Afstyla

B. PACKAGE LEAFLET

Package leaflet: information for the user

AFSTYLA 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, 2500 IU powder and solvent for solution for injection, 3000 IU powder and solvent for solution for injection

lonoctocog alfa (recombinant single-chain coagulation factor VIII)
Please read all of this leaflet carefully before you or your child start taking 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, pharmacist, or nurse.
• This medicine has been prescribed only for you or your child. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
• If any adverse reaction occurs, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What AFSTYLA is and what it is used for

AFSTYLA is a medicinal product containing human coagulation factor VIII produced using recombinant DNA technology. The active substance in AFSTYLA is onoctocog alfa.
AFSTYLA is used to treat and prevent bleeding episodes in patients with haemophilia A (congenital factor VIII deficiency). Factor VIII is a protein necessary for the blood coagulation process. Patients with haemophilia A lack this protein, therefore their blood does not clot properly and they have an increased tendency to bleed. AFSTYLA works by replacing the missing factor VIII in the blood of patients with haemophilia A, enabling their blood to clot normally.
AFSTYLA can be used in patients of any age.

2. What you should know before you or your child use AFSTYLA

Do not use AFSTYLA

• if the patient being treated with AFSTYLA has had an allergic reaction to AFSTYLA or to any of its ingredients (listed in section 6).
• if the patient being treated with AFSTYLA is allergic to hamster proteins.

Warnings and precautions
Traceability
It is important to keep track of the batch number of your AFSTYLA.
Therefore, each time you receive a new pack of AFSTYLA, record the date and the batch number
(located on the packaging after "Batch") and keep this information in a safe place.
Please consult your doctor, pharmacist, or nurse before using AFSTYLA.

• Allergic-type reactions (hypersensitivity) may occur. The medicine contains traces of hamster proteins (see also “Do not use AFSTYLA”). If you experience symptoms of allergic reactions, stop using the medicine immediately and contact your doctor. Your doctor will inform you about the first signs of allergic reactions. These include hives, widespread skin rash, chest tightness, wheezing, hypotension, and anaphylaxis (a severe allergic reaction causing serious breathing difficulties and dizziness).
• The development of inhibitors (antibodies) is a known complication that may occur during treatment with any factor VIII medicine. 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 inhibitors. If AFSTYLA does not control bleeding in you or your child, inform your doctor immediately.
• If you or your child has or is at risk of heart disease, inform your doctor or pharmacist.
• If a central venous access device (CVAD) is used to administer AFSTYLA, your doctor must consider and discuss with you the risk of complications, including local infections, presence of bacteria in the blood (bacteraemia), and formation of a blood clot (thrombosis) in the blood vessel where the catheter has been inserted.

Other medicines and AFSTYLA
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding

• If you are pregnant or breastfeeding, if you suspect you may be pregnant, or if you are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
• During pregnancy and breastfeeding, AFSTYLA should be administered only if absolutely necessary.

Driving and using machines
AFSTYLA does not affect the ability to drive vehicles or operate machinery.
AFSTYLA contains sodium
AFSTYLA may contain up to 35.0 mg of sodium (the main component of table salt) per vial. This is equivalent to 1.8% of the maximum daily sodium intake recommended for an adult.

3. How to use AFSTYLA

Treatment must be carried out under the supervision of a physician experienced in the treatment of
coagulation disorders.
AFSTYLA must always be administered as directed by your doctor. Consult your doctor if you have
any doubts about this.

Dose
The amount of AFSTYLA required by you or your child and the duration of treatment depend on:

• the severity of the condition
• the site and extent of bleeding
• your clinical condition and response to treatment
• your body weight.

Always follow the instructions provided by your doctor.

Reconstitution and administration
General instructions

• The powder must be mixed with the solvent (liquid) and withdrawn from the vial under aseptic conditions.
• AFSTYLA must not be mixed with other medicinal products or solvents except those listed in section 6.
• The solution should be clear or slightly opalescent, yellow to colourless; it may show some sparkle when exposed to light, but must not contain visible particles. After filtration or withdrawal (see below), the solution must be visually inspected again before use. Do not use solutions that are visibly cloudy or contain particles or deposits.
• Any unused product or waste material must be disposed of in accordance with local regulations and your doctor's instructions.

