injectable solution, 1500 IU Powder and solvent for injectable solution

octocog alfa (recombinant human coagulation factor VIII)
Please read this leaflet carefully before 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, consult your doctor.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be dangerous.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor. See section 4.

Contents of this leaflet:

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

1. WHAT ADVATE IS AND WHAT IT IS USED FOR

ADVATE contains the active substance octocog alfa, recombinant human coagulation factor VIII produced using recombinant DNA technology. Factor VIII is necessary for blood to form clots and to stop bleeding. In patients with haemophilia A (congenital factor VIII deficiency), this factor is missing or does not function properly.
ADVATE is used for the treatment and prevention of bleeding in patients of all age groups with haemophilia A (an inherited bleeding disorder caused by factor VIII deficiency).
ADVATE is manufactured without the addition of any human or animal proteins during the entire production process.

2. WHAT YOU SHOULD KNOW BEFORE USING ADVATE

Do not use ADVATE

• if you are allergic to 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 in doubt, consult your doctor.
Warnings and precautions
Talk to your doctor before using ADVATE. You must inform your doctor if you have previously been
treated with factor VIII-containing medicines, especially if you have developed inhibitors, as there may be an increased risk of this happening again. Inhibitors are neutralizing antibodies against factor VIII that reduce the effectiveness of ADVATE in preventing and controlling bleeding. The development of inhibitors is a well-known complication in the treatment of haemophilia A. If bleeding is not controlled with ADVATE, inform your doctor immediately.
There is a risk, although rare, that you may develop an anaphylactic reaction (a severe and sudden allergic reaction) to ADVATE. You should be aware of the early signs of such allergic reactions, which include: skin rash, hives, blisters (wheals), generalized itching, swelling of the lips and tongue, breathing difficulties, shortness of breath, chest tightness, feeling unwell, and dizziness. These symptoms may be early signs of anaphylactic shock, which may also include extreme dizziness, loss of consciousness, and severe breathing difficulties.
If any of these symptoms occur, stop the injection/infusion of the medicine immediately and consult your doctor. In case of severe symptoms, including difficulty breathing and fainting (or feeling faint), emergency medical treatment is required.
Patients who develop factor VIII inhibitors
The formation of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII-containing 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 these inhibitors. If ADVATE does not control bleeding in you or your child, inform your doctor immediately.
Children and adolescents
The warnings and precautions mentioned above apply to both adults and children (from 0 to 18 years of age).
Inform your doctor if you are currently taking, have recently taken, or might take any other medicines.
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, ask your doctor for advice before using this medicine.
Driving and use of machines
ADVATE does not affect the ability to drive or operate machinery.
ADVATE contains sodium
This medicine contains 10 mg of sodium (the main component of table salt) per vial. This corresponds to 0.5% of the maximum daily recommended dietary intake of sodium for an adult.
Incorrect administration of ADVATE
Incorrect administration (injection into an artery or outside a vein) should be avoided, as it may cause mild short-term reactions at the injection site, such as bruising and redness.

3. HOW TO USE ADVATE

Treatment with ADVATE should be initiated by a physician experienced in the management of patients with haemophilia A.
The physician will determine the dose of ADVATE (in International Units or IU) based on your physical condition, body weight, and whether it is being used for prevention or treatment of bleeding episodes.
The frequency of administration will depend on the assessment of ADVATE's effectiveness in your case. Generally, replacement therapy with ADVATE lasts for life.
Use this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.

Prevention of bleeding episodes
The usual dose of octocog alfa is between 20 IU and 40 IU per kg of body weight, administered every 2–3 days. However, in some cases, particularly in younger patients, more frequent injections or higher doses may be required.

Treatment of bleeding episodes
The dose of octocog alfa is calculated based on body weight and the desired factor VIII levels to be achieved. The optimal factor VIII levels will depend on the severity and location of the bleeding.

