ADVATE 250 IU powder and solvent for solution for injection

ADVATE contains the active substance octocog alfa, human coagulation factor VIII produced by recombinant DNA technology. Factor VIII is necessary for the blood to form clots and stop bleedings. In patients with haemophilia A (inborn factor VIII deficiency), it is missing or not working properly.

ADVATE is used in patients with haemophilia A for prevention or treatment of spontaneous or surgery-related bleeding.

ADVATE is prepared without the addition of any human- or animal-derived protein in the cell culture process, purification or final formulation.

Do not use ADVATE

• if you are allergic (hypersensitive) to octocog alfa or any of the other ingredients of ADVATE
• if you are allergic to mouse or hamster proteins If you are unsure about this, ask your doctor.

Take special care with ADVATE

You should tell your doctor if you have been previously treated with Factor VIII products, especially if you developed inhibitors, since there might be a higher risk that it happens again. Inhibitors are blocking antibodies against factor VIII that reduce the efficacy of ADVATE to prevent or control bleeding. Development of inhibitors is a known complication in the treatment of haemophilia A. If your bleeding is not controlled with ADVATE, tell your doctor immediately.

There is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to ADVATE. You should be aware of the early signs of allergic reactions such as rash, hives, wheals, generalised itching, swelling of lips and tongue, difficulty in breathing, wheezing, tightness in the chest, general feeling of being unwell, and dizziness. These symptoms can constitute an early

symptom of an anaphylactic shock, manifestations of which may additionally include extreme dizziness, loss of consciousness, and extreme difficulty in breathing.
If any of these symptoms occur, stop the injection immediately and contact your doctor. Severe symptoms, including difficulty in breathing and (near) fainting, require prompt emergency treatment.

Taking other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant or breast-feeding.
Your doctor will decide if ADVATE may be used during pregnancy and breast-feeding.

Driving and using machines
ADVATE has no influence on your ability to drive or to use machines.

Important information about some of the ingredients of ADVATE

This medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.

Treatment with ADVATE will be started by a doctor who is experienced in the care of patients with haemophilia A.

Your doctor will calculate your dose of ADVATE (in international units or IU) depending on your condition and body weight, and on whether it is used for prevention or treatment of bleeding. The frequency of administration will depend on how well ADVATE is working for you. Usually, the replacement therapy with ADVATE is a life-long treatment.

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

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

Dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal) x 0.5

If you have the impression that the effect of ADVATE is insufficient, talk to your doctor. Your doctor will perform appropriate laboratory tests to make sure that you have adequate Factor VIII levels. This is particularly important if you are having major surgery.

Patients developing Factor VIII inhibitors

If your plasma Factor VIII fails to reach expected levels with ADVATE, or if bleeding is not adequately controlled, it could be due to the development of Factor VIII inhibitors. This will be checked by your doctor. You might need a higher dose of ADVATE or even a different product to control bleedings. Do not increase the total dose of ADVATE to control your bleeding without consulting your doctor.

How ADVATE is given

ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or someone else might also administer ADVATE as an injection, but only after receiving adequate training. Detailed instructions for self-administration are given at the end of this package leaflet.

If you use more ADVATE than you should

Always take ADVATE exactly as your doctor has told you. You should check with your doctor if you are not sure. If you inject more ADVATE than recommended, tell your doctor as soon as possible.

If you forget to use ADVATE

Do not inject a double dose to make up for a forgotten dose. Proceed with the next injection as scheduled and continue as advised by your doctor.

If you stop using ADVATE

Do not stop using ADVATE without consulting your doctor.

If you have any further questions on the use of this product, ask your doctor.

Like all medicines, ADVATE can cause side effects, although not everybody gets them.

If severe, sudden allergic reactions (anaphylactic) occur, the injection must be stopped immediately. You must contact your doctor immediately if you have any of the following early symptoms of allergic (hypersensitivity) reactions:

• rash, hives, wheals, generalised itching,
• swelling of lips and tongue,
• difficulty in breathing, wheezing, tightness in the chest,
• general feeling of being unwell,
• dizziness and loss of consciousness. Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency treatment.

Side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.

Common side effects

dizziness, headache and fever.

Uncommon side effects

itching, increased sweating, unusual taste in the mouth, hot flushes, migraines, memory impairment, chills, diarrhoea, nausea, vomiting, shortness of breath, sore throat, infection of the lymphatic vessels, whitening of skin, eye inflammation, rashes, excessive sweating, foot and leg swelling, increase in enzymes that track liver function, reduced percentage of red blood cells and pain in the upper abdomen or lower chest.