Reconstitution and administration
Without opening the vials, ensure that the powder and liquid for AFSTYLA have reached room or body temperature, for example by leaving the vials at room temperature for about one hour or by holding them in your hands for a few minutes.
Do not expose the vials to direct heat. The vials must not be warmed to temperatures above body temperature (37°C).
Carefully remove the protective caps from the vials and clean the exposed rubber stoppers with an alcohol swab. Allow the vials to dry before opening the Mix2Vial set package (containing the transfer device with filter), then follow the instructions below:

1	1. Open the Mix2Vial set by removing the thin protective film. Do not remove the Mix2Vial set from its packaging!
2	2. Place the solvent vial on a flat and clean surface, holding it securely. Take the Mix2Vial set together with its packaging and, pressing the blue adapter tip downward, pierce the solvent vial stopper.
3	3. Carefully remove the Mix2Vial packaging by gripping its edge and pulling it upward, ensuring that only the packaging is removed and not the entire Mix2Vial set.
4	4. Place the powder vial on a flat and stable surface. Invert the solvent vial connected to the Mix2Vial set and, by pushing the transparent adapter tip downward, pierce the powder vial stopper. The solvent will automatically transfer into the powder vial.
5	5. Holding firmly with one hand the product side of the Mix2Vial set, grasp with the other hand the solvent side and carefully unscrew the two parts in an anti-clockwise direction to separate them. Dispose of the solvent vial together with the blue adapter of the Mix2Vial set attached to it.
6	6. Gently rotate the product vial with the transparent adapter attached until the content is completely dissolved. Do not shake.
7	7. Draw air into an empty sterile syringe. While holding the product vial in an upright position, attach the syringe to the "Luer Lock" connector of the Mix2Vial set by screwing it on clockwise. Inject air into the product vial.

Withdrawal and administration

8	8. While pressing the plunger of the syringe, invert the system and draw the solution into the syringe by slowly pulling back the plunger.
9	9. Once the solution has been drawn into the syringe, firmly hold the syringe barrel (with the plunger facing downward) and unscrew the transparent Mix2Vial adapter in an anticlockwise direction to disconnect it from the syringe.

Use the intravenous injection set supplied with the product, insert the needle into the vein. Allow the
blood to flow back into the tubing at its tip. Insert the syringe nozzle into the threaded connector of the cannula needle. Slowly inject the reconstituted solution
intravenously (at a rate comfortable for you, up to a maximum of 10 mL/min), following the instructions provided by your doctor. Take care not to allow any blood to enter the syringe containing the product.
Monitor for the possible occurrence of immediate adverse reactions. If you notice the onset of adverse reactions potentially related to the administration of AFSTYLA, stop the infusion (see section 2).
Use in children and adolescents
AFSTYLA can be used in children and adolescents of all ages. In children under 12 years of age, higher doses or more frequent infusions may be required. Children over 12 years of age can use the same doses as adults.
If you use more AFSTYLA than you should
If you have injected more AFSTYLA than you should, inform your doctor.
If you forget to use AFSTYLA
Do not inject a double dose to make up for a missed dose. Proceed directly with the next dose and continue treatment as advised by your doctor.
If you stop using AFSTYLA
If you stop using AFSTYLA, you may no longer be protected against bleeding episodes or may be unable to stop an ongoing hemorrhage. Do not stop using AFSTYLA without first consulting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, AFSTYLA can cause side effects, although not everyone experiences them.
Stop using the medicine immediately and contact your doctor if:

• you experience symptoms of allergic reactions Allergic reactions may present with the following symptoms: hives, generalized rash (pruritic skin rash), tightness in the chest, wheezing, low blood pressure, and anaphylaxis (a severe allergic reaction causing severe breathing difficulties or dizziness). In such a case, stop using the medicine immediately and contact your doctor.
• you notice the medicine is no longer working as it should (bleeding does not stop) In 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 patients); however, in patients who have previously received factor VIII treatment (more than 150 days of treatment), this is uncommon (less than 1 in 100 patients). If you or your child has developed an inhibitor to this medicine, you or your child may experience persistent bleeding. If this occurs, you must contact your doctor immediately.

Common side effects (may affect up to 1 in 10 people)

• Tingling or numbness (paraesthesia)
• Rash
• Fever

Uncommon side effects (may affect up to 1 in 100 people)

• Itching
• Skin redness
• Pain at injection site
• Chills
• Feeling of warmth

Side effects in children and adolescents
No age-related differences have been observed between children, adolescents, and adults regarding the occurrence of side effects.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. You may 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 AFSTYLA

• 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 packaging.
• Store this medicine in a refrigerator (between 2°C and 8°C).
• Prior to reconstitution, AFSTYLA may be stored at room temperature (not above 25°C) for a maximum period of 3 months before the expiry date stated on the carton and vial label. Remember to record the date when storage of AFSTYLA at room temperature is started on the product carton.
• Once the medicine has been removed from the refrigerator, do not return it to the refrigerator.
• Do not freeze this medicine.
• Keep the vials in the outer carton to protect from light.
• The reconstituted medicine should preferably be used immediately.
• If immediate use is not possible, any administration of the reconstituted product under different storage conditions and time frames from those specified will be under the sole responsibility of the user.

