Product Information for the User

ADVATE250UI powder andsolvent for injectable solution

ADVATE500UI powder andsolvent for injectable solution

ADVATE1000UI powder andsolvent for injectable solution

ADVATE1500UI powder andsolvent for injectable solution

Octocog alfa (recombinant human coagulation factor VIII)

Read this leaflet carefully before you start using the medicine, because it contains important information for you.

• Keep this leaflet, as 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 others even if their symptoms are the same. It may harm them.
• If you experience any side effects, talk to your doctor, even if they are not listed in this leaflet. See section 4.

1.What is ADVATE andwhat it is used for

2.What you need to know before you start using ADVATE

3.How to use ADVATE

4.Possible side effects

5.Storage of ADVATE

6.Contents of the pack and additional information

ADVATE contains the active ingredient octocog alfa, human coagulation factor VIII produced by recombinant DNA technology. Factor VIII is necessary for blood coagulation andstopping bleeding. In patients with hemophilia A, factor VIII is either lacking ordoes not function correctly (hereditary deficiency of factor VIII).

ADVATE is used for the treatment and prevention of bleeding in patients of all age groups who suffer from hemophilia A (a hereditary bleeding disorder caused by the absence of factor VIII).

ADVATE is prepared without adding any human oranimal-derived protein throughout the manufacturing process.

Do not use ADVATE

• If you are allergic (hypersensitive) to octocog alfa orto any of the other components ofthis medication (listed in section6).
• If you are allergic tomouse orhamster proteins

If you are unsure if you are allergic, consult your doctor.

Warnings and precautions

Consult your doctor before starting to use ADVATE. Inform your doctor if you have been previously treated with medications containing factor VIII, especially if you developed inhibitors as there may be a high risk of this happening again. Inhibitors are antibodies that block factor VIII, reducing the effectiveness of ADVATE in preventing bleeding. The development of inhibitors is a known complication in the treatment of hemophilia A. If your bleeding does not control with ADVATE, consult your doctor immediately.

There is a rare risk that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to ADVATE. Be aware that the first symptoms of an allergic reaction are hives, itching, redness, generalized itching, swelling of the lips andtongue, difficulty breathing, gasping, chest tightness, general feeling of discomfort, anddizziness. These symptoms may be a warning of anaphylactic shock, which can also cause severe dizziness, loss of consciousness, andsevere breathing difficulties.

If you experience any of these symptoms, stop administering the medication immediately andconsult a doctor. Severe symptoms, including difficulty breathing and(almost) fainting require rapid emergency treatment.

Patients who develop Factor VIII inhibitors

The formation of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII medications. These inhibitors, especially in large quantities, prevent the treatment from working correctly, so you and your child will be closely monitored for the development of these inhibitors. If your bleeding or your child's bleeding is not controlled with ADVATE, consult your doctor immediately.

Children and adolescents

The warnings and precautions indicated apply to adults and children (from0to18years of age).

Use of ADVATE with other medications

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

Pregnancy andlactation

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

Driving anduse of machines

The treatment with ADVATE has no influence on the ability to drive anduse machinery.

ADVATE contains sodium

This medication contains0.45mmol of sodium (10mg) per vial, which should be taken into account in patients with low-sodium diets.

Incorrect application of ADVATE

The incorrect application (injection into an artery oroutside the vein) should be avoided as it may cause mild andshort-term reactions at the injection site, such as redness andbruising.

The treatment with ADVATE will be started by a doctor with experience in treating patients with hemophilia A.

Your doctor will calculate your dose of ADVATE (in international units or UI) based on your condition, body weight, and whether it will be used for prevention or treatment of bleeding. The frequency of administration will depend on how ADVATE works. Replacement therapy with ADVATE is normally a lifelong treatment.

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

Bleeding Prevention

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

Bleeding Treatment

The dose of octocog alfa is calculated based on your body weight and the levels of factor VIII you want to achieve. The levels of factor VIII to be achieved will depend on the severity and location of the bleeding.

Dose (UI) = body weight (kg) x increase in Factor VIII desired (% of normal) x 0.5

If you feel that the effect of ADVATE is insufficient, consult your doctor.

Your doctor will perform the appropriate laboratory tests to ensure that you have the appropriate levels of factor VIII. This is especially important if you are going to undergo a major operation.