Related to surgery

catheter-related infection, decreased red cell blood count, swelling of limbs and joints, prolonged bleeding after drain removal, decreased Factor VIII level and post-operative bruise.

Rare side effects

Since the medicine has been on the market, there have been rare reports of severe and potentially life-threatening reactions (anaphylaxis) and other allergic reactions (see above).

If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Keep out of the reach and sight of children.

Do not use ADVATE after the expiry date, which is 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 powder vial may be kept at room temperature (up to 25°C) for a single period not exceeding 6 months. Please record the beginning of storage at room temperature on the product carton. The product may not be returned to refrigerated storage after storage at room temperature.

Keep the vial in the outer carton in order to protect from light.

This product is for single use only. Discard any unused solution appropriately.
Use the product immediately once the powder is completely dissolved.
Do not refrigerate the solution after preparation.

Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What ADVATE contains

• The active substance is octocog alfa (human coagulation Factor VIII produced by recombinant DNA technology). Each powder vial contains 250 IU octocog alfa.
• The other ingredients are mannitol, sodium chloride, histidine, trehalose, calcium chloride, trometamol, polysorbate 80, and glutathione (reduced).

Solvent vial: 5 ml sterilised water for injections

What ADVATE looks like and contents of the pack

ADVATE is a white to off-white friable powder.
After reconstitution, the solution is clear, colourless and free from foreign particles.

Each pack also contains a device for reconstitution (BAXJECT II).

Marketing Authorisation Holder

Baxter AG
Industriestrasse 67
A-1221 Vienna

Manufacturer

Baxter SA
Boulevard René Branquart 80
B-7860 Lessines
Belgium

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

BelgiëBelgiqueBelgien Baxter Belgium SPRL Bd. de la PlainePleinlaan 5 B-1050 BrusselBruxellesBrüssel TélTel 32 2 650 1711 LuxembourgLuxemburg Baxter Belgium SPRL Bd. de la PlainePleinlaan 5 B-1050 BruxellesBrüssel TélTel 32 2 650 1711

. 4 1000 . 359 2 9808482 Magyarország Baxter Hungary Kft Népfürd u. 22. H-1138 Budapest Tel. 361 202 19 80

eská republika Baxter Czech spol.s.r.o. Opletalova 55 CZ-110 00 Praha 1 Tel. 420 225774111 Malta Baxter Healthcare Ltd Wallingford Road, Compton Newbury Berkshire RG20 7QW - UK Tel. 44 1635 206345

Danmark Baxter AS Gydevang 43 DK-3450 Allerød Tlf 45 48 16 64 00 Nederland Baxter B.V. Kobaltweg 49 NL-3542 CE Utrecht Tel 31 30 2488911

Deutschland Baxter Deutschland GmbH Edisonstr. 4 D-85716 Unterschleißheim Tel 49 89 31 701-0 Norge Baxter AS Gjerdrumsvei 11 N-0486 Oslo Tlf 47 22 58 4800

Eesti AS Oriola Kungla 2 EE-76505 Saue Tel. 372 6 515 100 Österreich Baxter Vertriebs GmbH Landstraer Hauptstrae 99 Top 2A A-1031 Wien Tel. 43 1 71120 0

Polska Baxter Polska Sp. z o.o. ul. Kruczkowskiego 8 PL-00-380 Warszawa Tel. 48 22 4883 777 Baxter Hellas ... 34 GR-163 41 . 30-210-99 87 000

España Baxter S.L. Pouet de Camilo, 2 E- 46394 Ribarroja del Turia Valencia Tel 34 96 2722800 Portugal Baxter Médico Farmacêutica Lda Sintra Business Park Zona Industrial da Abrunheira, Edifício 10 P-2710-089 Sintra Tel 351 21 925 25 00

France Baxter SAS 6 Avenue Louis Pasteur F-78310 Maurepas Tél 33 1 3461 5050 România FARMACEUTICA REMEDIA SA B-dul Metalurgiei nr. 78 sector 4 Bucureti 041836-RO Tel. 40-21-321 16 40

Ireland Baxter Healthcare Ltd Unit 7 Deansgrange Industrial Estate IRL-Blackrock, Dublin Tel 353 1 2065500 Slovenija Baxter d.o.o. elezna cesta 14 SI-1000 Ljubljana Tel. 386 1 420 16 80

Ísland Lyfjaver ehf. Suðurlandsbraut 22 IS-108 Reykjavík Sími 354 533 6100 Slovenská republika Baxter AG, o. z. Dúbravská cesta 2 SK-841 04 Bratislava Tel 421 2 59418455

Italia Baxter S.p.A. Piazzale dellIndustria, 20 I-00144 Roma Tel 39 06 324911 SuomiFinland Baxter Oy Valimotie 15 A FIN-00380 Helsinki PuhTel 358 9 8621111