6. Package contents and other information

What AFSTYLA contains:
The active substance is:
250 IU per vial; after reconstitution with 2.5 mL of water for injectable preparations, the
solution contains 100 IU/mL of lonoctocog alfa.
500 IU per vial; after reconstitution with 2.5 mL of water for injectable preparations, the
solution contains 200 IU/mL of lonoctocog alfa.
1000 IU per vial; after reconstitution with 2.5 mL of water for injectable preparations, the
solution contains 400 IU/mL of lonoctocog alfa.
1500 IU per vial; after reconstitution with 5 mL of water for injectable preparations, the
solution contains 300 IU/mL of lonoctocog alfa.
2000 IU per vial; after reconstitution with 5 mL of water for injectable preparations, the
solution contains 400 IU/mL of lonoctocog alfa.
2500 IU per vial; after reconstitution with 5 mL of water for injectable preparations, the
solution contains 500 IU/mL of lonoctocog alfa.
3000 IU per vial; after reconstitution with 5 mL of water for injectable preparations, the
solution contains 600 IU/mL of lonoctocog alfa.

The other components are:
L-histidine, polysorbate 80, calcium chloride dihydrate, sodium chloride (see the last part of section 2), sucrose.
Solvent: water for injectable preparations.

What AFSTYLA looks like and contents of the pack
AFSTYLA is presented as a powder or friable mass, white to slightly yellowish in colour, and a clear, colourless solvent for injectable solution.
The reconstituted solution should be clear or slightly opalescent, yellow to colourless in appearance; it may show some sparkle when exposed to light, but must not contain visible particles.

Pack presentations
A pack containing 250, 500 or 1000 IU consists of:

• 1 vial with powder
• 1 vial with 2.5 mL of water for injectable preparations
• 1 transfer device with 20/20 filter
  An inner box containing:
• 1 single-use 5 mL syringe
• 1 intravenous injection set
• 2 alcohol-impregnated swabs
• 1 non-sterile plaster

A pack containing 1500, 2000, 2500 or 3000 IU consists of:

• 1 vial with powder
• 1 vial with 5 mL of water for injectable preparations
• 1 transfer device with 20/20 filter
  An inner box containing:
• 1 single-use 10 mL syringe
• 1 intravenous injection set
• 2 alcohol-impregnated swabs
• 1 non-sterile plaster

Not all pack sizes may be marketed.
Primary packaging

Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Straße 76
35041 Marburg
Germany
For information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
CSL Behring NV CentralPharma Communications UAB
Tél/Tel: +32 15 28 89 20 Tel: +370 5 243 0444
България Luxembourg/Luxemburg
МагнаФарм България ЕАД CSL Behring NV
Тел: +359 2 810 3949 Tél/Tel: +32 15 28 89 20
Česká republika Magyarország
CSL Behring s.r.o. CSL Behring Kft.
Tel: +420 702 137 233 Tel.: +36 1 213 4290
Danmark Malta
CSL Behring AB AM Mangion Ltd.
Tlf: +46 8 544 966 70 Tel: +356 2397 6333
Deutschland Nederland
CSL Behring GmbH CSL Behring BV
Tel: +49 69 30584437 Tel: +31 85 111 96 00
Eesti Norge
CentralPharma Communications OÜ CSL Behring AB
Tel: +3726015540 Tlf: +46 8 544 966 70
Ελλάδα Österreich
CSL Behring ΕΠΕ CSL Behring GmbH
Τηλ: +30 210 7255 660 Tel: +43 1 80101 2463
España Polska
CSL Behring S.A. CSL Behring Sp.z o.o.
Tel: +34 933 67 1870 Tel: +48 22 213 22 65
France Portugal
CSL Behring S.A. CSL Behring Lda
Tél: +33 –(0)-1 53 58 54 00 Tel: +351 21 782 62 30
Hrvatska România
Marti Farm d.o.o. Prisum Healthcare S.R.L
Tel: +385 1 5588297 Tel: +40 21 322 0171
Ireland Slovenija
CSL Behring UK Ltd. NEOX s.r.o.-podružnica v Sloveniji
Tel: +44 1444 447405 Tel:+386 41 42 0002
Ísland Slovenská republika
CSL Behring AB CSL Behring s.r.o.
Sími: +46 8 544 966 70 Tel: +421 911 653 862
Italia Suomi/Finland
CSL Behring S.p.A. CSL Behring AB
Tel: +39 02 34964 200 Puh/Tel: +46 8 544 966 70
Κύπρος Sverige
CSL Behring ΕΠΕ CSL Behring AB
Τηλ: +30 210 7255 660 Tel: +46 8 544 966 70
Latvija United Kingdom (Northern Ireland)
CentralPharma Communications SIA CSL Behring GmbH
Tel: +371 6 7450497 Tel: +49 69 305 17254
For detailed information on this medicinal product, please visit the website of the European Medicines Agency at http://www.ema.europa.eu