Use in Children and Adolescents(from 0 to 18 years of age)

For bleeding treatment, the dose in children does not differ from that of adult patients. To prevent bleeding in children under 6 years of age, doses of 20 to 50 UI per kg of body weight are recommended, administered 3 to 4 times a week. The administration of ADVATE in children (intravenous) does not differ from the administration in adults. It may be necessary to use a central venous access device (CVAD) to allow for frequent infusions of factor VIII products.

Due to the decrease in the injection volume of reconstituted ADVATE in 2 ml, the time to react to hypersensitivity reactions during an injection is reduced even further. Therefore, it is recommended to exercise caution during the injection of ADVATE reconstituted in 2 ml, especially in children.

How to Administer ADVATE

ADVATE is normally injected into a vein (intravenously) by your doctor or nurse. You or anyone else can also administer the ADVATE injection, but only after receiving proper training. Detailed instructions for its administration are described at the end of this prospectus.

If You Use More ADVATE Than You Should

Follow exactly the administration instructions of ADVATE indicated by your doctor. Consult your doctor if you have any doubts. If a higher dose of ADVATE than recommended is injected, consult your doctor as soon as possible.

If You Forget to Use ADVATE

Do not inject a double dose to compensate for the missed doses. Administer the next injection as scheduled and continue as your doctor had indicated.

If You Stop Treatment with ADVATE

Do not stop using ADVATE without consulting your doctor.

If you have any other questions about the use of this medication, ask your doctor.

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

If you experienceallergic reactions(anaphylactic)that are sudden andsevere, you should stop the injection immediately. Contact your doctor immediately if you have any of the following initial symptoms of allergic reactions:

• eruption, hives, andgeneralized itching,
• swelling of the lips andthe tongue,
• difficulty breathing, wheezing, chest tightness,
• general feeling of discomfort,
• dizziness andloss of consciousness.

Severe symptoms, such as difficulty breathing and(almost) syncope, require early emergency treatment.

In children who have not received previous treatment with factor VIII-containing medicines, the production of inhibitor antibodies (see section 2) can occur very frequently (more than 1 in 10 patients); however, in patients who have received previous treatment with factor VIII (more than 150 days of treatment), the risk is infrequent (less than 1 in 100 patients). If this happens, the medicines you or your child are taking may not work properly and you or your child may experience persistent bleeding. In this case, contact your doctor immediately.

Very common side effects(can affect more than 1 in 10 patients)

Factor VIII inhibitors (in children who have not received previous treatment with factor VIII-containing medicines).

Common side effects(can affect up to 1 in 10 patients)

Headache and fever

Uncommon side effects(can affect up to1in100patients)

Factor VIII inhibitors (in patients who have received previous treatment with factor VIII [more than 150 days of treatment]), dizziness, flu, fatigue, abnormal heartbeats, red spots associated with itching, chest discomfort, ecchymosis at the injection site, reaction at the injection site, itching, excessive sweating, strange taste in the mouth, hot flushes, migraines, memory loss, chills, diarrhea, nausea, vomiting, difficulty breathing, sore throat, lymphatic vessel infection, pallor, eye inflammation, hives, excessive sweating, inflammation of the feet andlegs, decrease in red blood cell count, increase in a type of white blood cell (monocytes) andabdominal orchest pain in the upper or lower part.

Related to surgery

surgical site infection, decrease in red blood cell count, swelling of the extremities andthe joints, prolonged bleeding after catheter removal, decrease in factor VIII levels andpostoperative hematoma

Related to central venous access devices (CVAD)

surgical site infection, systemic infection andlocal blood clot in the catheter side.

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

Reactions that can be fatal (anaphylaxis) andother allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional side effects in children

Aside from the development of inhibitors in pediatric patients without previous treatment and catheter-related complications, no age-specific differences in side effects were observed in clinical trials.

Reporting of side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendixV. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date refers to the last day of the month indicated.

Store in the refrigerator (between 2°C and 8°C).

Do not freeze.

Until the expiration date, the medication blister can be stored at room temperature (up to 25°C) for a single period not exceeding 6 months. In this case, this medication expires at the end of this 6-month period or on the expiration date printed on the blister, whichever occurs first. Please note on the medication packaging the date of the end of the 6-month storage period at room temperature. The medication cannot be refrigerated again after being stored at room temperature.