DOSE (IU) = body weight (kg) × desired increase in factor VIII (% of normal) × 0.5

If you feel that the effect of ADVATE is insufficient, consult your doctor.
Your doctor will perform appropriate laboratory tests to ensure that you have adequate levels of Factor VIII. This is particularly important if you are undergoing major surgical procedures.

Use in children and adolescents (from 0 to 18 years of age)
For treatment of bleeding episodes, the dose in children does not differ from that in adult patients. For prevention of bleeding episodes in children under 6 years of age, doses of 20 to 50 IU per kg of body weight, administered 3–4 times per week, are recommended. Administration of ADVATE in children (intravenously) does not differ from administration in adults. To allow frequent infusions of factor VIII products, a central venous access device (CVAD) may become necessary.
Due to the reduced reconstitution volume of ADVATE to 2 mL, the time available to respond to hypersensitivity reactions during injection is further shortened. Therefore, particular caution is advised during injection of ADVATE reconstituted to 2 mL, especially in paediatric patients.

How to administer ADVATE
ADVATE is generally administered intravenously by a physician or nurse. You or another person may administer the injection of ADVATE, but only after receiving adequate training. Detailed instructions for self-administration are provided at the end of this package leaflet.

If you use more ADVATE than you should
Always use ADVATE exactly as prescribed by your doctor. If you have any doubts, consult your doctor.
If you take more ADVATE than recommended, inform your doctor as soon as possible.

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

If you stop using ADVATE
Do not stop using ADVATE without first 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.
In case of severe and sudden allergic (anaphylactic) reactions, you must stop the infusion immediately.
You must contact your doctor immediately if you experience any of the following early symptoms of allergic reactions:

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

Severe symptoms such as difficulty breathing and fainting (a feeling of passing out) require immediate emergency treatment.
In children who have not previously been treated with factor VIII-containing medicines, the development of inhibitory antibodies (see section 2) may be very common (more than 1 in 10 people); however, in patients who have previously received treatment with factor VIII (more than 150 days of treatment), the risk is uncommon (less than 1 in 100 people). If this occurs, the medicine may no longer work properly and you or your child 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):
Factor VIII inhibitors (in children not previously treated with factor VIII-containing medicines).

Common side effects (may affect up to 1 in 10 people):
Headache and fever.

Uncommon side effects (may affect up to 1 in 100 people):
Factor VIII inhibitors (in patients previously treated with factor VIII (more than 150 days of treatment)), dizziness, influenza, fainting, abnormal heartbeat, red, swollen, itchy skin patches, chest discomfort, bruising at the injection site, injection site reaction, itching, increased sweating, unusual taste in the mouth, hot flushes, migraine, memory impairment, chills, diarrhea, nausea, vomiting, shortness of breath, laryngitis, lymphatic vessel infection, skin pallor, eye inflammation, rash, excessive sweating, swelling of the feet and legs, decrease in the cellular component of blood (hematocrit), increase in a type of white blood cells (monocytes), and pain in the upper abdomen or lower chest.

Surgery-related
Catheter-related infection, decreased hematocrit, swelling of limbs and joints, prolonged bleeding after drain removal, decreased factor VIII levels, and postoperative hematoma.

Related to central venous access devices (CVAD)
Catheter-related infection, systemic infection, and local blood clot at the catheter site.

Side effects with unknown frequency (frequency cannot be calculated from available data):
Potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional side effects in children
Apart from the development of inhibitors in previously untreated pediatric patients (PUP) and catheter-related complications, no age-specific differences in side effects were observed in clinical studies.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor. 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 ADVATE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp." The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C – 8 °C).
Do not freeze.
During the shelf life, the blister containing the product may be stored at room temperature (not above 25 °C) for a single period not exceeding 6 months. In this case, the medicine expires at the end of this 6-month period or on the expiry date printed on the blister, whichever comes first. Record the end of the 6-month room temperature storage period on the outer label. After storage at room temperature, the medicine must no longer be stored in the refrigerator.
Keep the blister containing the product in the outer packaging to protect the medicine from light.
This medicine is for single use only. Dispose of any unused residues properly.
Use the product immediately after complete dissolution of the lyophilized powder.
Do not refrigerate the solution after preparation.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. PACK CONTENTS AND OTHER INFORMATION