The following information is intended exclusively for healthcare professionals:

Treatment must be carried out under the supervision of a physician experienced in the management of hemophilia.
Monitoring of treatment
Appropriate measurement of factor VIII levels during treatment is recommended to determine the required dose and the frequency with which infusions should be repeated. Response to factor VIII may vary between patients, and individual patients may show different half-lives and different in vivo recovery levels. Dosing based on body weight may require dosage adjustments in underweight or overweight patients. In particular, during major surgical procedures, precise and careful monitoring of replacement therapy through coagulation analysis (plasma factor VIII activity) is essential.
When factor VIII activity in patient blood samples is determined using an in vitro one-stage assay for activated partial thromboplastin time (aPTT), results may be significantly affected by both the type of aPTT reagent and the reference standard used in the test. Significant discrepancies may also arise between results obtained using the one-stage aPTT assay and those obtained using the chromogenic method described in the European Pharmacopoeia. This is particularly important when testing is performed in different laboratories and/or with different reagents.
Plasma factor VIII activity in patients receiving AFSTYLA should be monitored using either a chromogenic method or a one-stage coagulation assay to manage the administered dose and the frequency of injection repetition. The chromogenic method is considered the method of choice, as it most accurately reflects the clinical hemostatic potential of AFSTYLA. Indeed, one-stage coagulation assays underestimate factor VIII activity levels by approximately 45% compared to chromogenic assay results. When the one-stage coagulation assay is used, the result must be multiplied by a conversion factor of 2 to determine the patient's factor VIII activity level.
Dosage
The dosage and duration of replacement therapy depend on the severity of factor VIII deficiency, the site and extent of bleeding, and the patient's clinical condition.
The amount of factor VIII administered is expressed in International Units (IU), a unit of measurement based on current WHO standards for factor VIII concentrate products. Plasma factor VIII activity is expressed as a percentage (relative to normal human plasma) or preferably in IU (based on an international standard for factor VIII plasma activity).
One IU of factor VIII activity corresponds to the amount of factor VIII present in 1 mL of normal human plasma.
Potency determination is performed using the chromogenic method. Factor VIII plasma activity levels can be monitored using either the chromogenic method or the one-stage coagulation assay.
On-demand treatment
The calculation of the required factor VIII dose is based on empirical evidence that 1 IU of factor VIII per kg of body weight increases plasma factor VIII activity by 2 IU/dL.
The required dose is determined using the following formula:
dose (IU) = body weight (kg) × desired increase in factor VIII (IU/dL or % of normal human) × 0.5 (IU/kg per IU/dL)
The amount to be administered and the frequency of administration should always be guided by clinical efficacy in the individual case.
In the presence of the following bleeding events, factor VIII activity must never fall below the indicated plasma activity level (IU/dL or % of normal human) throughout the corresponding period. The following table can be used as a guide for dosing in cases of bleeding episodes and surgical procedures:

Prophylaxis
The recommended initial dosing regimen is 20 to 50 IU/kg of AFSTYLA administered two or three
times a week. This initial regimen may be adjusted according to the patient's response.
Paediatric population
The recommended initial dosing regimen in children (from 0 to 12 years of age) is 30 to 50 IU of
AFSTYLA per kg administered two or three times a week. In children under 12 years of age, a higher
frequency of administration or higher doses may be required to compensate for the higher clearance
levels observed in patients in this age group.
For adolescents aged 12 years and older, the recommended dosage is the same as that recommended
for adults.
Elderly patients
Clinical studies conducted with AFSTYLA did not include patients over 65 years of age.