Baxter Hellas ... 34 GR-163 41 . 30-210-99 87 000 Sverige Baxter Medical AB Box 63 Torshamnsgatan 35 S-164 94 Kista Tel 46 8 6326400

Latvija BAXTER AG Latvijas filile Dzelzavas iela 117 Rga, LV 1021 Tel. 371 67 784 784 United Kingdom Baxter Healthcare Ltd Wallingford Road, Compton Newbury Berkshire RG20 7QW - UK Tel 44 1635 206345

Lietuva

UAB TAMRO atstovyb-
S. -ukausko g. 29-1
LT-09129 Vilnius
Tel: +370 5 269 16 91

This leaflet was last approved in

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INSTRUCTIONS FOR PREPARATION AND ADMINISTRATION

Aseptic technique is required during preparation of the solution and administration.

Use only the sterilised water for injections and the reconstitution device for preparation of the solution that are provided with each package of ADVATE. ADVATE must not be mixed with other medicinal products or solvents.

Instructions for reconstitution Do not use after the expiry date stated on the labels and carton. Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration as indicated by the symbol . Do not refrigerate the solution after preparation.

1. If the product is still stored in a refrigerator, take both the ADVATE powder and solvent vials from the refrigerator and let them reach room temperature (between 15°C and 25°C).

2. Wash your hands thoroughly using soap and warm water.

3. Remove caps from powder and solvent vials.

4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface.

5. Open the package of BAXJECT II device by peeling away the paper lid without touching the inside (Fig. a). Do not remove the device from the package. Do not use if the BAXJECT II device, its sterile barrier system or its packaging is damaged or shows any sign of deterioration.

6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap from the BAXJECT II device.

7. For reconstitution only the water for injections and the reconstitution device provided in the pack should be used. With BAXJECT II attached to the solvent vial, invert the system so that the solvent vial is on top of the device. Insert the white plastic spike through the ADVATE stopper. The vacuum will draw the solvent into the ADVATE vial (Fig. c).

8. Swirl gently until all material is dissolved. Be sure that ADVATE is completely dissolved, otherwise not all reconstituted solution will pass through the device filter. The product dissolves rapidly (usually in less than 1 minute). After reconstitution the solution should be clear, colourless and free from foreign particles.

Fig. a Fig. b Fig. c

Instructions for injection
For administration the use of a luer-lock syringe is required.
Important note:

• Do not try to administer the injection unless you have received special training from your doctor or nurse.
• Inspect the prepared solution for particulate matter and discoloration prior to administration (the solution should be clear, colourless and free from foreign particles). Do not use ADVATE if the solution is not fully clear or not completely dissolved.

1. Remove the blue cap from BAXJECT II. DO NOT DRAW AIR INTO THE SYRINGE. Connect the syringe to BAXJECT II (Fig. d).

2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly (Fig. e).

3. Disconnect the syringe.

4. Attach a butterfly needle to the syringe. and inject the reconstituted solution into a vein. The solution should be administered slowly, at a rate as determined by the patient?s comfort level, not to exceed 10 ml per minute. (See Section 4 ?Possible side effects?).

5. Discard any unused solution appropriately.

Fig. d Fig. e

------------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only:

In case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery.
The dose and frequency of administration should be adapted to the clinical response in the individual case. Under certain circumstances (e.g. presence of a low-titre inhibitor), doses larger than those calculated using the formula may be necessary.

Degree of haemorrhagetype of surgical procedure Factor VIII level required or IUdl Frequency of doses hoursduration of therapy days Haemorrhage 20 40 Early haemarthrosis, muscle bleeding or oral bleeding. Repeat injections every 12 to 24 hours 8 to 24 hours for patients under the age of 6 for at least 1 day, until the bleeding episode, as indicated by pain, is resolved or healing is achieved. 30 60 More extensive haemarthrosis, muscle bleeding or haematoma. Repeat injections every 12 to 24 hours 8 to 24 hours for patients under the age of 6 for 3 4 days or more until pain and acute disability are resolved. Life-threatening haemorrhages. 60 100 Repeat injections every 8 to 24 hours 6 to 12 hours for patients under the age of 6 until threat is resolved. Surgery 30 60 Minor Including tooth extraction. Every 24 hours 12 to 24 hours for patients under the age of 6, at least 1 day, until healing is achieved. Major 80 100 pre- and postoperative Repeat injections every 8 to 24 hours 6 to 24 hours for patients under the age of 6 until adequate wound healing, then continue therapy for at least another 7 days to maintain a factor VIII activity of 30 to 60 IUdl.