What ADVATE contains

• The active substance is octocog alfa (recombinant human coagulation Factor VIII). Each vial of powder contains nominally 250, 500, 1000, or 1500 IU of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trehalose, calcium chloride, tromethamine, polysorbate 80, and reduced glutathione.

Solvent vial: Water for injections 2 mL

Description of the appearance of ADVATE and contents of the pack
ADVATE is a white or almost white, friable powder.
After reconstitution, the solution is clear, colourless, and free from foreign particles.

Marketing Authorisation Holder
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna
Tel: +800 66838470
e-mail: [email protected]

Manufacturers
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
Tel/Tél: +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 Tel/Tél: +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 Drugsales Ltd
Tlf: +45 46 77 10 10 Tel: +356 21419070
[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 Hellas A.E. Takeda Pharma Ges.m.b.H.
Tel: +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: +48 223062447
[email protected] [email protected]

France Portugal
Takeda France SAS Takeda Farmacêuticos Portugal, Lda.
Tel: +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]

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
Tel: +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

ADVATE must not be mixed with other medicinal products or solvents.
It is strongly recommended that each time ADVATE is administered, the name and batch number of the product are recorded.

Instructions for reconstitution of the solution

• Do not use the product after the expiry date stated on the labels and carton.
• Do not use the product if the top of the blister is not fully sealed.
• Do not store the solution in the refrigerator after preparation.

1. If the product is still refrigerated, remove the sealed blister (containing the powder and solvent vials pre-assembled with the reconstitution system) from the refrigerator and allow it to reach room temperature (between 15 °C and 25 °C).
2. Wash hands thoroughly with soap and warm water.
3. Open the ADVATE packaging by removing the top cover. Remove the BAXJECT III system from the blister.
4. Place ADVATE on a flat surface with the solvent vial on top (Fig. 1). The solvent vial has a blue strip. Do not remove the blue cap until instructed to do so in a later step.
5. Holding the BAXJECT III system in one hand, firmly press the solvent vial with the other hand until the system is fully depressed and the solvent flows into the ADVATE vial (Fig. 2). Do not invert the system until the transfer is complete.
6. Ensure that the solvent transfer is complete. Gently swirl until the powder is completely dissolved. Make sure that the ADVATE 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

Instructions for injection

During administration, an aseptic technique must be used.
Use a luer-lock syringe for administration.

Important note:

• Do not attempt to administer the injection unless specific instructions have been received from medical or nursing personnel.
• Check the solution for undissolved particles or abnormal discolouration (the solution should be clear, colourless, and free from foreign particles). Do not use ADVATE if the solution is not completely clear or not fully dissolved.

1. Remove the blue cap from the BAXJECT III system. Do not allow air into the syringe. Attach the syringe to the BAXJECT III system.
2. Invert the system (the vial with reconstituted solution should be on top). Slowly draw the reconstituted solution into the syringe by pulling back the plunger.
3. Disconnect the syringe. Attach the 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 per minute (see section 4 "Possible side effects").
4. Dispose of any unused residues appropriately.

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The following information is intended exclusively for healthcare professionals:
Treatment
In the event of the following bleeding episodes, Factor VIII activity should not fall below the plasma activity levels (expressed as % or IU/dL) indicated in the table below relative to normal levels during the corresponding period. The following table may be used as a reference for dosing in bleeding episodes and surgery.
The dose and frequency of administration should be adjusted according to the individual clinical response. In certain circumstances (e.g., presence of a low-titre inhibitor), higher doses than those calculated using the formula may be required.