Store the medication blister in the outer packaging to protect it from light.

This medication is for single use only. Dispose of unused solution properly.

Use the medication immediately after complete dissolution of the powder.

Do not refrigerate the medication after preparation.

Medicines should not be thrown away through drains or in the trash. Ask your pharmacist how to dispose of the packaging and unused medications. By doing so, you will help protect the environment.

Composition of ADVATE

• The active ingredient is octocog alfa (human coagulation factor VIII produced by recombinant DNA technology). Each vial of powder contains nominally250,500,1000or1500UI of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trealosa, calcium chloride, trometamol, polisorbate80and reduced glutathione.

Concentrate Vial:2ml of sterile water for injection preparations

Appearance of the product andcontents of the package

ADVATE is a white to off-white powder.

After reconstitution, the solution is transparent, colorless andfree of foreign particles.

Marketing Authorization Holder

Takeda Manufacturing Austria AG

Industriestrasse 67

A-1221 Vienna

Phone: +800 66838470

Email: [email protected]

Manufacturers

Baxalta Belgium Manufacturing SA

Boulevard René Branquart80

B‑7860Lessines

Belgium

Last Review Date of this Leaflet

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu/.

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Instructions for Preparation andAdministration

ADVATE should not be mixed with other medicines orsolvents.

It is strongly recommended to record the name and batch number of the product each time it is administered.

Instructions for Reconstitution

• Do not use after the expiration date appearing on the labels andin the package.
• Do not use if the blister seal is not perfectly sealed.
• Do not refrigerate the preparation after reconstitution.

1.If the medicine is in the refrigerator, take the sealed blister (contains vials of powder and solvent precarried with the system for reconstitution) from the refrigerator and leave it at room temperature (between15°C and25°C).

2.Wash your hands with soap and warm water.

3.Open the ADVATE packaging by removing the cap. Remove the BAXJECTIII 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 stripe. Do not remove the blue cap until instructed to do so.

5.While holding ADVATE with one hand in the BAXJECTIII system, press the solvent vial with the other hand until the system is fully contracted and the solvent enters the ADVATE vial (Fig.2). Do not tilt the system until the transfer is complete.

6.Check that the transfer is complete. Gently shake until all the material is dissolved. Make sure the ADVATE powder is completely dissolved, if not, the entire reconstituted solution will not pass through the filter of the equipment. The medicine dissolves quickly (usually in less than1minute). After reconstitution, the solution must be transparent, colorless and free of foreign particles.

Instructions for Injection

Aseptic technique is required during administration.

A syringe with a Luer lock is required for administration.

Important Note:

• Do not attempt to administer the injection unless you have received special training from your doctor ornurse.
• Inspect the prepared solution for particles ordecoloration before administration (the solution must be transparent, colorless andfree of foreign particles).

Do not use ADVATE if the solution is not completely transparent ornot completely dissolved.

1.Remove the blue cap from the BAXJECTIII system.Do not introduce air into the syringe. Connect the syringe to the BAXJECTIII system.

2.Invert the system (the vial with the reconstituted solution on top). Introduce the reconstituted solution into the syringe, pulling the plunger back slowly.

3.Disconnect the syringe.

4.Connect a needle with wings tothe syringe. Administer intravenously. The solution must be administered slowly, at a rate determined by the patient's comfort level, not exceeding10ml per minute. Take the pulse before andduring the administration of ADVATE. If you observe a significant increase in pulse, reduce the administration rate orinterrupt the injection temporarily, usually allowing symptoms to disappear immediately (see section4“Possible Adverse Effects”).

5.Dispose of the unused solution properly.

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This information is intended only for healthcare professionals:

Treatment on Demand

In the case of post-hemorrhagic episodes, the factor VIII activity should not be less than the plasma activity level given (in % of normal orUI/dl) in the corresponding period. The following table can be used as a guide for dosing in hemorrhagic episodes andsurgery.

The dose andfrequency of administration should be adapted to the clinical response in each individual case. Incertain circumstances (e.g. presence of a low inhibitor titer), higher doses than those calculated using the formula may be required.